Cancers

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19 pages, 11314 KiB

Open AccessArticle

Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients

by Fabian Stögbauer, Barbara Geß, Christine Brambs, Manuela Lautizi, Tim Kacprowski, Iordanis Ourailidis, Holger Bronger, Marion Kiechle, Aurelia Noske, Gisela Keller, Moritz Jesinghaus, Christopher Poremba, Wilko Weichert and Melanie Boxberg

Cancers 2023, 15(15), 3832; https://doi.org/10.3390/cancers15153832 - 28 Jul 2023

Cited by 1 | Viewed by 1449

Abstract

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic [...] Read more.

The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), “microcystic, elongated, fragmented” (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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9 pages, 541 KiB

Open AccessArticle

Are CT-Derived Muscle Measurements Prognostic, Independent of Systemic Inflammation, in Good Performance Status Patients with Advanced Cancer?

by Josh McGovern, Ross D. Dolan, Claribel Simmons, Louise E. Daly, Aoife M. Ryan, Derek G. Power, Marie T. Fallon, Barry J. Laird and Donald C. McMillan

Cancers 2023, 15(13), 3497; https://doi.org/10.3390/cancers15133497 - 5 Jul 2023

Cited by 3 | Viewed by 1311

Abstract

The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score [...] Read more.

The present study examined the relationships between CT-derived muscle measurements, systemic inflammation, and survival in advanced cancer patients with good performance status (ECOG-PS 0/1). Data was collected prospectively from patients with advanced cancer undergoing anti-cancer therapy with palliative intent. The CT Sarcopenia score (CT-SS) was calculated by combining the CT-derived skeletal muscle index (SMI) and density (SMD). The systemic inflammatory status was determined using the modified Glasgow Prognostic Score (mGPS). The primary outcome of interest was overall survival (OS). Univariate and multivariate Cox regressions were used for survival analysis. Three hundred and seven patients met the inclusion criteria, out of which 62% (n = 109) were male and 47% (n = 144) were ≥65 years of age, while 38% (n = 118) were CT-SS ≥ 1 and 47% (n = 112) of patients with pre-study blood were inflamed (mGPS ≥ 1). The median survival from entry to the study was 11.1 months (1–68.1). On univariate analysis, cancer type (p < 0.05) and mGPS (p < 0.001) were significantly associated with OS. On multivariate analysis, only mGPS (p < 0.001) remained significantly associated with OS. In patients who were ECOG-PS 0, mGPS was significantly associated with CT-SS (p < 0.05). mGPS may dominate the prognostic value of CT-derived sarcopenia in good-performance-status patients with advanced cancer. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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17 pages, 10041 KiB

Open AccessArticle

Molecular Subtyping and Survival Analysis of Osteosarcoma Reveals Prognostic Biomarkers and Key Canonical Pathways

by Siddesh Southekal, Sushil Kumar Shakyawar, Prachi Bajpai, Amr Elkholy, Upender Manne, Nitish Kumar Mishra and Chittibabu Guda

Cancers 2023, 15(7), 2134; https://doi.org/10.3390/cancers15072134 - 4 Apr 2023

Cited by 7 | Viewed by 2471

Abstract

Osteosarcoma (OS) is a common bone malignancy in children and adolescents. Although histological subtyping followed by improved OS treatment regimens have helped achieve favorable outcomes, a lack of understanding of the molecular subtypes remains a challenge to characterize its genetic heterogeneity and subsequently [...] Read more.

Osteosarcoma (OS) is a common bone malignancy in children and adolescents. Although histological subtyping followed by improved OS treatment regimens have helped achieve favorable outcomes, a lack of understanding of the molecular subtypes remains a challenge to characterize its genetic heterogeneity and subsequently to identify diagnostic and prognostic biomarkers for developing effective treatments. In the present study, global analysis of DNA methylation, and mRNA and miRNA gene expression in OS patient samples were correlated with their clinical characteristics. The mucin family of genes, MUC6, MUC12, and MUC4, were found to be highly mutated in the OS patients. Results revealed the enrichment of molecular pathways including Wnt signaling, Calcium signaling, and PI3K-Akt signaling in the OS tumors. Survival analyses showed that the expression levels of several genes such as RAMP1, CRIP1, CORT, CHST13, and DDX60L, miRNAs and lncRNAs were associated with survival of OS patients. Molecular subtyping using Cluster-Of-Clusters Analysis (COCA) for mRNA, lncRNA, and miRNA expression; DNA methylation; and mutation data from the TARGET dataset revealed two distinct molecular subtypes, each with a distinctive gene expression profile. Between the two subtypes, three upregulated genes, POP4, HEY1, CERKL, and seven downregulated genes, CEACAM1, ABLIM1, LTBP2, ISLR, LRRC32, PTPRF, and GPX3, associated with OS metastasis were found to be differentially regulated. Thus, the molecular subtyping results provide a strong basis for classification of OS patients that could be used to develop better prognostic treatment strategies. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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23 pages, 6723 KiB

Open AccessArticle

Mass Spectrometry-Based Biomarkers to Detect Prostate Cancer: A Multicentric Study Based on Non-Invasive Urine Collection without Prior Digital Rectal Examination

by Maria Frantzi, Zoran Culig, Isabel Heidegger, Marika Mokou, Agnieszka Latosinska, Marie C. Roesch, Axel S. Merseburger, Manousos Makridakis, Antonia Vlahou, Ana Blanca-Pedregosa, Julia Carrasco-Valiente, Harald Mischak and Enrique Gomez-Gomez

Cancers 2023, 15(4), 1166; https://doi.org/10.3390/cancers15041166 - 11 Feb 2023

Cited by 6 | Viewed by 2220

Abstract

(1) Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Wide application of prostate specific antigen test has historically led to over-treatment, starting from excessive biopsies. Risk calculators based on molecular and clinical variables can be of value to determine [...] Read more.

(1) Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Wide application of prostate specific antigen test has historically led to over-treatment, starting from excessive biopsies. Risk calculators based on molecular and clinical variables can be of value to determine the risk of PCa and as such, reduce unnecessary and invasive biopsies. Urinary molecular studies have been mostly focusing on sampling after initial intervention (digital rectal examination and/or prostate massage). (2) Methods: Building on previous proteomics studies, in this manuscript, we aimed at developing a biomarker model for PCa detection based on urine sampling without prior intervention. Capillary electrophoresis coupled to mass spectrometry was applied to acquire proteomics profiles from 970 patients from two different clinical centers. (3) Results: A case-control comparison was performed in a training set of 413 patients and 181 significant peptides were subsequently combined by a support vector machine algorithm. Independent validation was initially performed in 272 negative for PCa and 138 biopsy-confirmed PCa, resulting in an AUC of 0.81, outperforming current standards, while a second validation phase included 147 PCa patients. (4) Conclusions: This multi-dimensional biomarker model holds promise to improve the current diagnosis of PCa, by guiding invasive biopsies. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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20 pages, 2496 KiB

Open AccessArticle

Systematic Evaluation of Antigenic Stimulation in Chronic Lymphocytic Leukemia: Humoral Immunity as Biomarkers for Disease Evolution

by Alicia Landeira-Viñuela, Miguel Alcoceba-Sanchez, Almudena Navarro-Bailón, Carlota Arias-Hidalgo, Pablo Juanes-Velasco, José Manuel Sánchez-Santos, Quentin Lecrevisse, Carlos Eduardo Pedreira, Marina L. García-Vaquero, Ángela-Patricia Hernández, Enrique Montalvillo, Rafael Góngora, Javier De las Rivas, Marcos González-Díaz, Alberto Orfao and Manuel Fuentes

Cancers 2023, 15(3), 891; https://doi.org/10.3390/cancers15030891 - 31 Jan 2023

Viewed by 2394

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Studies of CLL antibody reactivity have shown differential targets to autoantigens and antimicrobial molecular motifs that support the current hypothesis of CLL pathogenesis. Methods: In this study, we conducted a [...] Read more.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Studies of CLL antibody reactivity have shown differential targets to autoantigens and antimicrobial molecular motifs that support the current hypothesis of CLL pathogenesis. Methods: In this study, we conducted a quantitative serum analysis of 7 immunoglobulins in CLL and monoclonal B-cell lymphocytosis (MBL) patients (bead-suspension protein arrays) and a serological profile (IgG and IgM) study of autoantibodies and antimicrobial antigens (protein microarrays). Results: Significant differences in the IgA levels were observed according to disease progression and evolution as well as significant alterations in IgG1 according to IGHV mutational status. More representative IgG autoantibodies in the cohort were against nonmutagenic proteins and IgM autoantibodies were against vesicle proteins. Antimicrobial IgG and IgM were detected against microbes associated with respiratory tract infections. Conclusions: Quantitative differences in immunoglobulin serum levels could be potential biomarkers for disease progression. In the top 5 tumoral antigens, we detected autoantibodies (IgM and IgG) against proteins related to cell homeostasis and metabolism in the studied cohort. The top 5 microbial antigens were associated with respiratory and gastrointestinal infections; moreover, the subsets with better prognostics were characterized by a reactivation of Cytomegalovirus. The viral humoral response could be a potential prognosis biomarker for disease progression. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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23 pages, 7438 KiB

Open AccessArticle

EPHA3 Could Be a Novel Prognosis Biomarker and Correlates with Immune Infiltrates in Bladder Cancer

by Junpeng Liu, Zewen Zhou, Yifan Jiang, Yuzhao Lin, Yunzhi Yang, Chongjiang Tian, Jinwen Liu, Hao Lin and Bin Huang

Cancers 2023, 15(3), 621; https://doi.org/10.3390/cancers15030621 - 19 Jan 2023

Cited by 3 | Viewed by 2265

Abstract

Purpose: To assess the mechanism of EPH receptor A3 (EPHA3) and its potential value for immunotherapy in BLCA. Materials and Methods: The Cancer Genome Atlas (TCGA) bladder cancer (BLCA) database and the Gene Expression Omnibus (GEO) database were used for assessing whether EHPA3 [...] Read more.

Purpose: To assess the mechanism of EPH receptor A3 (EPHA3) and its potential value for immunotherapy in BLCA. Materials and Methods: The Cancer Genome Atlas (TCGA) bladder cancer (BLCA) database and the Gene Expression Omnibus (GEO) database were used for assessing whether EHPA3 could be used to predict BLCA prognosis. This work carried out in vitro and in vivo assays for exploring how EPHA3 affected the biological behaviors. The downstream pathway was explored using a Western blotting technique. The CIBERSORT, ESTIMATE, TIMER, and TIDE tools were used to predict the immunotherapy value of EPHA3 in BLCA. Results: EPHA3 was poorly expressed in BLCA (p < 0.05), its high expression is related to a good survival prognosis (p = 0.027 and p = 0.0275), and it has a good predictive ability for the histologic grade and status of BLCA (area under curve = 0.787 and 0.904). Overexpressed EPHA3 could inhibit BLCA cell biological behaviors, and it be associated with the downregulation of the Ras/pERK1/2 pathway. EPHA3 was correlated with several immune-infiltrating cells and the corresponding marker genes. Conclusions: EPHA3 could be regarded as an acceptable anti-cancer biomarker in BLCA. EPHA3 plays an inhibiting role in BLCA, and it could be the candidate immunotherapeutic target for BLCA. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 594 KiB

Open AccessArticle

Gene Screening for Prognosis of Non-Muscle-Invasive Bladder Carcinoma under Competing Risks Endpoints

by Chenlu Ke, Dipankar Bandyopadhyay and Devanand Sarkar

Cancers 2023, 15(2), 379; https://doi.org/10.3390/cancers15020379 - 6 Jan 2023

Cited by 1 | Viewed by 1447

Abstract

Background: Discovering clinically useful molecular markers for predicting the survival of patients diagnosed with non–muscle-invasive bladder cancer can provide insights into cancer dynamics and improve treatment outcomes. However, the presence of competing risks (CR) endpoints complicates the estimation and inferential framework. There is [...] Read more.

Background: Discovering clinically useful molecular markers for predicting the survival of patients diagnosed with non–muscle-invasive bladder cancer can provide insights into cancer dynamics and improve treatment outcomes. However, the presence of competing risks (CR) endpoints complicates the estimation and inferential framework. There is also a lack of statistical analysis tools and software for coping with the high-throughput nature of these data, in terms of marker screening and selection. Aims: To propose a gene screening procedure for proportional subdistribution hazards regression under a CR framework, and illustrate its application in using molecular profiling to predict survival for non-muscle invasive bladder carcinoma. Methods: Tumors from 300 patients diagnosed with bladder cancer were analyzed for genomic abnormalities while controlling for clinically important covariates. Genes with expression patterns that were associated with survival were identified through a screening procedure based on proportional subdistribution hazards regression. A molecular predictor of risk was constructed and examined for prediction accuracy. Results: A six-gene signature was found to be a significant predictor associated with survival of non–muscle-invasive bladder cancer, subject to competing risks after adjusting for age, gender, reevaluated WHO grade, stage and BCG/MMC treatment (p-value < 0.001). Conclusion: The proposed gene screening procedure can be used to discover molecular determinants of survival for non–muscle-invasive bladder cancer and in general facilitate high-throughput competing risks data analysis with easy implementation. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 2751 KiB

Open AccessArticle

Dynamic Prediction of Resectability for Patients with Advanced Ovarian Cancer Undergoing Neo-Adjuvant Chemotherapy: Application of Joint Model for Longitudinal CA-125 Levels

by Koceila Amroun, Raphael Chaltiel, Fabien Reyal, Reza Kianmanesh, Aude-Marie Savoye, Marine Perrier, Zoubir Djerada and Olivier Bouché

Cancers 2023, 15(1), 231; https://doi.org/10.3390/cancers15010231 - 30 Dec 2022

Cited by 1 | Viewed by 1420

Abstract

In patients with advanced ovarian cancer (AOC) receiving neoadjuvant chemotherapy (NAC), predicting the feasibility of complete interval cytoreductive surgery (ICRS) is helpful and may avoid unnecessary laparotomy. A joint model (JM) is a dynamic individual predictive model. The aim of this study was [...] Read more.

