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59 pages, 5631 KB

Open AccessArticle

A Ten-Gene Transcriptomic Biomarker Panel for Glioma Classification and Prognosis Identified via Integrative Hypergraph and Rough Set Analysis

by Ömer Akgüller, Mehmet Ali Balcı and Gabriela Cioca

Cancers 2026, 18(10), 1576; https://doi.org/10.3390/cancers18101576 - 12 May 2026

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Abstract

Background: Clinically actionable biomarkers that reliably distinguish glioblastoma (GBM) from lower-grade glioma (LGG) across expression platforms remain an unmet need. Existing transcriptomic signatures are frequently confounded by batch effects, platform heterogeneity, and the inability to translate to single-patient clinical workflows. Methods: We developed [...] Read more.

Background: Clinically actionable biomarkers that reliably distinguish glioblastoma (GBM) from lower-grade glioma (LGG) across expression platforms remain an unmet need. Existing transcriptomic signatures are frequently confounded by batch effects, platform heterogeneity, and the inability to translate to single-patient clinical workflows. Methods: We developed a topology-aware biomarker discovery framework in which analysis-of-variance ranking defines a candidate gene pool, hypergraph co-expression analysis at correlation threshold τ = 0.75 identifies densely connected hubs within this pool, rough set reduct optimisation selects a minimal sufficient subset of these hubs, and a Random Forest classifier with stratified cross-validation performs the final discrimination. The pipeline was trained exclusively on GSE16011, a single-platform single-institution Affymetrix microarray cohort free from batch-class confound, and validated on two independent RNA-sequencing cohorts (CGGA-325 and CGGA-693). Robustness was further assessed through bootstrap optimism correction, DeLong cross-cohort equivalence testing, leave-one-gene-out analysis, and a sensitivity analysis under WHO CNS5 (2021) class definitions. Results: The pipeline identified a ten-gene biomarker panel (CSMD3, CHI3L1, PLP2, FRY, FCHSD2, ADM, MCUB, ANXA1, DUSP26, and HK2), achieving a fivefold cross-validation AUROC of 0.906 ± 0.029 and a held-out AUROC of 0.831. External validation yielded AUROC = 0.838 in CGGA-325 and AUROC = 0.836 in CGGA-693. The biomarker-derived risk score demonstrated independent prognostic value in CGGA-693 (multivariate Cox hazard ratio = 9.195; p < 0.001) after adjustment for WHO histological grade, with Kaplan–Meier analysis confirming highly significant survival separation (log-rank p = 4.60 × 10⁻³⁷). Class definitions in the present work follow the histology-based pre-2021 WHO classification used in the source datasets and do not directly incorporate WHO CNS5 (2021) molecular criteria, such as IDH mutation status, that distinguish IDH-wild-type glioblastoma from IDH-mutant grade-IV astrocytoma. After excluding IDH-mutant grade-IV cases from the CGGA cohorts, the classification AUROCs increased to 0.906 in CGGA-325 and 0.872 in CGGA-693, with a Cox risk-score hazard ratio of 8.57 (p = 1.4 × 10⁻¹³) and log-rank p = 1.4 × 10⁻³² retained on the CNS5-aligned cohort. Conclusions: The methodological contributions introduced in this study, namely, the topology-aware hypergraph candidate pool construction, the rough set combinatorial reduct selection, the fixed-reference single-sample normalisation protocol, and the nested validation regime combining bootstrap optimism correction with cross-platform DeLong testing, are platform agnostic and directly applicable to future CNS5-aligned cohorts as such resources become publicly available, supporting the prospective re-derivation of molecularly defined glioma signatures within the integrated histopathological and molecular frameworks of contemporary neuro-oncology. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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27 pages, 2723 KB

Open AccessArticle

Prognostic Value of Regnase-1 in High-Grade Soft Tissue Sarcoma: Favourable in UPS, Yet Inverted in Adjuvantly Irradiated Patients

by Julie Zangarini, Axel Künstner, Florian Lenz, Lars Tharun, Jan Vorwerk, Niklas Gebauer, Jutta Kirfel, Hauke Busch, Bruno Christian Köhler, Eva Wardelmann, Dirk Rades, Anastassia Löser, Nikolas von Bubnoff, Cyrus Khandanpour and Maxim Kebenko

Cancers 2026, 18(9), 1419; https://doi.org/10.3390/cancers18091419 - 29 Apr 2026

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Abstract

Background: High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68⁺ tumour-associated [...] Read more.

Background: High-grade soft tissue sarcomas (STSs) are heterogeneous tumours lacking robust prognostic or predictive biomarkers. Regnase-1, an immune RNase, enhances antitumour immunity by limiting immunosuppressive tumour microenvironment (TME) components (e.g., myeloid-derived suppressor cells (MDSCs)), but remains unexplored in STS. As CD68⁺ tumour-associated macrophages (TAMs) drive TME suppression and poor prognosis in non-translocation-driven STS, we evaluated Regnase-1 and CD68⁺ TAMs to assess Regnase-1 as an indicator of an immunologically activated TME. Methods: Immunohistochemistry scoring of Regnase-1 and CD68⁺ TAMs was performed in 91 patients. Overall survival (OS) was assessed by Kaplan–Meier and Cox regression, and findings were validated in an independent “The Cancer Genome Atlas” Sarcoma (TCGA-SARC) cohort (n = 212). Results: In UPS, Regnase-1-high predicted longer OS (17.0 months vs. not reached; p = 0.0247) and lower mortality (univariate hazard ratio (HR) = 0.3; p = 0.0343; multivariate HR = 0.4; p = 0.0413), but not after radiotherapy. CD68⁺ TAM-high predicted shorter OS (13.0 months vs. not reached; p = 0.0274) and higher mortality (HR = 2.0, 95% CI 1.1–3.7; p = 0.0325). Both Regnase-1 effects were reproduced in TCGA-SARC. Regnase-1-high tumours showed inflammatory/interferon enrichment, reduced TGF-β signalling, and SERPINE1 upregulation. Conclusions: Regnase-1 marked a pro-inflammatory TME and favourable outcome in UPS, but this effect may reverse upon radiotherapy. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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26 pages, 6646 KB

