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Biomarkers for Early Detection of Cancer: Molecular Aspects

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 59921

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Guest Editor
Asper Clinical Research Institute, St. Boniface Hospital, Department of Pharmacology and Therapeutics Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R2H 2A6, Canada
Interests: oncology; research; pharmacology; ethics; cancer; cardiology; diabetes; innovation; regulatory
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Special Issue Information

Dear Colleagues,

According to the World Health Organization, cancer is the second leading cause of death in the world. Within 10 to 15 years, cancer will overtake cardiovascular disease as the leading cause of death. The current standards for determining and verifying the presence of cancer involve computed tomography, magnetic resonance imaging, and ultrasound technology. These techniques are expensive, often inaccessible, involve exposure to ionizing radiation, and have an unacceptable level of false positives. Recently, a number of blood-based cancer assays that detect protein, microRNA, circulating DNA, and methylated DNA biomarkers have been developed. Unfortunately, most are specific to late-stage cancer. In addition, biopsies for molecular and biomarker diagnosis are invasive and uncomfortable for patients. Furthermore, the issue of overdiagnosis is a limiting factor, causing anxiety for patients and further increasing expense for the healthcare system. Researchers have turned to developing low-cost, high-throughput, early detection tools with high selectivity and specificity, including the analysis of metabolite biomarkers for cancer detection. This Special Issue provides insight and discusses recent advances in molecular, proteomic, and metabolic markers for the early detection of cancer. Molecular aspects of biomarkers for early detection of cancer should be described. Novel approaches in the early detection of different cancer types will also be described for their potential in the screening and surveillance of cancer for improved prognostic value, survival, and quality of life.

Dr. Paramjit S. Tappia
Dr. Bram Ramjiawan
Guest Editors

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Keywords

  • Cancer
  • Early detection
  • Cancer staging
  • Diagnostic tools
  • Novel biomarkers
  • Proteomics
  • Molecular markers
  • Metabolic profiling
  • Prognostic value

Published Papers (10 papers)

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Editorial

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5 pages, 195 KiB  
Editorial
Biomarkers for Early Detection of Cancer: Molecular Aspects
by Paramjit S. Tappia and Bram Ramjiawan
Int. J. Mol. Sci. 2023, 24(6), 5272; https://doi.org/10.3390/ijms24065272 - 9 Mar 2023
Cited by 9 | Viewed by 1697
Abstract
According to the World Health Organization, cancer is a leading cause of death worldwide, representing almost 10 million deaths in 2020 [...] Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)