In patients with advanced ovarian cancer (AOC) receiving neoadjuvant chemotherapy (NAC), predicting the feasibility of complete interval cytoreductive surgery (ICRS) is helpful and may avoid unnecessary laparotomy. A joint model (JM) is a dynamic individual predictive model. The aim of this study was to develop a predictive JM combining CA-125 kinetics during NAC with patients’ and clinical factors to predict resectability after NAC in patients with AOC. A retrospective study included 77 patients with AOC treated with NAC. A linear mixed effect (LME) sub-model was used to describe the evolution of CA-125 during NAC considering factors influencing the biomarker levels. A Cox sub-model screened the covariates associated with resectability. The JM combined the LME sub-model with the Cox sub-model. Using the LME sub-model, we observed that CA-125 levels were influenced by the number of NAC cycles and the performance of paracentesis. In the Cox sub-model, complete resectability was associated with Performance Status (HR = 0.57, [0.34–0.95], p = 0.03) and the presence of peritoneal carcinomatosis in the epigastric region (HR = 0.39, [0.19–0.80], p = 0.01). The JM accuracy to predict complete ICRS was 88% [82–100] with a predictive error of 2.24% [0–2.32]. Using a JM of a longitudinal CA-125 level during NAC could be a reliable predictor of complete ICRS. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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16 pages, 864 KiB

Open AccessArticle

Impact of Change in Body Composition during Follow-Up on the Survival of GEP-NET

by Fernando Sebastian-Valles, Nuria Sánchez de la Blanca Carrero, Víctor Rodríguez-Laval, Rebeca Martinez-Hernández, Ana Serrano-Somavilla, Carolina Knott-Torcal, José Luis Muñoz de Nova, Elena Martín-Pérez, Mónica Marazuela and Miguel Antonio Sampedro-Nuñez

Cancers 2022, 14(21), 5189; https://doi.org/10.3390/cancers14215189 - 22 Oct 2022

Cited by 2 | Viewed by 2147

Abstract

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous rare diseases causing malnutrition and cachexia in which the study of body composition may have an impact in prognosis. Aim: Evaluation of muscle and fat tissues by computed tomography (CT) at the level of the third [...] Read more.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous rare diseases causing malnutrition and cachexia in which the study of body composition may have an impact in prognosis. Aim: Evaluation of muscle and fat tissues by computed tomography (CT) at the level of the third lumbar (L3 level) at diagnosis and at the end of follow-up in GET-NET patients and their relationships with clinical and biochemical variables as predictors of survival. Methodology: Ninety-eight GEP-NET patients were included. Clinical and biochemical parameters were evaluated. Total body, subcutaneous, visceral and total fat areas and very low-density, low-density, normal density, high-density, very high-density and total muscle areas were obtained from CT images. Results: Body composition measures and overall mortality correlated with age, ECOG (Eastern Cooperative Oncology Group performance status) metastases, lactate dehydrogenase (LDH), albumin and urea levels. Although there was no relationship between body composition variables at diagnosis and overall and specific mortality, an increase in low-density muscle and a decrease in normal-density muscle during follow-up were independently correlated to overall (p <0.05) and tumor-cause mortality (p < 0.05). Conclusion: Although body composition measures obtained by CT at diagnosis did not impact survival of GEP-NET patients, a loss of good quality muscle during follow-up was associated with an increased overall and tumor-related mortality. Nutritional status should therefore be supervised by nutrition specialists and an increase in good quality muscle could improve prognosis. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1988 KiB

Open AccessArticle

The Expression of the Immunoproteasome Subunit PSMB9 Is Related to Distinct Molecular Subtypes of Uterine Leiomyosarcoma

by Raul Maia Falcão, Georgia Kokaraki, Wout De Wispelaere, Frédéric Amant, Gustavo Antônio De Souza, Jorge Estefano Santana de Souza, Joseph Woodward Carlson and Tirzah Braz Petta

Cancers 2022, 14(20), 5007; https://doi.org/10.3390/cancers14205007 - 13 Oct 2022

Cited by 4 | Viewed by 2159

Abstract

Background: Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the myometrium cells and whose diagnosis is based on histopathological features. Identifying diagnostic biomarkers for uLMS is a challenge due to molecular heterogeneity and the scarcity of samples. In vivo and [...] Read more.

Background: Uterine leiomyosarcoma (uLMS) are rare and malignant tumors that arise in the myometrium cells and whose diagnosis is based on histopathological features. Identifying diagnostic biomarkers for uLMS is a challenge due to molecular heterogeneity and the scarcity of samples. In vivo and in vitro models for uLMS are urgently needed. Knockout female mice for the catalytic subunit of the immunoproteasome PSMB9 (MIM:177045) develop spontaneous uLMS. This study aimed to analyze the role of PSMB9 in uLMS tumorigenesis and patient outcome. Methods: Molecular data from 3 non-related uLMS cohorts were integrated and analyzed by proteotranscriptomic using gene expression and protein abundance levels in 68 normal adjacent myometrium (MM), 66 uterine leiomyoma (LM), and 67 uLMS. Results: the immunoproteasome pathway is upregulated and the gene PMSB9 shows heterogeneous expression values in uLMS. Quartile group analysis showed no significant difference between groups high and low PSMB9 expression groups at 3-years overall survival (OS). Using CYBERSORTx analysis we observed 9 out of 17 samples in the high group clustering together due to high M2 macrophages and CD4 memory resting, and high CD8+/PSMB9 ratio was associated with better OS. The main pathway regulated in the high group is IFNγ and in the low is the ECM pathway dependent on the proto-oncogene SRC. Conclusion: these findings suggest 2 subtypes of uLMS (immune-related and ECM-related) with different candidate mechanisms of malignancy. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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21 pages, 5736 KiB

Open AccessArticle

Systematic Analysis of Genetic and Pathway Determinants of Eribulin Sensitivity across 100 Human Cancer Cell Lines from the Cancer Cell Line Encyclopedia (CCLE)

by Pallavi Sachdev, Roy Ronen, Janusz Dutkowski and Bruce A. Littlefield

Cancers 2022, 14(18), 4532; https://doi.org/10.3390/cancers14184532 - 19 Sep 2022

Cited by 3 | Viewed by 2257

Abstract

Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine [...] Read more.

Eribulin, a natural product-based microtubule targeting agent with cytotoxic and noncytotoxic mechanisms, is FDA approved for certain patients with advanced breast cancer and liposarcoma. To investigate the feasibility of developing drug-specific predictive biomarkers, we quantified antiproliferative activities of eribulin versus paclitaxel and vinorelbine against 100 human cancer cell lines from the Cancer Cell Line Encyclopedia, and correlated results with publicly available databases to identify genes and pathways associated with eribulin response, either uniquely or shared with paclitaxel or vinorelbine. Mean expression ratios of 11,985 genes between the most and least sensitive cell line quartiles were sorted by p-values and drug overlaps, yielding 52, 29 and 80 genes uniquely associated with eribulin, paclitaxel and vinorelbine, respectively. Further restriction to minimum 2-fold ratios followed by reintroducing data from the middle two quartiles identified 9 and 13 drug-specific unique fingerprint genes for eribulin and vinorelbine, respectively; surprisingly, no gene met all criteria for paclitaxel. Interactome and Reactome pathway analyses showed that unique fingerprint genes of both drugs were primarily associated with cellular signaling, not microtubule-related pathways, although considerable differences existed in individual pathways identified. Finally, four-gene (C5ORF38, DAAM1, IRX2, CD70) and five-gene (EPHA2, NGEF, SEPTIN10, TRIP10, VSIG10) multivariate regression models for eribulin and vinorelbine showed high statistical correlation with drug-specific responses across the 100 cell lines and accurately calculated predicted mean IC50s for the most and least sensitive cell line quartiles as surrogates for responders and nonresponders, respectively. Collectively, these results provide a foundation for developing drug-specific predictive biomarkers for eribulin and vinorelbine. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 1558 KiB

Open AccessArticle

Meta-Analysis Reveals Both the Promises and the Challenges of Clinical Metabolomics

by Heidi E. Roth and Robert Powers

Cancers 2022, 14(16), 3992; https://doi.org/10.3390/cancers14163992 - 18 Aug 2022

Cited by 13 | Viewed by 2245

Abstract

Clinical metabolomics is a rapidly expanding field focused on identifying molecular biomarkers to aid in the efficient diagnosis and treatment of human diseases. Variations in study design, metabolomics methodologies, and investigator protocols raise serious concerns about the accuracy and reproducibility of these potential [...] Read more.

Clinical metabolomics is a rapidly expanding field focused on identifying molecular biomarkers to aid in the efficient diagnosis and treatment of human diseases. Variations in study design, metabolomics methodologies, and investigator protocols raise serious concerns about the accuracy and reproducibility of these potential biomarkers. The explosive growth of the field has led to the recent availability of numerous replicate clinical studies, which permits an evaluation of the consistency of biomarkers identified across multiple metabolomics projects. Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death and has the lowest five-year survival rate primarily due to the lack of an early diagnosis and the limited treatment options. Accordingly, PDAC has been a popular target of clinical metabolomics studies. We compiled 24 PDAC metabolomics studies from the scientific literature for a detailed meta-analysis. A consistent identification across these multiple studies allowed for the validation of potential clinical biomarkers of PDAC while also highlighting variations in study protocols that may explain poor reproducibility. Our meta-analysis identified 10 metabolites that may serve as PDAC biomarkers and warrant further investigation. However, 87% of the 655 metabolites identified as potential biomarkers were identified in single studies. Differences in cohort size and demographics, p-value choice, fold-change significance, sample type, handling and storage, data collection, and analysis were all factors that likely contributed to this apparently large false positive rate. Our meta-analysis demonstrated the need for consistent experimental design and normalized practices to accurately leverage clinical metabolomics data for reliable and reproducible biomarker discovery. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1104 KiB

Open AccessArticle

Elevated Serotonin and NT-proBNP Levels Predict and Detect Carcinoid Heart Disease in a Large Validation Study

by Sonja Levy, Aoife B. Kilgallen, Catharina M. Korse, Marish I. F. J. Oerlemans, Joost P. G. Sluijter, Linda W. van Laake, Gerlof D. Valk and Margot E. T. Tesselaar

Cancers 2022, 14(10), 2361; https://doi.org/10.3390/cancers14102361 - 10 May 2022

Cited by 6 | Viewed by 2170

Abstract

Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers [...] Read more.

Carcinoid heart disease (CHD) is a rare fibrotic cardiac complication of neuroendocrine tumors. Besides known biomarkers N-Terminal pro-B-type natriuretic peptide (NT-proBNP) and serotonin, activin A, connective tissue growth factor (CTGF), and soluble suppression of tumorigenicity 2 (sST2) have been suggested as potential biomarkers for CHD. Here, we validated the predictive/diagnostic value of these biomarkers in a case-control study of 114 patients between 1990 and 2021. Two time-points were analyzed: T₀: liver metastasis without CHD for all patients. T₁: confirmed CHD in cases (CHD+, n = 57); confirmed absence of CHD five or more years after liver metastasis in controls (CHD–, n = 57). Thirty-one (54%) and 25 (44%) females were included in CHD+ and CHD– patients, respectively. Median age was 57.9 years for CHD+ and 59.7 for CHD- patients (p = 0.290). At T₀: activin A was similar across both groups (p = 0.724); NT-proBNP was higher in CHD+ patients (17 vs. 6 pmol/L, p = 0.016), area under the curve (AUC) 0.84, and the most optimal cut-off at 6.5 pmol/L. At T₁: activin A was higher in CHD+ patients (0.65 vs. 0.38 ng/mL, p = 0.045), AUC 0.62, without an optimal cut-off value. NT-pro-BNP was higher in CHD+ patients (63 vs. 11 pmol/L, p < 0.001), AUC 0.89, with an optimal cut-off of 27 pmol/L. Serotonin (p = 0.345), sST2 (p = 0.867) and CTGF (p = 0.232) levels were similar across groups. This large validation study identified NT-proBNP as the superior biomarker for CHD. Patients with elevated serotonin levels and NT-proBNP levels between 6.5 and 27 pmol/L, and specifically >27 pmol/L, should be monitored closely for the development of CHD. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1651 KiB

Open AccessArticle

Implication of COPB2 Expression on Cutaneous Squamous Cell Carcinoma Pathogenesis

by Taiqin Chen, Ki-Yeol Kim, Yeongjoo Oh, Hei Cheul Jeung, Kee Yang Chung, Mi Ryung Roh and Xianglan Zhang

Cancers 2022, 14(8), 2038; https://doi.org/10.3390/cancers14082038 - 18 Apr 2022

Cited by 3 | Viewed by 2081

Abstract

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was [...] Read more.

The underlying molecular mechanisms of cutaneous squamous cell carcinoma (cSCC) pathogenesis are largely unknown. In the present study, we aimed to evaluate the effect of coatomer protein complex subunit beta 2 (COPB2) expression on cSCC pathogenesis. Clinicopathological significance of COPB2 in cSCC was investigated by analyzing the Gene Expression Omnibus (GEO) database and through a retrospective cohort study of 95 cSCC patients. The effect of COPB2 expression on the biological behavior of cSCC cells was investigated both in vitro and in vivo. We found that COPB2 expression was significantly higher in cSCC samples than in normal skin samples. In our cohort, a considerable association was found between COPB2 expression and indicators of tumor immune microenvironment (TIME), such as histocompatibility complex class (MHC) I, and MHC II, CD4+/ CD8+ tumor-infiltrating lymphocytes. Additionally, COPB2 expression had an independent impact on worsened recurrence-free survival in our cohort. Furthermore, decreased proliferation, invasion, tumorigenic activities, and increased apoptosis were observed after COPB2 knockdown in cSCC cells. COPB2 may act as a potential oncogene and candidate modulator of the TIME in cSCC. Therefore, it can serve as a novel predictive prognostic biomarker and candidate immunotherapeutic target in cSCC patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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20 pages, 3643 KiB

Open AccessArticle

Novel Risk Classification Based on Pyroptosis-Related Genes Defines Immune Microenvironment and Pharmaceutical Landscape for Hepatocellular Carcinoma

by Jianye Wang, Ying Wang, Marcella Steffani, Christian Stöß, Donna Ankerst, Helmut Friess, Norbert Hüser and Daniel Hartmann

Cancers 2022, 14(2), 447; https://doi.org/10.3390/cancers14020447 - 17 Jan 2022

Cited by 5 | Viewed by 3129

Abstract

Growing evidence has indicated that pyroptosis functions in the development of cancer. Nonetheless, specific roles of pyroptosis-related genes in tumor progression, immune response, prognosis, and immunotherapy have not been thoroughly elucidated. After a comprehensive evaluation of pyroptosis genes, unsupervised clustering was performed to [...] Read more.