Open AccessArticle

Comprehensive Pan-Cancer Analysis Identifies POFUT1 as a Prognostic Biomarker and Potential Therapeutic Target Associated with Immune Evasions

by Zakir Ullah, Xiaosong Pei, Perbhat Ali, Ikram Ullah, Yaqi Li and Shuai Liu

Cancers 2026, 18(9), 1342; https://doi.org/10.3390/cancers18091342 - 23 Apr 2026

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Abstract

Background: Aberrant protein O-fucosylation mediated by protein O-fucosyltransferase 1 (POFUT1), has emerged as a hallmark of tumorigenesis that regulates key signaling pathways, including Notch, which is frequently dysregulated in cancers. Protein O-fucosylation, catalyzed by POFUT1, regulates Notch signaling and has been implicated in [...] Read more.

Background: Aberrant protein O-fucosylation mediated by protein O-fucosyltransferase 1 (POFUT1), has emerged as a hallmark of tumorigenesis that regulates key signaling pathways, including Notch, which is frequently dysregulated in cancers. Protein O-fucosylation, catalyzed by POFUT1, regulates Notch signaling and has been implicated in individual cancers, but its pan-cancer expression patterns, clinical significance, and relationship to tumor immunity remain incompletely characterized. Methodology: We conducted a multi-omics bioinformatics analysis using TCGA and other public datasets to evaluate POFUT1 expression across 33 cancer types (n > 10,000). Differential expressions, tumor stage correlations, and survival outcomes were assessed. Immune cell infiltration was estimated using SangerBox and TIMER algorithms, while promoter methylation patterns were analyzed through UALCAN. Functional enrichment and protein–protein interaction networks were constructed to elucidate functional mechanism. Western blot validation in prostate and ovarian cancer cell lines confirmed our computational analysis. Results: POFUT1 showed significant overexpression in 16 of 33 cancer types (FDR-adjusted p < 0.05), with the highest elevation in BRCA (breast invasive carcinoma; log2FC = 2.31) and LUAD (lung adenocarcinoma; log2FC = 2.1). A high POFUT1 expression correlated with poor overall survival in eight cancer types (HR range: 1.8–3.2, p < 0.01) and disease-free survival in seven cancers. POFUT1 levels positively correlated with myeloid-derived suppressor cells (MDSCs) infiltrating in 15 cancer types, while inversely correlated with natural killer T (NKT) cells presence in 15 cancers (mean R = −0.34, p < 0.05), indicating an association with immunosuppressive microenvironments. Promoter hypomethylation in tumors suggested epigenetic dysregulation as a potential driver of its overexpression. Western blot analysis confirmed POFUT1 protein upregulations in prostate and ovarian cancer cell lines (1.7–2.1-fold. p < 0.01), corroborating transcriptomic findings. Conclusion: This pan-cancer study establishes POFUT1 as a critical oncogenic factor linked to aggressive disease, immune evasion, and poor prognosis. Its consistent overexpression and functional impact highlight its potential as a biomarker and target for anticancer therapy. While these computational findings require experimental validation, POFUT1 emerges as a candidate biomarker warranting functional studies and potential therapeutic targeting. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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22 pages, 157408 KB

Open AccessArticle

MDK Activates the PI3K/AKT Axis to Induce AP2A1 Expression and Epithelial–Mesenchymal Transition in Colorectal Cancer

by Tengfei Li, Chengyuan Xu, Yang Guo, Yanyan Xu, Kaiji Chen, Yunsheng Cheng, Kesavamoorthy Gandhervin, Jianming Zhang and Moubin Lin

Cancers 2026, 18(8), 1311; https://doi.org/10.3390/cancers18081311 - 21 Apr 2026

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Abstract

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully [...] Read more.