Research

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12 pages, 1330 KiB  
Article
Gemcitabine–Paclitaxel Chemotherapy for Patients with Advanced Urothelial Cancer Refractory to Cisplatin-Based Chemotherapy: Predictive Role of PGK1 for Treatment Response to Cytotoxic Chemotherapy
by Dai Koguchi, Kazumasa Matsumoto, Masaomi Ikeda, Yuriko Shimizu, Marie Nakamura, Yutaka Shiono, Hiroki Katsumata, Yuichi Sato and Masatsugu Iwamura
Int. J. Mol. Sci. 2022, 23(20), 12119; https://doi.org/10.3390/ijms232012119 - 11 Oct 2022
Cited by 2 | Viewed by 1372
Abstract
An investigation of alternatives to immune checkpoint inhibitors for advanced urothelial cancer (aUC), with biologic information, is urgently needed. Clinical data for 53 patients who received gemcitabine–paclitaxel therapy (GP) as 2nd-line chemotherapy for aUC refractory to platinum-based chemotherapy were retrospectively reviewed. The efficacy [...] Read more.
An investigation of alternatives to immune checkpoint inhibitors for advanced urothelial cancer (aUC), with biologic information, is urgently needed. Clinical data for 53 patients who received gemcitabine–paclitaxel therapy (GP) as 2nd-line chemotherapy for aUC refractory to platinum-based chemotherapy were retrospectively reviewed. The efficacy and tolerability of GP were evaluated, and the predictive value of phosphoglycerate kinase 1 (PGK1) immunostained in surgical specimens was investigated for treatment outcomes in 1st- and 2nd-line chemotherapy. GP was associated with an objective response rate of 35.8% and a median overall survival duration of 12.3 months. Multivariate analysis showed that PS2 and 1st- and 2nd-line non-response are independent predictors of worse progression-free survival and that PS2 and 1st-line non-response are independent predictors of worse overall survival. Adverse events were manageable, and no therapy-related deaths occurred. Non-response rates to 1st-line chemotherapy were significantly higher in patients with a high expression of PGK1 in the nucleus than in those with low expression (p = 0.006). Our study demonstrates the efficacy and tolerability of 2nd-line GP for patients with aUC who are refractory to platinum-based chemotherapy. Moreover, PGK1 in the nucleus was predictive values for resistance to platinum-based chemotherapy in aUC. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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17 pages, 4349 KiB  
Article
Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer
by Himali Gujrati, Siyoung Ha, Mohammad Waseem and Bi-Dar Wang
Int. J. Mol. Sci. 2022, 23(17), 9643; https://doi.org/10.3390/ijms23179643 - 25 Aug 2022
Cited by 14 | Viewed by 2135
Abstract
Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/ [...] Read more.
Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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19 pages, 3601 KiB  
Article
Identification of a Novel Five-Gene Signature as a Prognostic and Diagnostic Biomarker in Colorectal Cancers
by Souvik Ghatak, Syrina F. Mehrabi, Lubna M. Mehdawi, Shakti Ranjan Satapathy and Anita Sjölander
Int. J. Mol. Sci. 2022, 23(2), 793; https://doi.org/10.3390/ijms23020793 - 12 Jan 2022
Cited by 9 | Viewed by 2894
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that [...] Read more.
Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The current TNM (Tumor, Node, and Metastasis) classification approach is suboptimal in determining the prognosis of CRC patients. The prognosis for CRC is affected by a variety of features that are present at the initial diagnosis. Herein, we performed a systematic exploration and established a novel five-panel gene signature as a prognostic and early diagnosis biomarker after performing differential gene expression analyses in five independent in silico CRCs cohort and independently validating it in one clinical cohort, using immunohistochemistry. Four genes (BDNF, PTGS2, GSK3B, and CTNNB1) were significantly upregulated and one gene (HPGD) was significantly downregulated in primary tumor tissues compared with adjacent normal tissues throughout all the five in silico datasets. The univariate CoxPH analysis yielded a five-gene signature that accurately predicted overall survival (OS) and recurrence-free survival (RFS) in the in silico training (AUC = 0.73 and 0.69, respectively) and one independent in silico validation cohort (AUC = 0.69 and 0.74, respectively). This five-gene signature demonstrated significant associations with poor OS in independent clinical validation cohorts of colon cancer (CC) patients (AUC = 0.82). Intriguingly, a risk stratification model comprising of the five-gene signature together with TNM stage and gender status achieved an even superior AUC of 0.89 in the clinical cohorts. On the other hand, the circulating mRNA expression of the upregulated four-gene signature achieved a robust AUC = 0.83 with high sensitivity and specificity as a diagnosis marker in plasma from CRC patients. We have identified a novel, five-gene signature as an independent predictor of OS, which in combination with TNM stage and gender offers an easy-to-translate and facile assay for the personalized risk-assessment in CRC patients. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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12 pages, 2351 KiB  
Article
RNA Expression of DNA Damage Response Genes in Muscle-Invasive Bladder Cancer: Influence on Outcome and Response to Adjuvant Cisplatin-Based Chemotherapy
by Jonas Herrmann, Helena Schmidt, Katja Nitschke, Cleo-Aron Weis, Philipp Nuhn, Jost von Hardenberg, Maurice Stephan Michel, Philipp Erben and Thomas Stefan Worst
Int. J. Mol. Sci. 2021, 22(8), 4188; https://doi.org/10.3390/ijms22084188 - 18 Apr 2021
Cited by 6 | Viewed by 2244
Abstract
Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG [...] Read more.
Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and methods: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (n = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim n = 20 and TCGA n = 75). Results: Low expression of RAD52 was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim: p = 0.039; TCGA: p = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim: p = 0.0059; TCGA: p = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (BRCA2, ERCC2, FOXM1) where low expression was associated with poor DFS (p < 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of FOXM1 and BRCA2 correlated with poor DFS. Conclusion: Low expression of RAD52 correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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Review