Growing evidence has indicated that pyroptosis functions in the development of cancer. Nonetheless, specific roles of pyroptosis-related genes in tumor progression, immune response, prognosis, and immunotherapy have not been thoroughly elucidated. After a comprehensive evaluation of pyroptosis genes, unsupervised clustering was performed to generate three distinct clusters from hepatocellular carcinoma (HCC) samples. Three distinct pyroptosis-related molecular subtypes comprising three gene clusters that had differential prognostic effects on patient survival were then identified. Immune characteristics analyses revealed diversified immune cell infiltration among the subtypes. Two clusters served as immune-hot phenotypes associated with significantly poorer survival compared to a remaining third immune-cold cluster. Among these, the immune-hot clusters were characterized by abundant adaptive immune cell infiltration, active CD4+ and CD8+ T cells, high total leukocyte counts and tumor growth status, and lower Th17 cell and M2 macrophage densities. Then, risk scores indicated that low-risk patients were more sensitive to anti-tumor therapy. Subsequently, we found a significant correlation between pyroptosis and prognosis in HCC and that pyroptosis genes drive the heterogeneity of the tumor microenvironment. The risk scoring system, based on pyroptosis-related differentially expressed genes, was established to evaluate the individual outcomes and contribute to new insights into the molecular characterization of pyroptosis-related subtypes. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

GCC2 as a New Early Diagnostic Biomarker for Non-Small Cell Lung Cancer

by Hyesun Jeong, Byeong Hyeon Choi, JinA Park, Jik-Han Jung, Hyunku Shin, Ka-Won Kang, Yu Hua Quan, Jewon Yu, Ji-Ho Park, Yong Park, Yeonho Choi, Hyun Koo Kim and Sunghoi Hong

Cancers 2021, 13(21), 5482; https://doi.org/10.3390/cancers13215482 - 31 Oct 2021

Cited by 12 | Viewed by 4175

Abstract

No specific markers have been identified to detect non-small cell lung cancer (NSCLC) cell-derived exosomes circulating in the blood. Here, we report a new biomarker that distinguishes between cancer and non-cancer cell-derived exosomes. Exosomes isolated from patient plasmas at various pathological stages of [...] Read more.

No specific markers have been identified to detect non-small cell lung cancer (NSCLC) cell-derived exosomes circulating in the blood. Here, we report a new biomarker that distinguishes between cancer and non-cancer cell-derived exosomes. Exosomes isolated from patient plasmas at various pathological stages of NSCLC, NSCLC cell lines, and human pulmonary alveolar epithelial cells isolated using size exclusion chromatography were characterized. The GRIP and coiled-coil domain-containing 2 (GCC2) protein, involved in endosome-to-Golgi transport, was identified by proteomics analysis of NSCLC cell line-derived exosomes. GCC2 protein levels in the exosomes derived from early-stage NSCLC patients were higher than those from healthy controls. Receiver operating characteristic curve analysis revealed the diagnostic sensitivity and specificity of exosomal GCC2 to be 90% and 75%, respectively. A high area under the curve, 0.844, confirmed that GCC2 levels could effectively distinguish between the exosomes. These results demonstrate GCC2 as a promising early diagnostic biomarker for NSCLC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 2442 KiB

Open AccessArticle

Human DLG1 and SCRIB Are Distinctly Regulated Independently of HPV-16 during the Progression of Oropharyngeal Squamous Cell Carcinomas: A Preliminary Analysis

by Lucija Lulić, Antonia Jakovčević, Luka Manojlović, Emil Dediol, Lawrence Banks and Vjekoslav Tomaić

Cancers 2021, 13(17), 4461; https://doi.org/10.3390/cancers13174461 - 4 Sep 2021

Cited by 5 | Viewed by 2762

Abstract

The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of [...] Read more.

The major causative agents of head and neck squamous cell carcinomas (HNSCCs) are either environmental factors, such as tobacco and alcohol consumption, or infection with oncogenic human papillomaviruses (HPVs). An important aspect of HPV-induced oncogenesis is the targeting by the E6 oncoprotein of PDZ domain-containing substrates for proteasomal destruction. Tumor suppressors DLG1 and SCRIB are two of the principal PDZ domain-containing E6 targets. Both have been shown to play critical roles in the regulation of cell growth and polarity and in maintaining the structural integrity of the epithelia. We investigated how modifications in the cellular localization and protein expression of DLG1 and SCRIB in HPV16-positive and HPV-negative histologic oropharyngeal squamous cell carcinomas (OPSCC) might reflect disease progression. HPV presence was determined by p16 staining and HPV genotyping. Whilst DLG1 expression levels did not differ markedly between HPV-negative and HPV16-positive OPSCCs, it appeared to be relocated from cell–cell contacts to the cytoplasm in most samples, regardless of HPV16 positivity. This indicates that alterations in DLG1 distribution could contribute to malignant progression in OPSCCs. Interestingly, SCRIB was also relocated from cell–cell contacts to the cytoplasm in the tumor samples in comparison with normal tissue, regardless of HPV16 status, but in addition there was an obvious reduction in SCRIB expression in higher grade tumors. Strikingly, loss of SCRIB was even more pronounced in HPV16-positive OPSCCs. These alterations in SCRIB levels may contribute to transformation and loss of tissue architecture in the process of carcinogenesis and could potentially serve as markers in the development of OPSCCs. Full article

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18 pages, 31187 KiB

Open AccessArticle

SUMOylation Is Associated with Aggressive Behavior in Chondrosarcoma of Bone

by Jessie S. Kroonen, Alwine B. Kruisselbrink, Inge H. Briaire-de Bruijn, Olaejirinde O. Olaofe, Judith V. M. G. Bovée and Alfred C. O. Vertegaal

Cancers 2021, 13(15), 3823; https://doi.org/10.3390/cancers13153823 - 29 Jul 2021

Cited by 7 | Viewed by 2657

Abstract

Multiple components of the SUMOylation machinery are deregulated in various cancers and could represent potential therapeutic targets. Understanding the role of SUMOylation in tumor progression and aggressiveness would increase our insight in the role of SUMO in cancer and clarify its potential as [...] Read more.

Multiple components of the SUMOylation machinery are deregulated in various cancers and could represent potential therapeutic targets. Understanding the role of SUMOylation in tumor progression and aggressiveness would increase our insight in the role of SUMO in cancer and clarify its potential as a therapeutic target. Here we investigate SUMO in relation to conventional chondrosarcomas, which are malignant cartilage forming tumors of the bone. Aggressiveness of chondrosarcoma increases with increasing histological grade, and a multistep progression model is assumed. High-grade chondrosarcomas have acquired an increased number of genetic alterations. Using immunohistochemistry on tissue microarrays (TMA) containing 137 chondrosarcomas, we showed that higher expression of SUMO1 and SUMO2/3 correlates with increased histological grade. In addition, high SUMO2/3 expression was associated with decreased overall survival chances (p = 0. 0312) in chondrosarcoma patients as determined by log-rank analysis and Cox regression. Various chondrosarcoma cell lines (n = 7), especially those derived from dedifferentiated chondrosarcoma, were sensitive to SUMO inhibition in vitro. Mechanistically, we found that SUMO E1 inhibition interferes with cell division and as a consequence DNA bridges are frequently formed between daughter cells. In conclusion, SUMO expression could potentially serve as a prognostic biomarker. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

Combined Simplified Molecular Classification of Gastric Adenocarcinoma, Enhanced by Lymph Node Status: An Integrative Approach

by Till Daun, Ronny Nienhold, Aino Paasinen-Sohns, Angela Frank, Melanie Sachs, Inti Zlobec and Gieri Cathomas

Cancers 2021, 13(15), 3722; https://doi.org/10.3390/cancers13153722 - 24 Jul 2021

Cited by 7 | Viewed by 3172

Abstract

Gastric adenocarcinoma (GAC) is a heterogeneous disease and at least two major studies have recently provided a molecular classification for this tumor: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ARCG). Both classifications quote four molecular subtypes, but these subtypes [...] Read more.

Gastric adenocarcinoma (GAC) is a heterogeneous disease and at least two major studies have recently provided a molecular classification for this tumor: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ARCG). Both classifications quote four molecular subtypes, but these subtypes only partially overlap. In addition, the classifications are based on complex and cost-intensive technologies, which are hardly feasible for everyday practice. Therefore, simplified approaches using immunohistochemistry (IHC), in situ hybridization (ISH) as well as commercially available next generation sequencing (NGS) have been considered for routine use. In the present study, we screened 115 GAC by IHC for p53, MutL Homolog 1 (MLH1) and E-cadherin and performed ISH for Epstein–Barr virus (EBV). In addition, sequencing by NGS for TP53 and tumor associated genes was performed. With this approach, we were able to define five subtypes of GAC: (1) Microsatellite Instable (MSI), (2) EBV-associated, (3) Epithelial Mesenchymal Transition (EMT)-like, (4) p53 aberrant tumors surrogating for chromosomal instability and (5) p53 proficient tumors surrogating for genomics stable cancers. Furthermore, by considering lymph node metastasis in the p53 aberrant GAC, a better prognostic stratification was achieved which finally allowed us to separate the GAC highly significant in a group with poor and good-to-intermediate prognosis, respectively. Our data show that molecular classification of GAC can be achieved by using commercially available assays including IHC, ISH and NGS. Furthermore, we present an integrative workflow, which has the potential to overcome the uncertainty resulting from discrepancies from existing classification schemes. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

Longitudinal Circulating Tumor DNA Analysis in Blood and Saliva for Prediction of Response to Osimertinib and Disease Progression in EGFR-Mutant Lung Adenocarcinoma

by Chul Kim, Liqiang Xi, Constance M. Cultraro, Fang Wei, Gregory Jones, Jordan Cheng, Ahmad Shafiei, Trinh Hoc-Tran Pham, Nitin Roper, Elizabeth Akoth, Azam Ghafoor, Vikram Misra, Nina Monkash, Charles Strom, Michael Tu, Wei Liao, David Chia, Clive Morris, Seth M. Steinberg, Hadi Bagheri, David T. W. Wong, Mark Raffeld and Udayan Guha Show full author list Hide full author list

Cancers 2021, 13(13), 3342; https://doi.org/10.3390/cancers13133342 - 3 Jul 2021

Cited by 15 | Viewed by 5796

Abstract

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. [...] Read more.

Background: We assessed whether serial ctDNA monitoring of plasma and saliva predicts response and resistance to osimertinib in EGFR-mutant lung adenocarcinoma. Three ctDNA technologies—blood-based droplet-digital PCR (ddPCR), next-generation sequencing (NGS), and saliva-based EFIRM liquid biopsy (eLB)—were employed to investigate their complementary roles. Methods: Plasma and saliva samples were collected from patients enrolled in a prospective clinical trial of osimertinib and local ablative therapy upon progression (NCT02759835). Plasma was analyzed by ddPCR and NGS. Saliva was analyzed by eLB. Results: A total of 25 patients were included. We analyzed 534 samples by ddPCR (n = 25), 256 samples by NGS (n = 24) and 371 samples by eLB (n = 22). Among 20 patients who progressed, ctDNA progression predated RECIST 1.1 progression by a median of 118 days (range: 61–272 days) in 11 (55%) patients. Of nine patients without ctDNA progression by ddPCR, two patients had an increase in mutant EGFR by eLB and two patients were found to have ctDNA progression by NGS. Levels of ctDNA measured by ddPCR and NGS at early time points, but not volumetric tumor burden, were associated with PFS. EGFR/ERBB2/MET/KRAS amplifications, EGFR C797S, PIK3CA E545K, PTEN V9del, and CTNNB1 S45P were key resistance mechanisms identified by NGS. Conclusion: Serial assessment of ctDNA in plasma and saliva predicts response and resistance to osimertinib, with each assay having supplementary roles. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

Metastatic Risk Factors Associated with Class 1A Uveal Melanoma Patients

by Alexej Ballhausen, Elizabeth Urias, Stephen K. Gruschkus, Michelle Williams, Maura S. Glover, Yong Qin, Dan S. Gombos and Sapna P. Patel

Cancers 2021, 13(13), 3292; https://doi.org/10.3390/cancers13133292 - 30 Jun 2021

Cited by 7 | Viewed by 3327

Abstract

In uveal melanoma (UM), gene expression profiling (GEP) is commonly used to classify metastatic risk into three groups (Class 1A, 1B, and 2). Class 1A patients have a lower metastatic risk of 2% at 5 years compared to other groups. We aimed to [...] Read more.

In uveal melanoma (UM), gene expression profiling (GEP) is commonly used to classify metastatic risk into three groups (Class 1A, 1B, and 2). Class 1A patients have a lower metastatic risk of 2% at 5 years compared to other groups. We aimed to describe clinical features associated with the development of metastasis in this low-risk group. This single-center IRB-approved retrospective case series review included all UM patients between February 2006 and March 2019 with an archived or fresh specimen classified as Class 1A. Cox regression and receiver operating characteristics analyses were used to identify factors associated with metastasis development and OS. Among 73 UM patients with Class 1A, the 5-year cumulative incidence of local recurrence and distant metastasis was 4.2% and 17.0%, respectively. Stage III disease (HR 20.7; 95% confidence interval (95% CI) 1.4–300.6; p= 0.0264) was found to be independently associated with metastatic recurrence, while primary therapy was associated with OS (enucleation vs. brachytherapy, HR 13.5; 95% CI 1.3–147.6; p = 0.0348). Combined clinical decision-making utilizing factors such as GEP class, American Joint Committee on Cancer (AJCC) stage, and COMS size could have a significant clinical impact by improving risk stratification and adapting follow-up intervals in UM Class 1A patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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12 pages, 2353 KiB

Open AccessArticle

High Serum Elafin Prediction of Poor Prognosis of Locoregional Esophageal Squamous Cell Carcinoma

by I-Chen Wu, Yao-Kuang Wang, Yi-Hsun Chen, Chun-Chieh Wu, Meng-Chieh Wu, Wei-Chung Chen, Wen-Lun Wang, Hung-Shun Lin, Chou-Cheng Chen, Shah-Hwa Chou, Yu-Peng Liu and Ming-Tsang Wu

Cancers 2021, 13(12), 3082; https://doi.org/10.3390/cancers13123082 - 21 Jun 2021

Cited by 1 | Viewed by 2118

Abstract

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor known to have locally advanced and metastatic features which cause a dismal prognosis. We sought to determine whether elafin, a non-invasive and secretory small-molecule marker, could be used to predict prognosis in locoregional [...] Read more.