Background: Midkine (MDK), a secreted heparin-binding growth factor, is involved in tumor progression and metastasis. While serum MDK is widely recognized as a potential prognostic biomarker for colorectal cancer (CRC), its specific functional role and underlying mechanisms in CRC development are not fully understood. Methods: The four publicly available CRC microarray datasets—GSE41258, GSE44076, GSE81558, and GSE117606—along with TCGA-COAD and TCGA-READ datasets and their associated clinical data were obtained. MDK expression was measured at both the mRNA and protein levels using quantitative real-time PCR (qRT-PCR) and Western blotting. To investigate its oncogenic functions, a comprehensive set of assays was performed: transwell and wound healing assays for invasion and migration; CCK-8 and colony formation assays for proliferation; and tail vein/spleen injection models combined with xenograft models to study metastasis and tumor growth in vivo. To uncover underlying mechanisms, Western blotting was used to examine the involvement of epithelial–mesenchymal transition (EMT) and the PI3K/AKT signaling pathway. Results: MDK is significantly overexpressed in CRC tissues and cells compared to normal tissues and cells. Notably, patients with high MDK levels show poorer overall survival (OS). Overexpression of MDK increases CRC invasion, migration, proliferation, and metastasis both in vivo and in vitro, while its knockdown reverses these effects. Mechanistically, MDK activates the PI3K/AKT pathway, leading to increased AP2A1 expression and promotion of EMT in CRC. Conclusions: MDK promotes invasion, migration, proliferation, metastasis, and EMT in CRC cells through the PI3K/AKT pathway by inducing AP2A1 expression, which could serve as a diagnostic marker. The PI3K inhibitor LY294002 significantly reduces AP2A1 levels and inhibits MDK-induced malignant behaviors. Targeting MDK-related signaling pathways may offer new strategies for CRC treatment. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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10 pages, 320 KB

Open AccessArticle

Prediction of Bone Metastasis in Prostate Cancer Using Blood Glucose-6-Phosphate Dehydrogenase Activity: A Retrospective Medical Record Review

by Chang-Hwan Yeom, Jiewon Lee, Keun-Joo Bae, Kangseok Kim, Jongsoon Choi and Myeong-Hun Lim

Cancers 2026, 18(1), 41; https://doi.org/10.3390/cancers18010041 - 23 Dec 2025

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Abstract

Background: Globally, the incidence of prostate cancer is estimated to increase by approximately 80% by 2040 compared to 2018. Bone is the most common metastatic site in prostate cancer and accurate prediction of bone metastasis in prostate cancer is crucial for deciding [...] Read more.

Background: Globally, the incidence of prostate cancer is estimated to increase by approximately 80% by 2040 compared to 2018. Bone is the most common metastatic site in prostate cancer and accurate prediction of bone metastasis in prostate cancer is crucial for deciding treatment decisions. The aim of this study is to evaluate the potential of G6PD activity level as a biomarker for predicting bone metastasis in patients with prostate cancer. Methods: A total of 56 patients participated in this study and participants included in the study were prostate cancer patients aged 19 years or older who visited YCH Hospital. We compared G6PD activity levels according to presence of bone metastasis. Also, ROC analysis was conducted to evaluate the predictive performance of G6PD activity level for bone metastasis. Optimal cutoff value of G6PD activity level was determined using Youden’s index and corresponding sensitivity and specificity were calculated. Results: The median G6PD activity was significantly higher in the group with bone metastasis than in the group without bone metastasis. According to ROC curve analysis, the area under the curve (AUC) was 0.78 (95% CI, 0.66–0.90). The optimal cutoff value of G6PD activity level for predicting bone metastasis was determined to be 11.5 U/g Hb. At this cutoff value, sensitivity and specificity were 0.81 and 0.73, respectively. Conclusions: G6PD activity is a complementary non-invasive biomarker for predicting bone metastasis in patients with prostate cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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15 pages, 1323 KB

Open AccessArticle

Association of a CD44s-v5-v6 Null Phenotype with Advanced Stage Cholangiocarcinoma: A Preliminary Study

by Kyaw Zwar Myint, Thanakrit Mongkonsiri, Artit Jinawath and Rutaiwan Tohtong

Cancers 2026, 18(1), 21; https://doi.org/10.3390/cancers18010021 - 20 Dec 2025

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Abstract

Background/Objectives: Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis, creating an urgent need for novel biomarkers to improve risk stratification. The prognostic significance of the transmembrane glycoprotein CD44 and its isoforms (CD44s, v5, v6) in CCA remains controversial. This preliminary [...] Read more.

Background/Objectives: Cholangiocarcinoma (CCA) is an aggressive malignancy with a poor prognosis, creating an urgent need for novel biomarkers to improve risk stratification. The prognostic significance of the transmembrane glycoprotein CD44 and its isoforms (CD44s, v5, v6) in CCA remains controversial. This preliminary study aimed to investigate whether the combined loss of these isoforms could serve as a distinct prognostic indicator. Methods: We evaluated the expression of CD44s, CD44v5, and CD44v6 via immunohistochemistry on a retrospective cohort of 61 paraffin-embedded CCA patient tissue blocks from Ramathibodi Hospital, Bangkok, Thailand. Expression levels were correlated with clinicopathological parameters. Survival analyses, including Kaplan–Meier and Cox proportional hazards models, were used to determine the prognostic value of individual isoforms and the complete absence of all three. Results: Expression of CD44s, CD44v5, and CD44v6 was found in 52.5%, 47.5%, and 82.0% of tumors, respectively. In univariate and multivariate analyses, the expression of any single isoform was not a significant predictor of overall survival. However, a subgroup of 8 patients (13.1%) was identified whose tumors were negative for all three isoforms, a phenotype we termed “CD44s-v5-v6 Null”. This status was significantly associated with advanced TNM stages (p = 0.022). Patients with these Null tumors also showed a clinically relevant, though not statistically significant, trend towards poorer survival (median 7.0 vs. 12.0 months, p = 0.336). Conclusions: Individual CD44 isoforms did not serve as reliable independent prognostic markers in this cohort. Instead, the complete loss of the CD44 expression program characterizes a potential “CD44s-v5-v6 Null” phenotype associated with advanced-stage disease. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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12 pages, 346 KB