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13 pages, 1049 KiB  
Review
COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients
by Suresh C. Tyagi, Sathnur Pushpakumar, Utpal Sen, Sri Prakash L. Mokshagundam, Dinesh K. Kalra, Mohamed A. Saad and Mahavir Singh
Int. J. Mol. Sci. 2023, 24(1), 287; https://doi.org/10.3390/ijms24010287 - 24 Dec 2022
Cited by 2 | Viewed by 2807
Abstract
Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put [...] Read more.
Although progressive wasting and weakness of respiratory muscles are the prominent hallmarks of Duchenne muscular dystrophy (DMD) and long-COVID (also referred as the post-acute sequelae of COVID-19 syndrome); however, the underlying mechanism(s) leading to respiratory failure in both conditions remain unclear. We put together the latest relevant literature to further understand the plausible mechanism(s) behind diaphragm malfunctioning in COVID-19 and DMD conditions. Previously, we have shown the role of matrix metalloproteinase-9 (MMP9) in skeletal muscle fibrosis via a substantial increase in the levels of tumor necrosis factor-α (TNF-α) employing a DMD mouse model that was crossed-bred with MMP9-knockout (MMP9-KO or MMP9-/-) strain. Interestingly, recent observations from clinical studies show a robust increase in neopterin (NPT) levels during COVID-19 which is often observed in patients having DMD. What seems to be common in both (DMD and COVID-19) is the involvement of neopterin (NPT). We know that NPT is generated by activated white blood cells (WBCs) especially the M1 macrophages in response to inducible nitric oxide synthase (iNOS), tetrahydrobiopterin (BH4), and tetrahydrofolate (FH4) pathways, i.e., folate one-carbon metabolism (FOCM) in conjunction with epigenetics underpinning as an immune surveillance protection. Studies from our laboratory, and others researching DMD and the genetically engineered humanized (hACE2) mice that were administered with the spike protein (SP) of SARS-CoV-2 revealed an increase in the levels of NPT, TNF-α, HDAC, IL-1β, CD147, and MMP9 in the lung tissue of the animals that were subsequently accompanied by fibrosis of the diaphragm depicting a decreased oscillation phenotype. Therefore, it is of interest to understand how regulatory processes such as epigenetics involvement affect DNMT, HDAC, MTHFS, and iNOS that help generate NPT in the long-COVID patients. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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16 pages, 336 KiB  
Review
Molecular Biomarkers for the Early Detection of Ovarian Cancer
by Ruiqian Zhang, Michelle K. Y. Siu, Hextan Y. S. Ngan and Karen K. L. Chan
Int. J. Mol. Sci. 2022, 23(19), 12041; https://doi.org/10.3390/ijms231912041 - 10 Oct 2022
Cited by 57 | Viewed by 7907
Abstract
Ovarian cancer is the deadliest gynecological cancer, leading to over 152,000 deaths each year. A late diagnosis is the primary factor causing a poor prognosis of ovarian cancer and often occurs due to a lack of specific symptoms and effective biomarkers for an [...] Read more.
Ovarian cancer is the deadliest gynecological cancer, leading to over 152,000 deaths each year. A late diagnosis is the primary factor causing a poor prognosis of ovarian cancer and often occurs due to a lack of specific symptoms and effective biomarkers for an early detection. Currently, cancer antigen 125 (CA125) is the most widely used biomarker for ovarian cancer detection, but this approach is limited by a low specificity. In recent years, multimarker panels have been developed by combining molecular biomarkers such as human epididymis secretory protein 4 (HE4), ultrasound results, or menopausal status to improve the diagnostic efficacy. The risk of ovarian malignancy algorithm (ROMA), the risk of malignancy index (RMI), and OVA1 assays have also been clinically used with improved sensitivity and specificity. Ongoing investigations into novel biomarkers such as autoantibodies, ctDNAs, miRNAs, and DNA methylation signatures continue to aim to provide earlier detection methods for ovarian cancer. This paper reviews recent advancements in molecular biomarkers for the early detection of ovarian cancer. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
13 pages, 307 KiB  
Review
Diagnostic Potential of Circulating Tumor Cells, Urinary MicroRNA, and Urinary Cell-Free DNA for Bladder Cancer: A Review
by Dai Koguchi, Kazumasa Matsumoto, Izuru Shiba, Takahiro Harano, Satoshi Okuda, Kohei Mori, Shuhei Hirano, Kazuki Kitajima, Masaomi Ikeda and Masatsugu Iwamura
Int. J. Mol. Sci. 2022, 23(16), 9148; https://doi.org/10.3390/ijms23169148 - 15 Aug 2022
Cited by 12 | Viewed by 2620
Abstract
Early detection of primary bladder cancer (BCa) is vital, because stage and grade have been generally accepted not only as categorical but also as prognostic factors in patients with BCa. The widely accepted screening methods for BCa, cystoscopy and urine cytology, have unsatisfactory [...] Read more.