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive tumor known to have locally advanced and metastatic features which cause a dismal prognosis. We sought to determine whether elafin, a non-invasive and secretory small-molecule marker, could be used to predict prognosis in locoregional ESCC patients in human and in vitro studies. In our human study, 119 subjects were identified as having incident and pathologically-proved ESCC with stage I-IIIA tumors from southern Taiwan between 2000 and 2016. We measured their serum elafin levels at baseline and followed them until the date of cancer death or until January 2020, the end of this study. Those with high serum elafin levels were found to have a 1.99-fold risk (95% confidence interval: 1.17–3.38) shorter survival than those who did not. In our in vitro experiments, elevated elafin levels were found to drive ESCC cell proliferation, migration and invasion, while attenuation of elafin level by shRNA abrogated those effects. We concluded that elafin promotes ESCC motility and invasion and leads to a worse clinical prognosis in ESCC patients without distant metastasis. Full article

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Open AccessArticle

Metabolic Changes in Early-Stage Non–Small Cell Lung Cancer Patients after Surgical Resection

by Naseer Ahmed, Biniam Kidane, Le Wang, Zoann Nugent, Nataliya Moldovan, April McElrea, Shiva Shariati-Ievari, Gefei Qing, Lawrence Tan, Gordon Buduhan, Sadeesh K. Srinathan and Michel Aliani

Cancers 2021, 13(12), 3012; https://doi.org/10.3390/cancers13123012 - 16 Jun 2021

Cited by 11 | Viewed by 3011

Abstract

Metabolic alterations in malignant cells play a vital role in tumor initiation, proliferation, and metastasis. Biofluids from patients with non–small cell lung cancer (NSCLC) harbor metabolic biomarkers with potential clinical applications. In this study, we assessed the changes in the metabolic profile of [...] Read more.

Metabolic alterations in malignant cells play a vital role in tumor initiation, proliferation, and metastasis. Biofluids from patients with non–small cell lung cancer (NSCLC) harbor metabolic biomarkers with potential clinical applications. In this study, we assessed the changes in the metabolic profile of patients with early-stage NSCLC using mass spectrometry and nuclear magnetic resonance spectroscopy before and after surgical resection. A single cohort of 35 patients provided a total of 29 and 32 pairs of urine and serum samples, respectively, pre-and post-surgery. We identified a profile of 48 metabolites that were significantly different pre- and post-surgery: 17 in urine and 31 in serum. A higher proportion of metabolites were upregulated than downregulated post-surgery (p < 0.01); however, the median fold change (FC) was higher for downregulated than upregulated metabolites (p < 0.05). Purines/pyrimidines and proteins had a larger dysregulation than other classes of metabolites (p < 0.05 for each class). Several of the dysregulated metabolites have been previously associated with cancer, including leucyl proline, asymmetric dimethylarginine, isopentenyladenine, fumaric acid (all downregulated post-surgery), as well as N6-methyladenosine and several deoxycholic acid moieties, which were upregulated post-surgery. This study establishes metabolomic analysis of biofluids as a path to non-invasive diagnostics, screening, and monitoring in NSCLC. Full article

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Open AccessArticle

Deep Learning Improves Pancreatic Cancer Diagnosis Using RNA-Based Variants

by Ali Al-Fatlawi, Negin Malekian, Sebastián García, Andreas Henschel, Ilwook Kim, Andreas Dahl, Beatrix Jahnke, Peter Bailey, Sarah Naomi Bolz, Anna R. Poetsch, Sandra Mahler, Robert Grützmann, Christian Pilarsky and Michael Schroeder

Cancers 2021, 13(11), 2654; https://doi.org/10.3390/cancers13112654 - 28 May 2021

Cited by 9 | Viewed by 4239

Abstract

For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 [...] Read more.

For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 with RNA-based variants. We use deep sequencing and deep learning to improve differentiating pancreatic cancer and chronic pancreatitis. We obtained samples of nucleated cells found in peripheral blood from 268 patients suffering from resectable, non-resectable pancreatic cancer, and chronic pancreatitis. We sequenced RNA with high coverage and obtained millions of variants. The high-quality variants served as input together with CA19-9 values to deep learning models. Our model achieved an area under the curve (AUC) of 96% in differentiating resectable cancer from pancreatitis using a test cohort. Moreover, we identified variants to estimate survival in resectable cancer. We show that the blood transcriptome harbours variants, which can substantially improve noninvasive clinical diagnosis. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

Validation of the Combined Biomarker for Prediction of Response to Checkpoint Inhibitor in Patients with Advanced Cancer

by Jin-Chul Kim, You-Jeong Heo, So-Young Kang, Jeeyun Lee and Kyoung-Mee Kim

Cancers 2021, 13(10), 2316; https://doi.org/10.3390/cancers13102316 - 12 May 2021

Cited by 6 | Viewed by 2251

Abstract

Although immune checkpoint inhibitors can induce durable responses in patients with multiple types of advanced cancer, only a limited number of patients have a known reliable biomarker. This study aimed to validate the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, which was developed based [...] Read more.

Although immune checkpoint inhibitors can induce durable responses in patients with multiple types of advanced cancer, only a limited number of patients have a known reliable biomarker. This study aimed to validate the IMmunotherapy Against GastrIc Cancer (IMAGiC) model, which was developed based on a previous study of four-gene and PD-L1 level, to predict immunotherapy response. We developed a clinical assay for formalin-fixed paraffin-embedded samples using quantitative real-time polymerase chain reaction to measure the expression level of the previously published four-gene set. The predictive performance was validated in a cohort of 89 patients with several advanced tumor types. The IMAGiC score was derived from tumor samples of 89 patients consisting of eight cancer types, and 73 out of 89 patients available for clinical response were analyzed with clinicopathological factors. The IMAGiC group (responder vs. non-responder) was determined with a specific value of the IMAGiC score as a cutoff, which was set by log-rank statistics for progression-free survival (PFS) divided the patients into 56 (76.7%) non-responders and 17 (23.3%) responders. Clinical responders (complete response/partial response) were higher in the IMAGiC responder group than in the non-responder group (70.6 vs. 21.4%). The median PFS of the IMAGiC responder group and non-responder was 20.8 months (95% CI 9.1-not reached) and 6.7 months (95% CI 4.9–11.1, p = 0.007), respectively. Among the 17 IMAGiC responders, 11 patients had tumor mutation burden-low and microsatellite-stable tumors. This study validated a predictive model based on a four-gene expression signature. Along with conventional biomarkers, our model could be useful for predicting response to immunotherapy in patients with advanced cancer. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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Open AccessArticle

Clinical Implication of Liquid Biopsy in Colorectal Cancer Patients Treated with Metastasectomy

by Soohyeon Lee, Young-Soo Park, Won-Jin Chang, Jung Yoon Choi, Ahreum Lim, Boyeon Kim, Saet-Byeol Lee, Jong-Won Lee, Seon-Hahn Kim, Jin Kim, Jung-Myun Kwak, Kyung-Chul Yoon, Sung-Ho Lee and Yeul Hong Kim

Cancers 2021, 13(9), 2231; https://doi.org/10.3390/cancers13092231 - 6 May 2021

Cited by 13 | Viewed by 2250

Abstract

Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA [...] Read more.

Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker. Methods: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3–4 weeks after metastasectomy and serially, if patients agreed. Results: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis (p = 0.0045) and tumors measuring ≥1 cm (p = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease. Conclusion: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1189 KiB

Open AccessArticle

Characterization of Cell-Bound CA125 on Immune Cell Subtypes of Ovarian Cancer Patients Using a Novel Imaging Platform

by Germán González, Kornél Lakatos, Jawad Hoballah, Roberta Fritz-Klaus, Lojain Al-Johani, Jeff Brooker, Sinyoung Jeong, Conor L. Evans, Petra Krauledat, Daniel W. Cramer, Robert A. Hoffman, W. Peter Hansen and Manish S. Patankar

Cancers 2021, 13(9), 2072; https://doi.org/10.3390/cancers13092072 - 25 Apr 2021

Cited by 7 | Viewed by 3033

Abstract

MUC16, a sialomucin that contains the ovarian cancer biomarker CA125, binds at low abundance to leucocytes via the immune receptor, Siglec-9. Conventional fluorescence-based imaging techniques lack the sensitivity to assess this low-abundance event, prompting us to develop a novel “digital” optical cytometry technique [...] Read more.

MUC16, a sialomucin that contains the ovarian cancer biomarker CA125, binds at low abundance to leucocytes via the immune receptor, Siglec-9. Conventional fluorescence-based imaging techniques lack the sensitivity to assess this low-abundance event, prompting us to develop a novel “digital” optical cytometry technique for qualitative and quantitative assessment of CA125 binding to peripheral blood mononuclear cells (PBMC). Plasmonic nanoparticle labeled detection antibody allows assessment of CA125 at the near-single molecule level when bound to specific immune cell lineages that are simultaneously identified using multiparameter fluorescence imaging. Image analysis and deep learning were used to quantify CA125 per each cell lineage. PBMC from treatment naïve ovarian cancer patients (N = 14) showed higher cell surface abundance of CA125 on the aggregate PBMC population as well as on NK (p = 0.013), T (p < 0.001) and B cells (p = 0.024) compared to circulating lymphocytes of healthy donors (N = 7). Differences in CA125 binding to monocytes or NK-T cells between the two cohorts were not significant. There was no correlation between the PBMC-bound and serum levels of CA125, suggesting that these two compartments are not in stoichiometric equilibrium. Understanding where and how subset-specific cell-bound surface CA125 takes place may provide guidance towards a new diagnostic biomarker in ovarian cancer. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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17 pages, 1661 KiB

Open AccessArticle

Neo-Fs Index: A Novel Immunohistochemical Biomarker Panel Predicts Survival and Response to Anti-Angiogenetic Agents in Clear Cell Renal Cell Carcinoma

by Jisup Kim, Jee-Young Park, Su-Jin Shin, Beom Jin Lim and Heounjeong Go

Cancers 2021, 13(6), 1199; https://doi.org/10.3390/cancers13061199 - 10 Mar 2021

Cited by 3 | Viewed by 2496

Abstract

Background: Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Here, to develop biomarkers that predict survival and response [...] Read more.

Background: Frameshift indels have emerged as a predictor of immunotherapy response but were not evaluated yet to predict anti-angiogenetic agent (AAA) response or prognosis in clear cell renal cell carcinoma (ccRCC). Methods: Here, to develop biomarkers that predict survival and response to AAA, we evaluated the immunohistochemical expression of proteins whose genes frequently harbor frameshift indels in 638 ccRCC patients and correlated the individual and integrated markers with prognosis and AAA response. The mutational landscape was evaluated using targeted next-generation sequencing in 12 patients concerning protein markers. Immune gene signatures were retrieved from TCGA RNA seq data. Results: Five proteins (APC, NOTCH1, ARID1A, EYS, and filamin A) were independent adverse prognosticators and were incorporated into the Neo-fs index. Better overall, disease-specific and recurrence-free survival were observed with high Neo-fs index in univariate and multivariate survival analyses. Better AAA responses were observed with a high Neo-fs index, which reflected increased MHC class I, CD8+ T cell, cytolytic activity, and plasmacytoid dendritic cell signatures and decreased type II-IFN response signatures, as well as greater single-nucleotide variant (SNV) and indel counts. Conclusions: Neo-fs index, reflecting antitumor immune signature and more SNVs. and indels, is a powerful predictor of survival and AAA response in ccRCC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 1765 KiB

Open AccessArticle

HER2 Expression Is Predictive of Survival in Cetuximab Treated Patients with RAS Wild Type Metastatic Colorectal Cancer

by Said A. Khelwatty, Soozana Puvanenthiran, Sharadah Essapen, Izhar Bagwan, Alan M. Seddon and Helmout Modjtahedi

Cancers 2021, 13(4), 638; https://doi.org/10.3390/cancers13040638 - 5 Feb 2021

Cited by 11 | Viewed by 2850

Abstract

The overexpressed HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, only in patients with breast and gastric cancers, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and [...] Read more.

The overexpressed HER2 is an important target for treatment with monoclonal antibody (mAb) trastuzumab, only in patients with breast and gastric cancers, and is an emerging therapeutic biomarker in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab. In this study, we investigated the relative expression and predictive value of all human epidermal growth factor receptor (HER) family members in 144 cetuximab-treated patients with wild type RAS mCRC. The relative expression of EGFR and HER2 have also been examined in 21-paired primary tumours and their metastatic sites by immunohistochemistry. Of the 144 cases examined, 25%, 97%, 79%, 48%, and 10% were positive for EGFR, HER2, HER3, and HER4 and all four HER family members, respectively. The expression of EGFR was an indicator of poorer overall survival and the membranous expression of HER2 and HER3 3+ intensity was associated with a shorter progression free survival (PFS). In contrast, the cytoplasmic expression of HER2 was associated with better PFS. In 48% and 71% of the cases, there were discordance in the expression of EGFR or one or more HER family members in paired primary and related metastatic tumours, respectively. Our results implicate the importance of a large prospective investigation of the expression level and predictive value of not only the therapeutic target (i.e., EGFR protein) but also HER2 and other HER family members as therapeutic targets, or for response to therapy with anti-EGFR mAbs and other forms of HER inhibitors, in both the primary tumours and metastatic sites in mCRC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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12 pages, 1498 KiB

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Early Prostate-Specific Antigen (PSA) Change at Four Weeks of the First-Line Treatment Using Abiraterone and Enzalutamide Could Predict Early/Primary Resistance in Metastatic Castration-Resistant Prostate Cancer

by Taizo Uchimoto, Kazumasa Komura, Wataru Fukuokaya, Takahiro Kimura, Kazuhiro Takahashi, Kazuki Nishimura, Keita Nakamori, Yuya Fujiwara, Tomohisa Matsunaga, Takeshi Tsutsumi, Takuya Tsujino, Ryoichi Maenosono, Yuki Yoshikawa, Kohei Taniguchi, Tomohito Tanaka, Hirofumi Uehara, Naokazu Ibuki, Hajime Hirano, Hayahito Nomi, Kiyoshi Takahara, Teruo Inamoto, Shin Egawa and Haruhito Azuma Show full author list Hide full author list

Cancers 2021, 13(3), 526; https://doi.org/10.3390/cancers13030526 - 30 Jan 2021

Cited by 6 | Viewed by 3485

Abstract

The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment [...] Read more.