Open AccessArticle

Serum Glucose-6-Phosphate Dehydrogenase Activity as a Biomarker for Gastric Cancer Stage Prediction

by Chang-Hwan Yeom, Jiewon Lee, Keun-Joo Bae, Kangseok Kim, Jongsoon Choi and Myeong-Hun Lim

Cancers 2025, 17(23), 3798; https://doi.org/10.3390/cancers17233798 - 27 Nov 2025

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Abstract

Background: Gastric cancer is the fifth most prevalent cancer diagnosed worldwide, and approximately 40% of patients who experience recurrence within five years develop hematogenous metastasis. Given that early prediction of recurrence may improve overall survival, there is a need for a biomarker [...] Read more.

Background: Gastric cancer is the fifth most prevalent cancer diagnosed worldwide, and approximately 40% of patients who experience recurrence within five years develop hematogenous metastasis. Given that early prediction of recurrence may improve overall survival, there is a need for a biomarker that allows for repeated measurements and can accurately predict cancer stage. This study aimed to evaluate the potential of glucose-6-phosphate dehydrogenase activity, which is a factor associated with cancer progression, as a biomarker for predicting the stage of gastric cancer. Methods: This cross-sectional study retrospectively analyzed the medical records of patients with gastric cancer. Patients were classified into early-stage (Stage I–II) and advanced-stage (Stage III–IV) groups, and serum G6PD activity was compared between the two groups. Receiver operating characteristic (ROC) curve analysis was conducted to calculate the area under the curve (AUC), identifying the optimal cutoff value, and to determine the corresponding sensitivity and specificity. Results: Serum G6PD activity was significantly higher in the advanced-stage group compared to the early-stage group. Moreover, ROC curve analysis yielded an AUC of 0.70, indicating fair diagnostic performance. The optimal G6PD cutoff point was determined to be 12.05 U/g Hb, corresponding to a sensitivity of 0.59 and a specificity of 0.78. Conclusions: This study demonstrated the clinical utility of serum G6PD activity in predicting the stage of gastric cancer. As the test requires only a single drop of blood and provides rapid results, the test could be a practical tool for monitoring of recurrence in gastric cancer follow-up settings. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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13 pages, 2607 KB

Open AccessArticle

SMARCD3 Promotes Epithelial–Mesenchymal Transition in Gastric Cancer by Integrating PI3K-AKT and WNT/β-Catenin Pathways

by Ji-Ho Park, Sun Yi Park, Eun-Jung Jung, Young-Tae Ju, Chi-Young Jeong, Ju-Yeon Kim, Taejin Park, Miyeong Park, Young-Joon Lee and Sang-Ho Jeong

Cancers 2025, 17(21), 3526; https://doi.org/10.3390/cancers17213526 - 31 Oct 2025

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Abstract

Background: Epithelial–mesenchymal transition (EMT) is a fundamental process that drives invasion and metastasis in patients with diffuse-type gastric cancer (DGC). The role of SMARCD3, a subunit of the SWI/SNF chromatin remodeling complex, in this process is largely unknown. The aim of this [...] Read more.

Background: Epithelial–mesenchymal transition (EMT) is a fundamental process that drives invasion and metastasis in patients with diffuse-type gastric cancer (DGC). The role of SMARCD3, a subunit of the SWI/SNF chromatin remodeling complex, in this process is largely unknown. The aim of this study is to elucidate the molecular mechanism through which SMARCD3 integrates with the PI3K-AKT and WNT/β-catenin signaling pathways to promote EMT and gastric cancer progression. Methods: Stable SMARCD3-overexpressing MKN45 and MKN74 cell lines were established. RNA sequencing (RNA-seq) was performed to investigate signaling alterations. Western blot analysis confirmed the expression of EMT markers (Snail and Slug) and the phosphorylation of AKT (Ser473) and GSK3β (Ser9). PI3K dependency was tested using the inhibitor LY294002. Cooperative effects were examined by activating the WNT pathway with WNT3A. Results: SMARCD3 overexpression upregulated PI3K-AKT and WNT signaling, which correlated with increased Snail/Slug expression and increased AKT/GSK3β phosphorylation. GSK3β inactivation (pSer9) stabilizes Snail, driving EMT. LY294002 treatment suppressed Snail/Slug expression, attenuated AKT activation, and reversed the mesenchymal phenotype. Furthermore, WNT3A treatment synergistically increased nuclear Snail accumulation. Conclusions: SMARCD3 acts as a critical epigenetic regulator that promotes EMT in patients with gastric cancer through the integration of the PI3K-AKT and WNT/β-catenin pathways. Targeting this SMARCD3-mediated mechanism offers a promising therapeutic strategy to inhibit metastasis and improve outcomes for patients with gastric cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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13 pages, 481 KB

Open AccessArticle

Serum Iodine Levels and 8-Year Survival in Patients After Kidney Cancer Diagnosis

by Elżbieta Złowocka-Perłowska, Piotr Baszuk, Adam Kiljańczyk, Wojciech Marciniak, Róża Derkacz, Aleksandra Tołoczko-Grabarek, Andrzej Sikorski, Marcin Słojewski, Adam Gołąb, Artur Lemiński, Michał Soczawa, Magdalena Marciniak, Rodney J. Scott, Jacek Gronwald and Jan Lubiński

Cancers 2025, 17(21), 3400; https://doi.org/10.3390/cancers17213400 - 22 Oct 2025

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Abstract

Background/Objectives: The aim of this study was to evaluate the association between serum iodine (I) levels and kidney cancer mortality. The role of serum iodine levels in relation to 8-year survival rates in survivors of kidney cancer has not previously been established. In [...] Read more.