Early detection of primary bladder cancer (BCa) is vital, because stage and grade have been generally accepted not only as categorical but also as prognostic factors in patients with BCa. The widely accepted screening methods for BCa, cystoscopy and urine cytology, have unsatisfactory diagnostic accuracy, with high rates of false negatives, especially for flat-type BCa with cystoscopy and for low-risk disease with urine cytology. Currently, liquid biopsy has attracted much attention as being compensatory for that limited diagnostic power. In this review, we survey the literature on liquid biopsy for the detection of BCa, focusing on circulating tumor cells (CTCs), urinary cell-free DNA (ucfDNA), and urinary microRNA (umiRNA). In diagnostic terms, CTCs and umiRNA are determined by quantitative analysis, and ucfDNA relies on finding genetic and epigenetic changes. The ideal biomarkers should be highly sensitive in detecting BCa. Currently, CTCs produce an unfavorable result; however, umiRNA and ucfDNA, especially when analyzed using a panel of genes, produce promising results. However, given the small cohort size in most studies, no conclusions can yet be drawn about liquid biopsy’s immediate application to clinical practice. Further large studies to validate the diagnostic value of liquid biopsy for clinical use are mandatory. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
17 pages, 733 KiB  
Review
Metabolomic Fingerprinting for the Detection of Early-Stage Lung Cancer: From the Genome to the Metabolome
by Jean-François Haince, Philippe Joubert, Horacio Bach, Rashid Ahmed Bux, Paramjit S. Tappia and Bram Ramjiawan
Int. J. Mol. Sci. 2022, 23(3), 1215; https://doi.org/10.3390/ijms23031215 - 21 Jan 2022
Cited by 13 | Viewed by 4627
Abstract
The five-year survival rate of lung cancer patients is very low, mainly because most newly diagnosed patients present with locally advanced or metastatic disease. Therefore, early diagnosis is key to the successful treatment and management of lung cancer. Unfortunately, early detection methods of [...] Read more.
The five-year survival rate of lung cancer patients is very low, mainly because most newly diagnosed patients present with locally advanced or metastatic disease. Therefore, early diagnosis is key to the successful treatment and management of lung cancer. Unfortunately, early detection methods of lung cancer are not ideal. In this brief review, we described early detection methods such as chest X-rays followed by bronchoscopy, sputum analysis followed by cytological analysis, and low-dose computed tomography (LDCT). In addition, we discussed the potential of metabolomic fingerprinting, compared to that of other biomarkers, including molecular targets, as a low-cost, high-throughput blood-based test that is both feasible and affordable for early-stage lung cancer screening of at-risk populations. Accordingly, we proposed a paradigm shift to metabolomics as an alternative to molecular and proteomic-based markers in lung cancer screening, which will enable blood-based routine testing and be accessible to those patients at the highest risk for lung cancer. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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18 pages, 322 KiB  
Review
Current and Future Development in Lung Cancer Diagnosis
by Reem Nooreldeen and Horacio Bach
Int. J. Mol. Sci. 2021, 22(16), 8661; https://doi.org/10.3390/ijms22168661 - 12 Aug 2021
Cited by 290 | Viewed by 30212
Abstract
Lung cancer is the leading cause of cancer-related deaths in North America and other developed countries. One of the reasons lung cancer is at the top of the list is that it is often not diagnosed until the cancer is at an advanced [...] Read more.
Lung cancer is the leading cause of cancer-related deaths in North America and other developed countries. One of the reasons lung cancer is at the top of the list is that it is often not diagnosed until the cancer is at an advanced stage. Thus, the earliest diagnosis of lung cancer is crucial, especially in screening high-risk populations, such as smokers, exposure to fumes, oil fields, toxic occupational places, etc. Based on the current knowledge, it looks that there is an urgent need to identify novel biomarkers. The current diagnosis of lung cancer includes different types of imaging complemented with pathological assessment of biopsies, but these techniques can still not detect early lung cancer developments. In this review, we described the advantages and disadvantages of current methods used in diagnosing lung cancer, and we provide an analysis of the potential use of body fluids as carriers of biomarkers as predictors of cancer development and progression. Full article
(This article belongs to the Special Issue Biomarkers for Early Detection of Cancer: Molecular Aspects)
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