The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of >30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved >30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved >30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits >30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve >30% PSA decline at four weeks consequently achieved >30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving >30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving >30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC ≤ 12 months and Eastern Cooperative Oncology Group Performance Status ≥ 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing >30% PSA decline at four weeks—particularly in patients with a modest effect of ADT and poor performance status. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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16 pages, 1787 KiB

Open AccessArticle

Radiomics Features of ¹⁸F-Fluorodeoxyglucose Positron-Emission Tomography as a Novel Prognostic Signature in Colorectal Cancer

by Jeonghyun Kang, Jae-Hoon Lee, Hye Sun Lee, Eun-Suk Cho, Eun Jung Park, Seung Hyuk Baik, Kang Young Lee, Chihyun Park, Yunku Yeu, Jean R. Clemenceau, Sunho Park, Hongming Xu, Changjin Hong and Tae Hyun Hwang

Cancers 2021, 13(3), 392; https://doi.org/10.3390/cancers13030392 - 21 Jan 2021

Cited by 12 | Viewed by 2862

Abstract

The aim of this study was to investigate the prognostic value of radiomics signatures derived from ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron-emission tomography (PET) in patients with colorectal cancer (CRC). From April 2008 to Jan 2014, we identified CRC patients who underwent ¹⁸ [...] Read more.

The aim of this study was to investigate the prognostic value of radiomics signatures derived from ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron-emission tomography (PET) in patients with colorectal cancer (CRC). From April 2008 to Jan 2014, we identified CRC patients who underwent ¹⁸F-FDG-PET before starting any neoadjuvant treatments and surgery. Radiomics features were extracted from the primary lesions identified on ¹⁸F-FDG-PET. Patients were divided into a training and validation set by random sampling. A least absolute shrinkage and selection operator Cox regression model was applied for prognostic signature building with progression-free survival (PFS) using the training set. Using the calculated radiomics score, a nomogram was developed, and its clinical utility was assessed in the validation set. A total of 381 patients with surgically resected CRC patients (training set: 228 vs. validation set: 153) were included. In the training set, a radiomics signature labeled as a rad_score was generated using two PET-derived features, such as gray-level run length matrix long-run emphasis (GLRLM_LRE) and gray-level zone length matrix short-zone low-gray-level emphasis (GLZLM_SZLGE). Patients with a high rad_score in the training and validation set had a shorter PFS. Multivariable analysis revealed that the rad_score was an independent prognostic factor in both training and validation sets. A radiomics nomogram, developed using rad_score, nodal stage, and lymphovascular invasion, showed good performance in the calibration curve and comparable predictive power with the staging system in the validation set. Textural features derived from ¹⁸F-FDG-PET images may enable detailed stratification of prognosis in patients with CRC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1337 KiB

Open AccessArticle

Prognostic Value of Plasma hPG₈₀ (Circulating Progastrin) in Metastatic Renal Cell Carcinoma

by Manish Kohli, Winston Tan, Bérengère Vire, Pierre Liaud, Mélina Blairvacq, Frederic Berthier, Daniel Rouison, George Garnier, Léa Payen, Thierry Cousin, Dominique Joubert and Alexandre Prieur

Cancers 2021, 13(3), 375; https://doi.org/10.3390/cancers13030375 - 20 Jan 2021

Cited by 10 | Viewed by 2828

Abstract

Precise management of kidney cancer requires the identification of prognostic factors. hPG₈₀ (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of [...] Read more.

Precise management of kidney cancer requires the identification of prognostic factors. hPG₈₀ (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of plasma hPG₈₀ in 143 prospectively collected patients with metastatic RCC (mRCC). The prognostic impact of hPG₈₀ levels on overall survival (OS) in mRCC patients after controlling for hPG₈₀ levels in non-cancer age matched controls was determined and compared to the International Metastatic Database Consortium (IMDC) risk model (good, intermediate, poor). ROC curves were used to evaluate the diagnostic accuracy of hPG₈₀ using the area under the curve (AUC). Our results showed that plasma hPG₈₀ was detected in 94% of mRCC patients. hPG₈₀ levels displayed high predictive accuracy with an AUC of 0.93 and 0.84 when compared to 18–25 year old controls and 50–80 year old controls, respectively. mRCC patients with high hPG₈₀ levels (>4.5 pM) had significantly lower OS compared to patients with low hPG₈₀ levels (<4.5 pM) (12 versus 31.2 months, respectively; p = 0.0031). Adding hPG₈₀ levels (score of 1 for patients having hPG₈₀ levels > 4.5 pM) to the six variables of the IMDC risk model showed a greater and significant difference in OS between the newly defined good-, intermediate- and poor-risk groups (p = 0.0003 compared to p = 0.0076). Finally, when patients with IMDC intermediate-risk group were further divided into two groups based on hPG₈₀ levels within these subgroups, increased OS were observed in patients with low hPG₈₀ levels (<4.5 pM). In conclusion, our data suggest that hPG₈₀ could be used for prognosticating survival in mRCC alone or integrated to the IMDC score (by adding a variable to the IMDC score or by substratifying the IMDC risk groups), be a prognostic biomarker in mRCC patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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21 pages, 2756 KiB

Open AccessArticle

Prognostic Inflammatory Index Based on Preoperative Peripheral Blood for Predicting the Prognosis of Colorectal Cancer Patients

by Jinming Fu, Ji Zhu, Fenqi Du, Lijie Zhang, Dapeng Li, Hao Huang, Tian Tian, Yupeng Liu, Lei Zhang, Ying Liu, Yuanyuan Zhang, Jing Xu, Shuhan Meng, Chenyang Jia, Simin Sun, Xue Li, Liyuan Zhao, Ding Zhang, Lixin Kang, Lijing Gao, Ting Zheng, Sanjun Cai, Yanlong Liu and Yashuang Zhao Show full author list Hide full author list

Cancers 2021, 13(1), 3; https://doi.org/10.3390/cancers13010003 - 22 Dec 2020

Cited by 8 | Viewed by 2998

Abstract

Host inflammation is a critical component of tumor progression and its status can be indicated by peripheral blood cell counts. We aimed to construct a comprehensively prognostic inflammatory index (PII) based on preoperative peripheral blood cell counts and further evaluate its prognostic value [...] Read more.

Host inflammation is a critical component of tumor progression and its status can be indicated by peripheral blood cell counts. We aimed to construct a comprehensively prognostic inflammatory index (PII) based on preoperative peripheral blood cell counts and further evaluate its prognostic value for patients with colorectal cancer (CRC). A total of 9315 patients with stage II and III CRC from training and external validation cohorts were included. The PII was constructed by integrating all the peripheral blood cell counts associated with prognosis in the training cohort. Cox analyses were performed to evaluate the association between PII and overall survival (OS) and disease-free survival (DFS). In the training cohort, multivariate Cox analyses indicated that high OS-PII (>4.27) was significantly associated with worse OS (HR: 1.330, 95% CI: 1.189–1.489, p < 0.001); and high DFS-PII (>4.47) was significantly associated with worse DFS (HR: 1.366, 95% CI: 1.206–1.548, p < 0.001). The prognostic values of both OS-PII and DFS-PII were validated in the external validation cohort. The nomograms achieved good accuracy in predicting both OS and DFS. Time-dependent ROC analyses showed that both OS-PII and DFS-PII have a stable prognostic performance at various follow-up times. The prognostic value of tumor-node-metastasis staging could be enhanced by combining it with either OS-PII or DFS-PII. We demonstrated that PIIs are independent prognostic predictors for CRC patients, and the nomograms based on PIIs can be recommended for personalized survival prediction of patients with CRC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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19 pages, 3964 KiB

Open AccessArticle

Serum-Derived Exosomal MicroRNA Profiles Can Predict Poor Survival Outcomes in Patients with Extranodal Natural Killer/T-Cell Lymphoma

by Kyung Ju Ryu, Ji Young Lee, Myung Eun Choi, Sang Eun Yoon, Junhun Cho, Young Hyeh Ko, Joon Ho Shim, Won Seog Kim, Chaehwa Park and Seok Jin Kim

Cancers 2020, 12(12), 3548; https://doi.org/10.3390/cancers12123548 - 27 Nov 2020

Cited by 12 | Viewed by 2866

Abstract

Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable (n = 22) and [...] Read more.

Exosomes containing microRNAs (miRNAs) might have utility as biomarkers to predict the risk of treatment failure in extranodal NK/T-cell lymphoma (ENKTL) because exosomal cargo miRNAs could reflect tumor aggressiveness. We analyzed the exosomal miRNAs of patients in favorable (n = 22) and poor outcome (n = 23) groups in a training cohort. Then, using the Nanostring nCounter^® microRNA array, we compared them with miRNAs identified in human NK/T lymphoma (NKTL) cell line-derived exosomes to develop exosomal miRNA profiles. We validated the prognostic value of serum exosomal miRNA profiles with an independent cohort (n = 85) and analyzed their association with treatment resistance using etoposide-resistant cell lines. A comparison of the top 20 upregulated miRNAs in the training cohort with poor outcomes with 16 miRNAs that were upregulated in both NKTL cell lines, identified five candidate miRNAs (miR-320e, miR-4454, miR-222-3p, miR-21-5p, and miR-25-3p). Among these, increased levels of exosomal miR-4454, miR-21-5p, and miR-320e were associated with poor overall survival in the validation cohort. Increased levels were also found in relapsed patients post-treatment. These three miRNAs were overexpressed in NKTL cell lines that were resistant to etoposide. Furthermore, transfection of NKTL cell lines with miR-21-5p and miR-320e induced an increase in expression of the proinflammatory cytokines such as macrophage inflammatory protein 1 alpha. These studies show that serum levels of exosomal miR-21-5p, miR-320e, and miR-4454 are increased in ENKTL patients with poor prognosis. Upregulation of these exosomal miRNAs in treatment-resistant cell lines suggests they have a role as biomarkers for the identification of ENKTL patients at high risk of treatment failure. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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16 pages, 2645 KiB

Open AccessArticle

Prognostic Interactions between FAP+ Fibroblasts and CD8a+ T Cells in Colon Cancer

by Mercedes Herrera, Artur Mezheyeuski, Lisa Villabona, Sara Corvigno, Carina Strell, Christian Klein, Gabriele Hölzlwimmer, Bengt Glimelius, Giuseppe Masucci, Tobias Sjöblom and Arne Östman

Cancers 2020, 12(11), 3238; https://doi.org/10.3390/cancers12113238 - 3 Nov 2020

Cited by 15 | Viewed by 3198

Abstract

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might [...] Read more.

Inter-case variations in immune cell and fibroblast composition are associated with prognosis in solid tumors, including colon cancer. A series of experimental studies suggest immune-modulatory roles of marker-defined fibroblast populations, including FAP-positive fibroblasts. These studies imply that the fibroblast status of tumors might affect the prognostic significance of immune-related features. Analyses of a population-based colon cancer cohort demonstrated good prognosis associations of FAP intensity and CD8a density. Notably, a significant prognostic interaction was detected between these markers (p = 0.013 in nonadjusted analyses and p = 0.003 in analyses adjusted for cofounding factors) in a manner where the good prognosis association of CD8 density was restricted to the FAP intensity-high group. This prognostic interaction was also detected in an independent randomized trial-derived colon cancer cohort (p = 0.048 in nonadjusted analyses). In the CD8-high group, FAP intensity was significantly associated with a higher total tumor density of FoxP3-positive immune cells and a higher ratio of epithelial-to-stromal density of CD8a T cells. The study presents findings relevant for the ongoing efforts to improve the prognostic performance of CD8-related markers and should be followed by additional validation studies. Furthermore, findings support, in general, earlier model-derived studies implying fibroblast subsets as clinically relevant modulators of immune surveillance. Finally, the associations between FAP intensity and specific immune features suggest mechanisms of fibroblast-immune crosstalk with therapeutic potential. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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22 pages, 537 KiB

Open AccessArticle

Effect of Citric Acid Cycle Genetic Variants and Their Interactions with Obesity, Physical Activity and Energy Intake on the Risk of Colorectal Cancer: Results from a Nested Case-Control Study in the UK Biobank

by Sooyoung Cho, Nan Song, Ji-Yeob Choi and Aesun Shin

Cancers 2020, 12(10), 2939; https://doi.org/10.3390/cancers12102939 - 12 Oct 2020

Cited by 8 | Viewed by 3511

Abstract

Colorectal cancer is a common malignancy worldwide. Physical activity and a healthy diet contribute to energy balance and have been recommended for the prevention of colorectal cancer. We suggest that the individual differences in energy balance can be explained by genetic polymorphisms involved [...] Read more.

Colorectal cancer is a common malignancy worldwide. Physical activity and a healthy diet contribute to energy balance and have been recommended for the prevention of colorectal cancer. We suggest that the individual differences in energy balance can be explained by genetic polymorphisms involved in mitochondria, which play a central role in energy metabolism at the cellular level. This study aimed to evaluate the association between genetic variants of the mitochondrial citric acid cycle and colorectal cancer. Study participants comprised 3523 colorectal cancer cases and 10,522 matched controls from the UK Biobank study. Odds ratios (ORs) and 95% confidence intervals (CIs) for colorectal cancer were estimated using a conditional logistic regression model. We found a significant association between the SUCLG2 gene rs35494829 and colon cancer (ORs [95% CIs] per increment of the minor allele, 0.82 [0.74–0.92]). Statistical significance was observed in the interactions of the citric acid cycle variants with obesity, energy intake, and vigorous physical activity in colorectal cancer. We also identified significant SNP-SNP interactions among citric acid cycle SNPs in colorectal cancer. The results of this study may provide evidence for bioenergetics in the development of colorectal cancer and for establishing a precise prevention strategy. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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16 pages, 3833 KiB

Open AccessArticle

Screening for Early Gastric Cancer Using a Noninvasive Urine Metabolomics Approach

by Hyuk Nam Kwon, Hyuk Lee, Ji Won Park, Young-Ho Kim, Sunghyouk Park and Jae J. Kim

Cancers 2020, 12(10), 2904; https://doi.org/10.3390/cancers12102904 - 9 Oct 2020

Cited by 26 | Viewed by 3431

Abstract

The early detection of gastric cancer (GC) could decrease its incidence and mortality. However, there are currently no accurate noninvasive markers for GC screening. Therefore, we developed a noninvasive diagnostic approach, employing urine nuclear magnetic resonance (NMR) metabolomics, to discover putative metabolic markers [...] Read more.