Background/Objectives: The aim of this study was to evaluate the association between serum iodine (I) levels and kidney cancer mortality. The role of serum iodine levels in relation to 8-year survival rates in survivors of kidney cancer has not previously been established. In this prospective study, we analyzed 284 consecutive, unselected survivors of kidney cancer and determined their 8-year survival in relation to iodine levels. Methods: Micronutrient levels were measured using inductively coupled plasma mass spectrometry (ICP-MS). Each survivors of kidney cancer was assigned to one of four groups based on the quartile distribution of iodine levels, ranked in ascending order. The multivariable models included covariates such as age at diagnosis, sex, smoking status, type of surgery, histopathological classification and serum levels of selenium, zinc, copper and the zinc-to-copper ratio. Results: We observed that survivors of kidney cancer with serum iodine levels in quartiles III and IV had significantly higher all-cause mortality compared to those in quartile II (reference quartile) (HR = 2.83; p = 0.012; HR = 2.64; p = 0.017). Furthermore, multivariable analysis revealed a significant association between serum iodine levels (quartiles III and IV vs. quartile II) and mortality due to kidney cancer progression (HR = 4.17; p = 0.031; HR = 3.94; p = 0.038, respectively). This association was significant only among men in quartile IV (HR = 16.5; p = 0.027). Additionally a positive association was observed between iodine levels in quartile IV and all-cause mortality from non–kidney cancer–related deaths (HR = 5.41; p = 0.05). Conclusions: To our knowledge, this study is the first investigation of relationship between serum iodine levels and survival of survivors of kidney cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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22 pages, 5410 KB

Open AccessArticle

Diagnostic Biomarker Candidates Proposed Using Targeted Lipid Metabolomics Analysis of the Plasma of Patients with PDAC

by Sung-Sik Han, Sang Myung Woo, Jun Hwa Lee, Joon Hee Kang, Sang-Jae Park, Woo Jin Lee, Hyeong Min Park, Jung Won Chun, Su Jung Kim, Hyun Ju Yoo, Kyung-Hee Kim and Soo-Youl Kim

Cancers 2025, 17(18), 2988; https://doi.org/10.3390/cancers17182988 - 12 Sep 2025

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Abstract

Background/Objectives: We recently discovered that tumors rely on blood fatty acids as an energy source for growth. Therefore, we investigated biomarkers in the lipid fractions of plasma from patients with pancreatic ductal adenocarcinoma (PDAC) for the screening diagnosis of PDAC. Methods: [...] Read more.

Background/Objectives: We recently discovered that tumors rely on blood fatty acids as an energy source for growth. Therefore, we investigated biomarkers in the lipid fractions of plasma from patients with pancreatic ductal adenocarcinoma (PDAC) for the screening diagnosis of PDAC. Methods: We screened common fatty acid types in human (normal 99, PDAC 103) and mouse (normal 7, KPC 22) plasma samples using a non-targeted approach. Subsequently, we identified targets in human plasma (set A: normal 68, PC 102) that could distinguish between healthy individuals and patients with cancer. Next, we verified whether the identified targets were useful in a new human set (set B: 96 normal, 78 PC). We combined sets A and B to create set C and further divided it into a training set (7:3 ratio; normal 115, pancreatic cancer 126) and a validation set (normal 49, PC 54). The identified targets were used to train three statistical models (logistic regression (LR), random forest (RF), and support vector machine (SVM) with a radial basis function (RBF) kernel). Results: The comparison of human and mouse plasma identified eight common lipid metabolites. We further identified four platforms containing these metabolites for target analysis: acylcarnitines, phospholipids, fatty acid amides, and sphingolipids. We analyzed the four platforms using sets A, B, and C and found 20 lipids (1 acylcarnitine, 1 sphingolipid, and 18 phospholipids) that met the criterion of AUC ≥ 0.75 in all three sets. Based on an average AUC for LR models with 11 or more phospholipids, the separation performance between healthy individuals and patients with cancer was 0.9207 (sensitivity, 90.74%; specificity, 86.22%; PPV, 87.90%; NPV, 89.42%), and the AUC of the validation set for CA19-9 in the same groups was 0.7354. The addition of CA19-9 to the LR models resulted in a separation performance of 0.9427 (90.74%; 88.01%; 89.32%; 89.61%) for the validation set. Conclusions: We identified 18 candidate fatty acid metabolites that could serve as biological markers in the serum lipid fractions of pancreatic cancer patients and confirmed that all of them decreased in patients. Additionally, we developed an algorithm utilizing these markers, which demonstrated a 25% increase in discriminatory power compared to the AUC value of CA19-9, an FDA-approved biomarker for pancreatic cancer. In summary, we identified candidate metabolites and algorithms that could serve as biomarkers in the lipid fractions of plasma from patients with pancreatic cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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25 pages, 5512 KB

Open AccessArticle

Unraveling the Clinical Landscape of RNA Modification Regulators with Multi-Omics Insights in Pan-Cancer

by Qingman Li, Jingjing Zhang, Zuyi Cao, Jiale Wang, Jiaxing Song and Xianfu Yi

Cancers 2025, 17(16), 2695; https://doi.org/10.3390/cancers17162695 - 19 Aug 2025

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Abstract

Background/Objectives: Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. Methods: We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer [...] Read more.