The early detection of gastric cancer (GC) could decrease its incidence and mortality. However, there are currently no accurate noninvasive markers for GC screening. Therefore, we developed a noninvasive diagnostic approach, employing urine nuclear magnetic resonance (NMR) metabolomics, to discover putative metabolic markers associated with GC. Changes in urine metabolite levels during oncogenesis were evaluated using samples from 103 patients with GC and 100 age- and sex-matched healthy controls. Approximately 70% of the patients with GC (n = 69) had stage I GC, with the majority (n = 56) having intramucosal cancer. A multivariate statistical analysis of the urine NMR data well discriminated between the patient and control groups and revealed nine metabolites, including alanine, citrate, creatine, creatinine, glycerol, hippurate, phenylalanine, taurine, and 3-hydroxybutyrate, that contributed to the difference. A diagnostic performance test with a separate validation set exhibited a sensitivity and specificity of more than 90%, even with the intramucosal cancer samples only. In conclusion, the NMR-based urine metabolomics approach may have potential as a convenient screening method for the early detection of GC and may facilitate consequent endoscopic examination through risk stratification. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 1861 KiB

Open AccessArticle

Genomic Instability Signature of Palindromic Non-Coding Somatic Mutations in Bladder Cancer

by Sophie Vacher, Voreak Suybeng, Elodie Girard, Julien Masliah Planchon, Grégory Thomson, Constance Le Goux, Simon Garinet, Anne Schnitzler, Walid Chemlali, Virginie Firlej, Diane Damotte, Yves Allory, Maud Kamal, Géraldine Pignot and Ivan Bieche

Cancers 2020, 12(10), 2882; https://doi.org/10.3390/cancers12102882 - 8 Oct 2020

Cited by 12 | Viewed by 3377

Abstract

Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified [...] Read more.

Numerous pan-genomic studies identified alterations in protein-coding genes and signaling pathways involved in bladder carcinogenesis, while non-coding somatic alterations remain weakly explored. The goal of this study was to identify clinical biomarkers in non-coding regions for bladder cancer patients. We have previously identified in bladder tumors two non-coding mutational hotspots occurring at high frequencies (≥30%). These mutations are located close to the GPR126 and PLEKHS1 genes, at the guanine or the cytosine of a TGAACA core motif flanked, on both sides, by a stretch of palindromic sequences. Here, we hypothesize that such a pattern of recurrent non-coding mutations could be a signature of somatic genomic instability specifically involved in bladder cancer. We analyzed 26 additional mutable non-coding sites with the same core motif in a cohort of 103 bladder cancers composed of 44 NMIBC cases and 59 MIBC cases using high-resolution melting (HRM) and Sanger sequencing. Five bladder cancers were additionally analyzed for protein-coding gene mutations using a targeted NGS panel composed of 571 genes. Expression levels of three members of the APOBEC3 family genes were assessed using real-time quantitative RT-PCR. Non-coding somatic mutations were observed for at least one TGAACA core motif locus in 62.1% (64/103) of bladder tumor samples. These non-coding mutations co-occurred in the bladder tumors but were absent in prostate tumor, HPV-positive Head and Neck Squamous Cell Carcinoma, and high microsatellite instability (MSI-H) colorectal tumor series. This signature of palindromic non-coding somatic mutations, specific to bladder tumors, was not associated with patients’ outcome and was more frequent in females. Interestingly, this signature was associated with high tumor mutational burden (TMB) and high expression levels of APOBEC3B and interferon inducible genes. We identified a new type of somatic genomic instability targeting the TGAACA core motif loci flanked by palindromic sequences in bladder cancer. This mutational signature is a promising candidate clinical biomarker for the early detection of relapse and a major low-cost alternative to the TMB to monitor the response to immunotherapy for bladder cancer patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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19 pages, 3969 KiB

Open AccessArticle

Nanoparticles in 472 Human Cerebrospinal Fluid: Changes in Extracellular Vesicle Concentration and miR-21 Expression as a Biomarker for Leptomeningeal Metastasis

by Kyue-Yim Lee, Ji Hye Im, Weiwei Lin, Ho-Shin Gwak, Jong Heon Kim, Byong Chul Yoo, Tae Hoon Kim, Jong Bae Park, Hyeon Jin Park, Ho-Jin Kim, Ji-Woong Kwon, Sang Hoon Shin, Heon Yoo and Changjin Lee

Cancers 2020, 12(10), 2745; https://doi.org/10.3390/cancers12102745 - 24 Sep 2020

Cited by 14 | Viewed by 3088

Abstract

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes [...] Read more.

Leptomeningeal metastasis (LM) has a poor prognosis and is difficult to diagnose and predict the response of treatment. In this study, we suggested that the monitoring of changes in the concentration of extracellular vesicles in cerebrospinal fluid could help diagnose or predict outcomes for LM. We measured nanoparticles in 472 human cerebrospinal fluid (CSF) from patients including LM with both Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) after two-step centrifugations. NTA revealed that the concentration of CSF nanoparticles was significantly increased in LM compared to other groups (2.80 × 10⁸ /mL vs. 1.49 × 10⁸ /mL, p < 0.01). Changes in NTA-measured nanoparticles concentration after intra-CSF chemotherapy were further examined in 33 non-small cell lung cancer patients with LM. Overall survival was longer for patients with increased EV than the others (442 vs. 165 days, p < 0.001). Markers of extracellular vesicles (CD9/CD63/CD81) significantly decreased in the EV-decreased group. MicroRNA-21 expression decreased in this favorable prognostic group, whereas it increased in the EV-decreased group. In conclusion, the elevated concentration of extracellular vesicles in cerebrospinal fluid in patients with LM may be a predictive marker for survival duration. Moreover, EV changes combined with microRNA-21 might be a biomarker for monitoring the efficacy of intracranial chemotherapy of LM in non-small cell lung cancer patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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16 pages, 3647 KiB

Open AccessArticle

The FMS like Tyrosine Kinase 3 (FLT3) Is Overexpressed in a Subgroup of Multiple Myeloma Patients with Inferior Prognosis

by Normann Steiner, Karin Jöhrer, Selina Plewan, Andrea Brunner-Véber, Georg Göbel, David Nachbaur, Dominik Wolf, Eberhard Gunsilius and Gerold Untergasser

Cancers 2020, 12(9), 2341; https://doi.org/10.3390/cancers12092341 - 19 Aug 2020

Cited by 4 | Viewed by 2620

Abstract

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with [...] Read more.

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). FLT3 gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by ³H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1–6) revealed that a high FES (>3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (p = 0.04). RNAseq and real-time PCR confirmed the expression of FLT3 in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 691 KiB

Open AccessArticle

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

by Pau Riera, Benjamín Rodríguez-Santiago, Adriana Lasa, Lidia Gonzalez-Quereda, Berta Martín, Juliana Salazar, Ana Sebio, Anna C. Virgili, Jordi Minguillón, Cristina Camps, Jordi Surrallés and David Páez

Cancers 2020, 12(8), 2245; https://doi.org/10.3390/cancers12082245 - 11 Aug 2020

Cited by 2 | Viewed by 3120

Abstract

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor [...] Read more.

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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18 pages, 3469 KiB

Open AccessArticle

The Roles of Imprinted SLC22A18 and SLC22A18AS Gene Overexpression Caused by Promoter CpG Island Hypomethylation as Diagnostic and Prognostic Biomarkers for Non-Small Cell Lung Cancer Patients

by José Francisco Noguera-Uclés, Laura Boyero, Ana Salinas, Juan Antonio Cordero Varela, Johana Cristina Benedetti, Reyes Bernabé-Caro, Amparo Sánchez-Gastaldo, Miriam Alonso, Luis Paz-Ares and Sonia Molina-Pinelo

Cancers 2020, 12(8), 2075; https://doi.org/10.3390/cancers12082075 - 27 Jul 2020

Cited by 11 | Viewed by 4373

Abstract

Genomic imprinting is a process that involves one gene copy turned-off in a parent-of-origin-dependent manner. The regulation of imprinted genes is broadly dependent on promoter methylation marks, which are frequently associated with both oncogenes and tumor suppressors. The purpose of this study was [...] Read more.

Genomic imprinting is a process that involves one gene copy turned-off in a parent-of-origin-dependent manner. The regulation of imprinted genes is broadly dependent on promoter methylation marks, which are frequently associated with both oncogenes and tumor suppressors. The purpose of this study was to assess the DNA methylation patterns of the imprinted solute-carrier family 22 member 18 (SLC22A18) and SLC22A18 antisense (SLC22A18AS) genes in non-small cell lung cancer (NSCLC) patients to study their relevance to the disease. We found that both genes were hypomethylated in adenocarcinoma and squamous cell carcinoma patients. Due to this imprinting loss, SLC22A18 and SLC22A18AS were found to be overexpressed in NSCLC tissues, which is significantly more evident in lung adenocarcinoma patients. These results were validated through analyses of public databases of NSCLC patients. The reversed gene profile of both genes was achieved in vitro by treatment with ademetionine. We then showed that high SLC22A18 and SLC22A18AS expression levels were significantly associated with worsening disease progression. In addition, low levels of SLC22A18AS were also correlated with better overall survival for lung adenocarcinoma patients. We found that SLC22A18 and SLC22A18AS knockdown inhibits cell proliferation in vitro. All these results suggest that both genes may be useful as diagnostic and prognostic biomarkers in NSCLC, revealing novel therapeutic opportunities. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 1937 KiB

Open AccessArticle

Ultra-Short Circulating Tumor DNA (usctDNA) in Plasma and Saliva of Non-Small Cell Lung Cancer (NSCLC) Patients

by Feng Li, Fang Wei, Wei-Lun Huang, Chien-Chung Lin, Liang Li, Macy M. Shen, Qingxiang Yan, Wei Liao, David Chia, Michael Tu, Jason H. Tang, Ziding Feng, Yong Kim, Wu-Chou Su and David T. W. Wong

Cancers 2020, 12(8), 2041; https://doi.org/10.3390/cancers12082041 - 24 Jul 2020

Cited by 31 | Viewed by 5287

Abstract

Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A [...] Read more.

Mutations identified in the epidermal growth factor receptor (EGFR) predict sensitivity to EGFR-targeted therapy for non-small cell lung carcinoma (NSCLC). We previously reported that Electric Field-Induced Release and Measurement (EFIRM)-based liquid biopsy could detect EGFR ctDNA with >94% concordance with tissue-based genotyping. A side-by-side comparison of concordance of EFIRM and droplet digital PCR (ddPCR) for the detection of the two front-line actionable EFGR mutations was performed with paired plasma and saliva samples from 13 NSCLC patients. Deep sequencing analysis based on single-strand DNA library preparation was employed to determine the size distributions of EGFR L858R ctDNA in plasma and saliva samples. EFIRM detected both EGFR mutations with 100% sensitivity in both plasma and saliva samples, whereas ddPCR detected EGFR mutations with sensitivities of 84.6% and 15.4%, respectively. In saliva samples, the majority of EGFR L858R ctDNA fragments detected were <80 bp. Deep sequencing analysis of ctDNA enriched for the EGFR L858R mutation revealed the significant presence of EGFR L858R ctDNA as ultra-short circulating tumor DNA (usctDNA) with the size of 40–60 bp in patient plasma and saliva. Most of usctDNAs are not amplifiable with the current ddPCR assay. Further examination using cell lines and patient biofluids revealed that the majority of usctDNAs were predominately localized in the exosomal fraction. Our study revealed the abundant existence of EGFR ctDNA in the plasma and saliva of NSCLC patients is usctDNA. usctDNA is a novel type of targets for liquid biopsy that can be efficiently detected by EFIRM technology. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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8 pages, 710 KiB

Open AccessCommunication

A Panel of Urinary Volatile Biomarkers for Differential Diagnosis of Prostate Cancer from Other Urological Cancers

by Ana Rita Lima, Joana Pinto, Carina Carvalho-Maia, Carmen Jerónimo, Rui Henrique, Maria de Lourdes Bastos, Márcia Carvalho and Paula Guedes de Pinho

Cancers 2020, 12(8), 2017; https://doi.org/10.3390/cancers12082017 - 23 Jul 2020

Cited by 19 | Viewed by 3190

Abstract

Our group recently developed a urinary 6-biomarker panel for the diagnosis of prostate cancer (PCa) which has a higher level of accuracy compared to the serum prostate specific antigen (PSA) test. Herein, urine from an independent cohort of PCa patients and cancer-free controls [...] Read more.

Our group recently developed a urinary 6-biomarker panel for the diagnosis of prostate cancer (PCa) which has a higher level of accuracy compared to the serum prostate specific antigen (PSA) test. Herein, urine from an independent cohort of PCa patients and cancer-free controls was analyzed to further validate the discriminative power of that panel. Additionally, urine from patients diagnosed with bladder cancer (BC) and renal cancer (RC) were included to evaluate the site-specificity of the panel. Results confirmed the ability of the 6-biomarker panel to discriminate PCa patients from controls, but not from other urological cancers. To overcome this limitation, an untargeted approach was performed to unveil discriminant metabolites among the three cancer types. A 10-biomarker panel comprising the original panel plus four new metabolites was established to discriminate PCa from controls, BC, and RC, with 76% sensitivity, 90% specificity, and 92% accuracy. This improved panel also disclosed better accuracy than serum PSA test and provides the basis for a new non-invasive early detection tool for PCa. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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14 pages, 681 KiB

Open AccessArticle

Study of Ras Mutations’ Prognostic Value in Metastatic Colorectal Cancer: STORIA Analysis

by Alessandro Ottaiano, Nicola Normanno, Sergio Facchini, Antonino Cassata, Anna Nappi, Carmela Romano, Lucrezia Silvestro, Alfonso De Stefano, Anna Maria Rachiglio, Cristin Roma, Monica R. Maiello, Stefania Scala, Paolo Delrio, Fabiana Tatangelo, Annabella Di Mauro, Gerardo Botti, Antonio Avallone and Guglielmo Nasti

Cancers 2020, 12(7), 1919; https://doi.org/10.3390/cancers12071919 - 16 Jul 2020

Cited by 27 | Viewed by 3327

Abstract

Background: Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. Methods: Two [...] Read more.