Background/Objectives: Cancer remains a major global health challenge, with RNA modifications increasingly recognized as key regulators of tumor progression. However, integrated pan-cancer analyses across multiple modification types are limited. Methods: We performed a comprehensive analysis of 170 RNA modification-related genes across 33 cancer types, uncovering diverse expression, mutation, and epigenetic patterns. Results: Key regulators such as IGF2BP3, CFI, and ELF3 showed cancer-specific prognostic significance. We developed an RNA Modification Score (RMS) with strong prognostic performance (AUC up to 0.92), correlating with the tumor stage, immune infiltration, and immunotherapy response. High-risk groups exhibited immune checkpoint dysregulation and enriched M1 macrophages in glioblastoma. Drug screening highlighted oncrasin-72 as a potential therapy. Validation via single-cell/spatial transcriptomics and immunohistochemistry confirmed the spatial localization of critical genes like CFI and ELF3. Conclusions: Our study reveals the multifaceted role of RNA modifications in cancer, providing a translational framework for personalized prognosis and therapy in precision oncology. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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13 pages, 1195 KB

Open AccessArticle

Urinary microRNAs as Prognostic Biomarkers for Predicting the Efficacy of Immune Checkpoint Inhibitors in Patients with Urothelial Carcinoma

by Yosuke Hirasawa, Atsushi Satomura, Mitsuo Okada, Mieko Utsugi, Hiroki Ogura, Tsuyoshi Yanagi, Yuta Nakamori, Masayuki Takehara, Kokichi Murakami, Go Nagao, Takeshi Kashima, Naoya Satake, Yoriko Ando, Motoki Mikami, Mika Mizunuma, Yuki Ichikawa and Yoshio Ohno

Cancers 2025, 17(16), 2640; https://doi.org/10.3390/cancers17162640 - 13 Aug 2025

Cited by 1 | Viewed by 1792

Abstract

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of urothelial carcinoma (UC); however, their efficacy varies among patients. Identifying reliable biomarkers to predict response to ICIs remains challenging. We aimed to explore urinary microRNAs (miRNAs) as potential biomarkers for predicting ICI [...] Read more.

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of urothelial carcinoma (UC); however, their efficacy varies among patients. Identifying reliable biomarkers to predict response to ICIs remains challenging. We aimed to explore urinary microRNAs (miRNAs) as potential biomarkers for predicting ICI efficacy in patients with UC. Methods: We prospectively collected urinary samples from patients with UC before ICI initiation and investigated the predictive value of urinary miRNAs in patients with UC receiving ICIs. The expression levels of these miRNAs in pretreated urine samples were analyzed using next-generation sequencing. The patients were categorized as responders (those with stable disease or better for >6 months) or nonresponders (those who experienced disease progression within 6 months of treatment initiation). Urinary miRNA levels were compared between the groups to assess their potential as predictive biomarkers. Results: Elevated expression of miR-185-5p and miR-425-5p in the responder group was significantly associated with improved overall and progression-free survival in patients with bladder cancer treated with ICIs (p < 0.05). Conversely, higher levels of miR-30a-5p and miR-542-3p in the nonresponder group were correlated with a poorer response to ICIs, suggesting a potential role in immune resistance. Conclusions: miR-185-5p and miR-425-5p can serve as predictive biomarkers of favorable ICI efficacy in bladder cancer, whereas miR-30a-5p and miR-542-3p could be associated with resistance mechanisms. These findings highlight the potential of miRNA-based biomarkers, particularly those found in urine samples, to guide personalized immunotherapeutic strategies for UC treatment. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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27 pages, 1798 KB

Open AccessArticle

Genetic Insights into Breast Cancer in Northeastern Mexico: Unveiling Gene–Environment Interactions and Their Links to Obesity and Metabolic Diseases

by Hugo Leonid Gallardo-Blanco, María de Lourdes Garza-Rodríguez, Diana Cristina Pérez-Ibave, Carlos Horacio Burciaga-Flores, Víctor Michael Salinas-Torres, Moisés González-Escamilla, Rafael Piñeiro-Retif, Ricardo M. Cerda-Flores, Oscar Vidal-Gutiérrez and Celia N. Sanchez-Dominguez

Cancers 2025, 17(6), 982; https://doi.org/10.3390/cancers17060982 - 14 Mar 2025

Cited by 2 | Viewed by 2646

Abstract

Background: Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. Methods: Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP [...] Read more.