Background: Colorectal cancer (CRC) is the second most common cause of cancer-specific death in both sexes in Western countries. KRAS mutations occur in about 50% of metastatic CRCs (mCRCs). The prognostic value of specific KRAS mutations still remains unexplored and unclear. Methods: Two hundred and forty KRAS wild-type and 206 KRAS/NRAS mutant consecutive unresectable mCRC patients with PS Eastern Cooperative Oncology Group (ECOG) 0 or 1, aged < 80 years, and with a life expectancy >3 months entered into this study. DNA was extracted from paraffin-embedded formalin-fixed tumour tissues, and it was sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Data were analysed using the Torrent Suite Software v5.0 (Thermo Fisher Scientific). The primary outcome was the analysis of the prognostic role of different KRAS mutations in terms of overall survival (OS). Results: There were no significant differences among the most prevalent mutations (p.G12D, p.G12V, p.G13D, p.G12A, p.G12C, and p.G12S) in terms of age (<65 vs. ≥65 years), gender (male vs. female), grading (G1/G2 vs. G3), side of primary tumour (left vs. right), pT, and pN. At the median follow-up of 25.6 months, there were 77 deaths in KRAS-mutated patients and 94 in wild-type patients. Three homogeneous prognostic groups were identified: wild-type patients (group A, median survival: 27.5 months), p.G13D/p.G12A/p.G12V/p.G12D mutants (group B, median survival: 17.3 months), and p.G12C/p.G12S mutants (group C, median survival: 5.0 months, p < 0.0001 according to Log Rank test). Upon multivariate analysis, metastatic involvement and p.G12C/p.G12S KRAS mutation group C (vs. other mutations) emerged as independent prognostic variables for survival. Conclusions: We show that mutant KRAS is a negative prognostic factor and that p.G12C/p.G12S variants present the worst clinical courses. This information suggests a clear difference among KRAS mutations, and it will be useful to test potentiated and/or innovative therapeutic strategies in p.G12C/p.G12S metastatic CRC patients. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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31 pages, 4315 KiB

Open AccessArticle

Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

by Pak Hin Chow, Joanne Bowen and Andrea J Yool

Cancers 2020, 12(7), 1911; https://doi.org/10.3390/cancers12071911 - 15 Jul 2020

Cited by 25 | Viewed by 3929

Abstract

Aquaporin (AQP) channels enable regulated transport of water and solutes essential for fluid homeostasis, but they are gaining attention as targets for anticancer therapies. Patterns of AQP expression and survival rates for patients were evaluated by systematic review (PubMed and Embase) and transcriptomic [...] Read more.

Aquaporin (AQP) channels enable regulated transport of water and solutes essential for fluid homeostasis, but they are gaining attention as targets for anticancer therapies. Patterns of AQP expression and survival rates for patients were evaluated by systematic review (PubMed and Embase) and transcriptomic analyses of RNAseq data (Human Protein Atlas database). Meta-analyses confirmed predominantly negative associations between AQP protein and RNA expression levels and patient survival times, most notably for AQP1 in lung, breast and prostate cancers; AQP3 in esophageal, liver and breast cancers; and AQP9 in liver cancer. Patterns of AQP expression were clustered for groups of cancers and associated with risk of death. A quantitative transcriptomic analysis of AQP1-10 in human cancer biopsies similarly showed that increased transcript levels of AQPs 1, 3, 5 and 9 were most frequently associated with poor survival. Unexpectedly, increased AQP7 and AQP8 levels were associated with better survival times in glioma, ovarian and endometrial cancers, and increased AQP11 with better survival in colorectal and breast cancers. Although molecular mechanisms of aquaporins in pathology or protection remain to be fully defined, results here support the hypothesis that overexpression of selected classes of AQPs differentially augments cancer progression. Beyond fluid homeostasis, potential roles for AQPs in cancers (suggested from an expanding appreciation of their functions in normal tissues) include cell motility, membrane process extension, transport of signaling molecules, control of proliferation and apoptosis, increased mechanical compliance, and gas exchange. AQP expression also has been linked to differences in sensitivity to chemotherapy treatments, suggesting possible roles as biomarkers for personalized treatments. Development of AQP pharmacological modulators, administered in cancer-specific combinations, might inspire new interventions for controlling malignant carcinomas. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 5614 KiB

Open AccessArticle

Loss of Function SETD2 Mutations in Poorly Differentiated Metastases from Two Hürthle Cell Carcinomas of the Thyroid

by Valeria Pecce, Antonella Verrienti, Luana Abballe, Raffaella Carletti, Giorgio Grani, Rosa Falcone, Valeria Ramundo, Cosimo Durante, Cira Di Gioia, Diego Russo, Sebastiano Filetti and Marialuisa Sponziello

Cancers 2020, 12(7), 1892; https://doi.org/10.3390/cancers12071892 - 14 Jul 2020

Cited by 11 | Viewed by 3446

Abstract

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. [...] Read more.

Hürthle cell carcinomas (HCC) are rare differentiated thyroid cancers that display low avidity for radioactive iodine and respond poorly to kinase inhibitors. Here, using next-generation sequencing, we analyzed the mutational status of primary tissue and poorly differentiated metastatic tissue from two HCC patients. In both cases, metastatic tissues harbored a mutation of SETD2, each resulting in loss of the SRI and WW domains of SETD2, a methyltransferase that trimethylates H3K36 (H3K36me3) and also interacts with p53 to promote its stability. Functional studies of the novel p.D1890fs6* mutation (case 1) revealed significantly reduced H3K36me3 levels in SETD2-mutated tissue and primary cell cultures and decreased levels of the active form of p53. Restoration of SETD2-wildtype expression in the SETD2-mutant cells significantly reduced the expression of four well-known stemness markers (OCT-4, SOX2, IPF1, Goosecoid). These findings suggest potential roles for SETD2 loss-of-function mutations in HCC progression, possibly involving p53 destabilization and promotion of stemness. Their prevalence and potential treatment implications in thyroid cancer, especially HCC, require further study. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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14 pages, 2329 KiB

Open AccessArticle

Identification of Novel microRNA Prognostic Markers Using Cascaded Wx, a Neural Network-Based Framework, in Lung Adenocarcinoma Patients

by Jeong Seon Kim, Sang Hoon Chun, Sungsoo Park, Sieun Lee, Sae Eun Kim, Ji Hyung Hong, Keunsoo Kang, Yoon Ho Ko and Young-Ho Ahn

Cancers 2020, 12(7), 1890; https://doi.org/10.3390/cancers12071890 - 14 Jul 2020

Cited by 7 | Viewed by 3128

Abstract

The evolution of next-generation sequencing technology has resulted in a generation of large amounts of cancer genomic data. Therefore, increasingly complex techniques are required to appropriately analyze this data in order to determine its clinical relevance. In this study, we applied a neural [...] Read more.

The evolution of next-generation sequencing technology has resulted in a generation of large amounts of cancer genomic data. Therefore, increasingly complex techniques are required to appropriately analyze this data in order to determine its clinical relevance. In this study, we applied a neural network-based technique to analyze data from The Cancer Genome Atlas and extract useful microRNA (miRNA) features for predicting the prognosis of patients with lung adenocarcinomas (LUAD). Using the Cascaded Wx platform, we identified and ranked miRNAs that affected LUAD patient survival and selected the two top-ranked miRNAs (miR-374a and miR-374b) for measurement of their expression levels in patient tumor tissues and in lung cancer cells exhibiting an altered epithelial-to-mesenchymal transition (EMT) status. Analysis of miRNA expression from tumor samples revealed that high miR-374a/b expression was associated with poor patient survival rates. In lung cancer cells, the EMT signal induced miR-374a/b expression, which, in turn, promoted EMT and invasiveness. These findings demonstrated that this approach enabled effective identification and validation of prognostic miRNA markers in LUAD, suggesting its potential efficacy for clinical use. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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12 pages, 1891 KiB

Open AccessArticle

Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer

by Andrew McGuire, Maire-Caitlin Casey, Ronan M. Waldron, Helen Heneghan, Olga Kalinina, Emma Holian, Ailbhe McDermott, Aoife J. Lowery, John Newell, Róisín M. Dwyer, Nicola Miller, Maccon Keane, James A.L. Brown and Michael J. Kerin

Cancers 2020, 12(7), 1820; https://doi.org/10.3390/cancers12071820 - 7 Jul 2020

Cited by 31 | Viewed by 4452

Abstract

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) [...] Read more.

Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308–0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 2126 KiB

Open AccessArticle

Circulating Plasma Gelsolin: A Predictor of Favorable Clinical Outcomes in Head and Neck Cancer and Sensitive Biomarker for Early Disease Diagnosis Combined with Soluble Fas Ligand

by Chen-Tzu Chiu, Pei-Wen Wang, Meshach Asare-Werehene, Benjamin K. Tsang and Dar-Bin Shieh

Cancers 2020, 12(6), 1569; https://doi.org/10.3390/cancers12061569 - 13 Jun 2020

Cited by 12 | Viewed by 2921

Abstract

Head and neck cancer (HNC) accounts for more than 330,000 cancer deaths annually worldwide. Despite late diagnosis being a major factor contributing to HNC mortality, no satisfactory biomarkers exist for early disease detection. Cytoplasmic gelsolin (cGSN) was discovered to predict disease progression in [...] Read more.

Head and neck cancer (HNC) accounts for more than 330,000 cancer deaths annually worldwide. Despite late diagnosis being a major factor contributing to HNC mortality, no satisfactory biomarkers exist for early disease detection. Cytoplasmic gelsolin (cGSN) was discovered to predict disease progression in HNC and other malignancies, and circulating plasma gelsolin (pGSN) levels are significantly correlated with infectious and inflammatory disease prognoses. Here, the plasma levels of five candidate biomarkers (circulating pGSN, squamous cell carcinoma antigen, cytokeratin 19 fragment, soluble Fas, and soluble Fas ligand (sFasL)) in 202 patients with HNC and 45 healthy controls were measured using enzyme-linked immunosorbent assay or Millipore cancer multiplex assay. The results demonstrated that circulating pGSN levels were significantly lower in patients with HNC than in healthy controls. Moreover, circulating pGSN outperformed other candidate biomarkers as an independent diagnostic biomarker of HNC in both sensitivity (82.7%) and specificity (95.6%). Receiver operating characteristic curves indicated that combined pGSN and sFasL levels further augmented this sensitivity (90.6%) for early disease detection. Moreover, higher pGSN levels predicted improved prognosis at both 5-year overall survival and progression-free survival. In conclusion, circulating pGSN could be an independent predictor of favorable clinical outcomes and a novel biomarker for the early HNC detection in combination with sFasL. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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14 pages, 1229 KiB

Open AccessArticle

Serum Type XIX Collagen is Significantly Elevated in Non-Small Cell Lung Cancer: A Preliminary Study on Biomarker Potential

by Jeppe Thorlacius-Ussing, Tina Manon-Jensen, Shu Sun, Diana J. Leeming, Jannie M. Sand, Morten Karsdal and Nicholas Willumsen

Cancers 2020, 12(6), 1510; https://doi.org/10.3390/cancers12061510 - 9 Jun 2020

Cited by 15 | Viewed by 2688

Abstract

Type XIX collagen is a poorly characterized collagen associated with the basement membrane. It is abnormally regulated during breast cancer progression and the NC1 (XIX) domain has anti-tumorigenic signaling properties. However, little is known about the biomarker potential of collagen XIX in cancer. [...] Read more.

Type XIX collagen is a poorly characterized collagen associated with the basement membrane. It is abnormally regulated during breast cancer progression and the NC1 (XIX) domain has anti-tumorigenic signaling properties. However, little is known about the biomarker potential of collagen XIX in cancer. In this study, we describe a competitive ELISA, named PRO-C19, targeting the C-terminus of collagen XIX using a monoclonal antibody. PRO-C19 was measured in serum of patients with a range of cancer types and was elevated in non-small cell lung cancer (NSCLC) (p < 0.0001), small cell lung cancer (p = 0.0081), breast (p = 0.0005) and ovarian cancer (p < 0.0001) compared to healthy controls. In a separate NSCLC cohort, PRO-C19 was elevated compared to controls when evaluating adenocarcinoma (AD) (p = 0.0003) and squamous cell carcinoma (SCC) (p < 0.0001) patients but was not elevated in chronic obstructive pulmonary disease patients. SCC also had higher PRO-C19 levels than AD (p = 0.0457). PRO-C19 could discriminate between NSCLC and healthy controls (AUROC:0.749 and 0.826 for AD and SCC, respectively) and maintained discriminatory performance in patients of tumor stages I+II (AUROC:0.733 and 0.818 for AD and SCC, respectively). Lastly, we confirmed the elevated type XIX collagen levels using gene expression data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) initiatives. In conclusion, type XIX collagen is released into circulation and is significantly elevated in the serum of cancer patients and PRO-C19 shows promise as a cancer biomarker. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 2918 KiB

Open AccessArticle

Prognostic Significance of CHIP and RIPK3 in Non-Small Cell Lung Cancer

by Jisup Kim, Joon-Yong Chung, Young Soo Park, Se Jin Jang, Hyeong Ryul Kim, Chang-Min Choi and Joon Seon Song

Cancers 2020, 12(6), 1496; https://doi.org/10.3390/cancers12061496 - 8 Jun 2020

Cited by 8 | Viewed by 2534

Abstract

RIPK3 is a key regulator of necroptosis, which plays a double-edged sword role in tumor progression. CHIP is an E3 ubiquitin ligase that regulates necroptosis by degrading RIPK3. Here, we investigated the prognostic value of RIPK3 and CHIP expression in 404 patients with [...] Read more.

RIPK3 is a key regulator of necroptosis, which plays a double-edged sword role in tumor progression. CHIP is an E3 ubiquitin ligase that regulates necroptosis by degrading RIPK3. Here, we investigated the prognostic value of RIPK3 and CHIP expression in 404 patients with non-small cell lung cancer (NSCLC). Expressions of CHIP and RIPK3 showed opposite correlations with survival. CHIP expression was associated with the longer overall survival (OS), whereas RIPK3 expression was associated with the shorter OS. RIPK3 positivity showed marginal association with shorter OS and disease-free survival (DFS) in adjuvant radiotherapy recipients but not in non-recipients, suggesting that necroptosis may induce radioresistance. In multivariate analysis, CHIP expression was associated with longer OS. Compared with other patients, CHIP(−)/RIPK3(+) patients had shorter OS and DFS. In summary, in patients with NSCLC, the expression of CHIP was an independent favorable prognostic factor while that of RIPK3 was an adverse prognostic factor. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 5181 KiB

Open AccessArticle

EGFR and αvβ6 as Promising Targets for Molecular Imaging of Cutaneous and Mucosal Squamous Cell Carcinoma of the Head and Neck Region

by Victor M. Baart, Chayenne van Duijn, Sylvia L. van Egmond, Willem A. Dijckmeester, Jeroen C. Jansen, Alexander L. Vahrmeijer, Cornelis F. M. Sier and Danielle Cohen

Cancers 2020, 12(6), 1474; https://doi.org/10.3390/cancers12061474 - 5 Jun 2020

Cited by 21 | Viewed by 3934

Abstract

R0 resection is paramount in cutaneous squamous cell carcinoma (CSCC) and head and neck squamous cell carcinoma (HNSCC). However, in the setting of recurrence, immunocompromised patients, or non-keratinizing squamous cell carcinoma (SCC) with a spindle growth pattern, tumor borders are difficult, if not [...] Read more.