Background: Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. Methods: Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP classified as ancestry markers) in 92 confirmed BC cases and 126 unaffected BC women from Northeastern Mexico. The relationship of these 121 SNPs with BC, considering BMI, menopause status, and age as cofactors, was explored using a gene–environment (G × E) interaction multi-locus model. Results: Twelve gene variants were significantly associated with BC: three located in exome (rs3856806 PPARG, rs12792229 MMP8, and rs5218 KCNJ11-ABCC8), and nine in non-coding regions, which are involved in accelerated decay of the mRNA transcripts, regulatory regions, and flanking regions (rs3917542 PON1; rs3750804 and rs3750805 TCF7L2; rs1121980 and rs3751812 FTO; rs12946618 RPTOR; rs2833483 SCAF4; rs11652805 AMZ2P1-GNA13; and rs1800955 SCT-DEAF1-DRD4). Conclusions: This study identified an association between BC and menopause, age (above 45), obesity, and overweight status with gene variants implicated in diabetes mellitus, obesity, insulin resistance, inflammation, and remodeling of the extracellular matrix. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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13 pages, 1832 KB

Open AccessArticle

Absolute Quantification of Nucleotide Variants in Cell-Free DNA via Quantitative NGS: Clinical Application in Non-Small Cell Lung Cancer Patients

by Guillaume Herbreteau, Marie Marcq, Chloé Sauzay, Maxime Carpentier, Elise Pierre-Noël, Elvire Pons-Tostivint, Audrey Vallée, Sandrine Théoleyre, Acya Bizieux, Jaafar Bennouna and Marc G. Denis

Cancers 2025, 17(5), 783; https://doi.org/10.3390/cancers17050783 - 25 Feb 2025

Cited by 1 | Viewed by 1972

Abstract

Background/Objectives: Circulating tumor DNA (ctDNA) analysis is a powerful tool for non-invasive monitoring of tumor burden and treatment response. Reliable quantification methods are critical for the effective use of ctDNA as a tumor biomarker. Digital PCR (dPCR) offers high sensitivity and quantification, [...] Read more.

Background/Objectives: Circulating tumor DNA (ctDNA) analysis is a powerful tool for non-invasive monitoring of tumor burden and treatment response. Reliable quantification methods are critical for the effective use of ctDNA as a tumor biomarker. Digital PCR (dPCR) offers high sensitivity and quantification, but requires the prior knowledge of tumor-specific genomic alterations. Next-generation sequencing (NGS) provides a more comprehensive approach but is semi-quantitative, relying on variant allelic fraction (VAF), which can be influenced by non-tumor cell-free DNA. Methods: We developed a novel quantitative NGS (qNGS) method for absolute quantification of nucleotide variants, utilizing unique molecular identifiers (UMIs) and of quantification standards (QSs), short synthetic DNA sequences modified to include characteristic mutations for unique identification in sequencing data. We evaluated the performance of this method using plasma samples spiked with mutated DNA and plasma pools from cancer patients. We further applied our technique to plasma samples from four non-small cell lung cancer (NSCLC) patients enrolled in the ELUCID trial. Results: Our qNGS approach demonstrated robust linearity and correlation with dPCR in both spiked and patient-derived plasma samples. Notably, the analysis of clinical samples from the ELUCID trial revealed the ability of our method to simultaneously quantify multiple variants in a single plasma sample. Significant differences in ctDNA levels were observed between baseline and post-treatment samples collected after three weeks of front-line therapy. Conclusions: We introduce a novel qNGS method that enables the absolute quantification of ctDNA, independent of non-tumor circulating DNA variations. This technique was applied for the first time to serial samples from NSCLC patients, demonstrating its ability to simultaneously monitor multiple variants, making it a robust and versatile tool for precision oncology. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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Review

Jump to: Research

31 pages, 1757 KB

Open AccessReview

Precision-Engineered CD3 T-Cell Engagers for Solid Tumours: Conditional Activation, Microenvironment Modulation, and Clinical Translation

by Md. Zeyaullah, Abdullah M. AlShahrani, Mohammad Suhail Khan, Md Faruque Ahmad, Abdelrhman A. G. Altijani, Awad Osman Abdalla Mohamed, Hytham Hummad, Ali Mohieldin and S. Rehan Ahmad

Cancers 2026, 18(7), 1088; https://doi.org/10.3390/cancers18071088 - 27 Mar 2026

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Abstract

Background: T-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab > 40% complete remission), yet solid tumour efficacy remains limited (<15% response rates) due to antigen heterogeneity, immunosuppressive microenvironments, and T-cell dysfunction. Systematic molecular engineering, biomarker-driven patient selection, and rational tumour microenvironment [...] Read more.

Background: T-cell-engaging bispecific antibodies (TCEs) have transformed haematological malignancy treatment (blinatumomab > 40% complete remission), yet solid tumour efficacy remains limited (<15% response rates) due to antigen heterogeneity, immunosuppressive microenvironments, and T-cell dysfunction. Systematic molecular engineering, biomarker-driven patient selection, and rational tumour microenvironment modulation are now collectively transforming TCEs from experimental agents into an adaptable platform therapy for solid tumours. Methods: Review of 55 phase I–III trials of CD3-based TCEs in solid tumours, including tarlatamab (DLL3-targeted, small-cell lung cancer) and xaluritamig (STEAP1-targeted, prostate cancer). Analysis of next-generation engineering strategies and resistance mechanisms via genomic and immunohistochemical data. Result: Response rates now approach ~40% in selected settings, marking an inflection point. In extensive-stage small-cell lung cancer, tarlatamab achieved ~40% responses with definitive survival benefit (phase III HR 0.60, 95% CI 0.47–0.77; p < 0.001; median OS 13.6 months). In metastatic castration-resistant prostate cancer, xaluritamig produced ~41% responses in heavily pretreated patients. Step-up dosing reduced severe cytokine release syndrome to <1% (as low as 0.6% with teclistamab), enabling outpatient administration. Neurological adverse events require monitoring but are less frequent than with cellular therapies. Together these results mark a decisive transition from proof-of-concept to clinically validated platform therapy. Discussion: Three resistance mechanisms limit durability: (i) antigen heterogeneity (28–60% of progressors develop antigen-negative subclones); (ii) immunosuppressive microenvironments (stromal barriers, myeloid-derived suppressor cells, hypoxia); (iii) T-cell exhaustion (PD-1/TIM-3/LAG-3 co-expression). Conclusions: Next-generation TCE platforms integrating conditional activation, cytokine payloads, and checkpoint modulation—deployed with biomarker-guided selection and TME-modulating combinations—represent a transformative therapeutic strategy. With tarlatamab’s phase III survival benefit establishing clinical proof-of-concept, and pivotal trials underway for xaluritamig and next-generation agents, TCEs are positioned to become standard-of-care platform therapies in biomarker-defined solid tumours by 2028–2030. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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16 pages, 553 KB