R0 resection is paramount in cutaneous squamous cell carcinoma (CSCC) and head and neck squamous cell carcinoma (HNSCC). However, in the setting of recurrence, immunocompromised patients, or non-keratinizing squamous cell carcinoma (SCC) with a spindle growth pattern, tumor borders are difficult, if not impossible, to determine. Fluorescence-guided surgery (FGS) aids in this differentiation. Potential targets for FGS of CSCC and HNSCC were evaluated. Most sections stained intensely for αvβ6 and epidermal growth factor receptor (EGFR) on tumor cells. Normal epithelium stained less for αvβ6 than for EGFR. In addition, soft tissue and stroma stained negative for both, allowing for clear discrimination of the soft tissue margin. Tumor cells weakly expressed urokinase plasminogen activator receptor (uPAR) while expression on stromal cells was moderate. Normal epithelium rarely expressed uPAR, resulting in clear discrimination of superficial margins. Tumors did not consistently express integrin β3, carcinoembryonic antigen, epithelial cell adhesion molecule, or vascular endothelial growth factor A. In conclusion, αvβ6 and EGFR allowed for precise discrimination of SSC at the surgically problematic soft tissue margins. Superficial margins are ideally distinguished with uPAR. In the future, FGS in the surgically challenging setting of cutaneous and mucosal SCC could benefit from a tailor-made approach, with EGFR and αvβ6 as targets. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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13 pages, 1116 KiB

Open AccessArticle

A Germline Mutation in the POT1 Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer

by Aayushi Srivastava, Beiping Miao, Diamanto Skopelitou, Varun Kumar, Abhishek Kumar, Nagarajan Paramasivam, Elena Bonora, Kari Hemminki, Asta Försti and Obul Reddy Bandapalli

Cancers 2020, 12(6), 1441; https://doi.org/10.3390/cancers12061441 - 1 Jun 2020

Cited by 30 | Viewed by 5224

Abstract

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. [...] Read more.

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the Protection of Telomeres 1 (POT1) gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying POT1 p.V29L showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in POT1 has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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17 pages, 2682 KiB

Open AccessArticle

BAX Redistribution Induces Apoptosis Resistance and Selective Stress Sensitivity in Human HCC

by Kathrin Funk, Carolin Czauderna, Ramona Klesse, Diana Becker, Jovana Hajduk, Aline Oelgeklaus, Frank Reichenbach, Franziska Fimm-Todt, Joachim Lauterwasser, Peter R. Galle, Jens U. Marquardt and Frank Edlich

Cancers 2020, 12(6), 1437; https://doi.org/10.3390/cancers12061437 - 31 May 2020

Cited by 13 | Viewed by 3780

Abstract

Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative [...] Read more.

Cancer therapies induce differential cell responses, ranging from efficient cell death to complete stress resistance. The BCL-2 proteins BAX and BAK govern the cellular decision between survival and mitochondrial apoptosis. Therefore, the status of BAX/BAK regulation can predict the cellular apoptosis predisposition. Relative BAX/BAK localization was analyzed in tumor and corresponding non-tumor samples from 34 hepatocellular carcinoma (HCC) patients. Key transcriptome changes and gene expression profiles related to the status of BAX regulation were applied to two independent cohorts including over 500 HCC patients. The prediction of apoptotic response was tested using cell lines and polyclonal tumor isolates. Cellular protection from BAX was confirmed by challenging cells with mitochondrial BAX. We discovered a subgroup of HCC with selective protection from BAX-dependent apoptosis. BAX-protected tumors showed enrichment of signaling pathways associated with oxidative stress response and DNA repair as well as increased genetic heterogeneity. Gene expression profiles characteristic to BAX-specific protection are enriched in poorly differentiated HCCs and show significant association to the overall survival of HCC patients. Consistently, addiction to DNA repair of BAX-protected cancer cells caused selective sensitivity to PARP inhibition. Molecular characteristics of BAX-protected HCC were enriched in cells challenged with mitochondrial BAX. Our results demonstrate that predisposition to BAX activation impairs tumor biology in HCC. Selective BAX inhibition or lack thereof delineates distinct subgroups of HCC patients with molecular features and differential response pattern to apoptotic stimuli and inhibition of DNA repair mechanisms. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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15 pages, 1274 KiB

Open AccessArticle

Clinical Significance of Systemic Inflammation Markers in Newly Diagnosed, Previously Untreated Hepatocellular Carcinoma

by Jeong Il Yu, Hee Chul Park, Gyu Sang Yoo, Seung Woon Paik, Moon Seok Choi, Hye-Seung Kim, Insuk Sohn and Heerim Nam

Cancers 2020, 12(5), 1300; https://doi.org/10.3390/cancers12051300 - 21 May 2020

Cited by 17 | Viewed by 2566

Abstract

This study aimed to investigate the clinical significance of systemic inflammation markers (SIMs)—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)—in patients with newly diagnosed, previously untreated hepatocellular carcinoma (HCC). The present study was performed using prospectively collected registry data of [...] Read more.

This study aimed to investigate the clinical significance of systemic inflammation markers (SIMs)—including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)—in patients with newly diagnosed, previously untreated hepatocellular carcinoma (HCC). The present study was performed using prospectively collected registry data of newly diagnosed, previously untreated HCC from a single institution. The training set included 6619 patients from 2005 to 2013 and the validation set included 2084 patients from 2014 to 2016. The SIMs as continuous variables significantly affected the overall survival (OS), and the optimal cut-off value of NLR, PLR, and LMR was 3.0, 100.0, and 3.0, respectively. There were significant correlations between SIMs and the albumin-bilirubin grade/Child-Turcotte-Pugh class (indicative of liver function status) and the staging system/portal vein invasion (indicative of the tumor burden). The OS curves were well stratified according to the prognostic model of SIMs and validated using the bootstrap method (1000 times, C-index 0.6367, 95% confidence interval (CI) 0.6274–0.6459) and validation cohort (C-index 0.6810, 95% CI 0.6570–0.7049). SIMs showed significant prognostic ability for OS, independent of liver function and tumor extent, although these factors were significantly correlated with SIMs in patients with newly diagnosed, previously untreated HCC. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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21 pages, 3377 KiB

Open AccessArticle

Circulating MicroRNAs Regulating DNA Damage Response and Responsiveness to Cisplatin in the Prognosis of Patients with Non-Small Cell Lung Cancer Treated with First-Line Platinum Chemotherapy

by Chara Papadaki, Alexia Monastirioti, Konstantinos Rounis, Dimitrios Makrakis, Konstantinos Kalbakis, Christoforos Nikolaou, Dimitrios Mavroudis and Sofia Agelaki

Cancers 2020, 12(5), 1282; https://doi.org/10.3390/cancers12051282 - 19 May 2020

Cited by 18 | Viewed by 3223

Abstract

The expression of microRNA (miR)-21, miR-128, miR-155, and miR-181a involved in DNA damage response (DDR) and tumor responsiveness to platinum was assessed by RT-qPCR in the plasma of patients with non-small cell lung cancer (NSCLC; n = 128) obtained prior to initiation of [...] Read more.

The expression of microRNA (miR)-21, miR-128, miR-155, and miR-181a involved in DNA damage response (DDR) and tumor responsiveness to platinum was assessed by RT-qPCR in the plasma of patients with non-small cell lung cancer (NSCLC; n = 128) obtained prior to initiation of first-line platinum chemotherapy. U6 small nuclear RNA (snRNA) was used for normalization, and fold change of each miRNA expression relative to the expression in healthy controls was calculated by the 2^−ΔΔCt method. MicroRNA expression levels were correlated with patients’ outcomes. Integrated function and pathway enrichment analysis was performed to identify putative target genes. MiR-128, miR-155, and miR-181a expressions were higher in patients compared to healthy donors. MiRNA expression was not associated with response to treatment. High miR-128 and miR-155 were correlated with shorter overall survival (OS), whereas performance status (PS) 2 and high miR-128 independently predicted for decreased OS. In the squamous (SqCC) subgroup (n = 41), besides miR-128 and miR-155, high miR-21 and miR-181a expressions were also associated with worse survival and high miR-155 independently predicted for shorter OS. No associations of miRNA expression with clinical outcomes were observed in patients with non-SqCC (n = 87). Integrated function and pathway analysis on miRNA targets revealed significant enrichments in hypoxia-related pathways. Our study shows for the first time that plasma miR-128 and miR-155 hold independent prognostic implications in NSCLC patients treated with platinum-based chemotherapy possibly related to their involvement in tumor response to hypoxia. Further studies are needed to investigate the potential functional role of these miRNAs in an effort to exploit their therapeutic potential. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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21 pages, 1661 KiB

Open AccessArticle

Proteomic Tissue-Based Classifier for Early Prediction of Prostate Cancer Progression

by Yuqian Gao, Yi-Ting Wang, Yongmei Chen, Hui Wang, Denise Young, Tujin Shi, Yingjie Song, Athena A. Schepmoes, Claire Kuo, Thomas L. Fillmore, Wei-Jun Qian, Richard D. Smith, Sudhir Srivastava, Jacob Kagan, Albert Dobi, Isabell A. Sesterhenn, Inger L. Rosner, Gyorgy Petrovics, Karin D. Rodland, Shiv Srivastava, Jennifer Cullen and Tao Liu Show full author list Hide full author list

Cancers 2020, 12(5), 1268; https://doi.org/10.3390/cancers12051268 - 17 May 2020

Cited by 11 | Viewed by 4130

Abstract

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa [...] Read more.

Although ~40% of screen-detected prostate cancers (PCa) are indolent, advanced-stage PCa is a lethal disease with 5-year survival rates around 29%. Identification of biomarkers for early detection of aggressive disease is a key challenge. Starting with 52 candidate biomarkers, selected from existing PCa genomics datasets and known PCa driver genes, we used targeted mass spectrometry to quantify proteins that significantly differed in primary tumors from PCa patients treated with radical prostatectomy (RP) across three study outcomes: (i) metastasis ≥1-year post-RP, (ii) biochemical recurrence ≥1-year post-RP, and (iii) no progression after ≥10 years post-RP. Sixteen proteins that differed significantly in an initial set of 105 samples were evaluated in the entire cohort (n = 338). A five-protein classifier which combined FOLH1, KLK3, TGFB1, SPARC, and CAMKK2 with existing clinical and pathological standard of care variables demonstrated significant improvement in predicting distant metastasis, achieving an area under the receiver-operating characteristic curve of 0.92 (0.86, 0.99, p = 0.001) and a negative predictive value of 92% in the training/testing analysis. This classifier has the potential to stratify patients based on risk of aggressive, metastatic PCa that will require early intervention compared to low risk patients who could be managed through active surveillance. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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14 pages, 1025 KiB

Open AccessArticle

Methylation-Based Signatures for Gastroesophageal Tumor Classification

by Nikolay Alabi, Dropen Sheka, Ashar Siddiqui and Edwin Wang

Cancers 2020, 12(5), 1208; https://doi.org/10.3390/cancers12051208 - 11 May 2020

Cited by 4 | Viewed by 3311

Abstract

Contention exists within the field of oncology with regards to gastroesophageal junction (GEJ) tumors, as in the past, they have been classified as gastric cancer, esophageal cancer, or a combination of both. Misclassifications of GEJ tumors ultimately influence treatment options, which may be [...] Read more.

Contention exists within the field of oncology with regards to gastroesophageal junction (GEJ) tumors, as in the past, they have been classified as gastric cancer, esophageal cancer, or a combination of both. Misclassifications of GEJ tumors ultimately influence treatment options, which may be rendered ineffective if treating for the wrong cancer attributes. It has been suggested that misclassification rates were as high as 45%, which is greater than reported for junctional cancer occurrences. Here, we aimed to use the methylation profiles of GEJ tumors to improve classifications of GEJ tumors. Four cohorts of DNA methylation profiles, containing ~27,000 (27k) methylation sites per sample, were collected from the Gene Expression Omnibus and The Cancer Genome Atlas. Tumor samples were assigned into discovery (n_EC = 185, n_GC = 395; EC, esophageal cancer; GC gastric cancer) and validation (n_EC = 179, n_GC = 369) sets. The optimized Multi-Survival Screening (MSS) algorithm was used to identify methylation biomarkers capable of distinguishing GEJ tumors. Three methylation signatures were identified: They were associated with protein binding, gene expression, and cellular component organization cellular processes, and achieved precision and recall rates of 94.7% and 99.2%, 97.6% and 96.8%, and 96.8% and 97.6%, respectively, in the validation dataset. Interestingly, the methylation sites of the signatures were very close (i.e., 170–270 base pairs) to their downstream transcription start sites (TSSs), suggesting that the methylations near TSSs play much more important roles in tumorigenesis. Here we presented the first set of methylation signatures with a higher predictive power for characterizing gastroesophageal tumors. Thus, they could improve the diagnosis and treatment of gastroesophageal tumors. Full article

(This article belongs to the Special Issue Cancer Biomarkers)

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18 pages, 5277 KiB

Open AccessArticle

USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2

by Jinhong Cho, Jinyoung Park, Sang Chul Shin, Mihue Jang, Jae-Hong Kim, Eunice EunKyeong Kim and Eun Joo Song

Cancers 2020, 12(5), 1137; https://doi.org/10.3390/cancers12051137 - 1 May 2020

Cited by 19 | Viewed by 4769

Abstract

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have [...] Read more.

p53 is activated in response to cellular stresses such as DNA damage, oxidative stress, and especially ribosomal stress. Although the regulations of p53 by E3 ligase and deubiquitinating enzymes (DUBs) have been described, the cellular roles of DUB associated with ribosomal stress have not been well studied. In this study, we report that Ubiquitin Specific Protease 47 (USP47) fun

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