Open AccessReview

The Role of COL6A3 in Tumorigenesis, Metastasis, Diagnosis, and Disease Management

by Joshua J. Lingo, Maggie M. Balas, Philipp E. Scherer and Jason C. Klein

Cancers 2025, 17(21), 3449; https://doi.org/10.3390/cancers17213449 - 28 Oct 2025

Viewed by 1786

Abstract

Collagens comprise a large, diverse family of proteins that are abundantly expressed throughout most tissues. As a main component of the extracellular matrix (ECM), it is becoming increasingly appreciated how vital collagens are to tumor development, progression, and metastasis. COL6A3, which encodes [...] Read more.

Collagens comprise a large, diverse family of proteins that are abundantly expressed throughout most tissues. As a main component of the extracellular matrix (ECM), it is becoming increasingly appreciated how vital collagens are to tumor development, progression, and metastasis. COL6A3, which encodes the alpha 3 chain of type VI collagen, is a unique member of the collagen family that encodes a C-terminal peptide with powerful signaling capabilities, named endotrophin (ETP). Expression of COL6A3 is required for the survival, migration, and invasion of many cancer cell lines, including breast, bladder, liver, and colorectal cancers. ETP, which was originally discovered to be enriched in the adipocytes of mammary tumors, is a powerful oncopeptide that can alter signaling of tumor and stromal cells. ETP has greater signaling potential than the parental COL6A3 as it can induce EMT and promote chemoresistance, metastasis, and stemness in an TGF-β-like manner. ETP can also function independently of TGF-β to recruit endothelial cells and macrophages. In this review, we examine the molecular implications of COL6A3 and ETP expression and their effects on tumor growth, metastasis, and therapeutic response. Finally, we speculate on the potential of serum ETP as a prognostic biomarker in both carcinomas and sarcomas. In summary, COL6A3 and ETP are powerful drivers of tumor growth that have potential as noninvasive diagnostic and prognostic tools for the clinical management of cancer. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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13 pages, 481 KB

Open AccessReview

Whispers in the Lungs: Small Extracellular Vesicles in Lung Cancer and COPD Crosstalk

by Yetemwork Aleka, Fantahun Biadglegne and Ulrich Sack

Cancers 2025, 17(10), 1612; https://doi.org/10.3390/cancers17101612 - 9 May 2025

Viewed by 2267

Abstract

Lung cancer is one of the deadliest forms of cancer. Its prognosis becomes even worse when it co-occurs with other diseases, such as chronic obstructive pulmonary disease (COPD). Both illnesses have numerous shared risk factors, including the use of tobacco smoke, and have [...] Read more.

Lung cancer is one of the deadliest forms of cancer. Its prognosis becomes even worse when it co-occurs with other diseases, such as chronic obstructive pulmonary disease (COPD). Both illnesses have numerous shared risk factors, including the use of tobacco smoke, and have similar underlying mechanisms like long-term inflammation. There are some other less studied but equally important molecules, like small extracellular vesicles (sEVs), that have been shown to mediate effective communication at the cellular level and may affect the progression of a disease or cause resistance to therapies. In sEVs from lung cancer tumors, there are onco-proteins (e.g., tumor initiator EGFR mutations, onco-miR, miR-21), while in sEVs from patients with COPD, there are pro-inflammatory cytokines like IL-6 and TNF-α that enhance airway inflammation. These potential biomarkers of sEVs from chronic lung disease have great value in defense against emerging health problems; however, limitations in sample extraction and analysis are obstacles that hinder clinical enhanced applicability. This review focuses on sEV-derived biomarkers in lung cancer and COPD for diagnostic, prognostic, and therapeutic monitoring purposes. To make these molecules more useful in real-life therapy and determine their signature’s role, further investigation with a high-scale study is necessary. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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22 pages, 1391 KB

Open AccessReview

Liquid Biopsy in HPV-Associated Head and Neck Cancer: A Comprehensive Review

by Federica Maria Parisi, Mario Lentini, Carlos M. Chiesa-Estomba, Miguel Mayo-Yanez, Jerome R. Leichen, Matthew White, Giovanni Giurdanella, Salvatore Cocuzza, Maria Rita Bianco, Nicolas Fakhry and Antonino Maniaci

Cancers 2025, 17(6), 977; https://doi.org/10.3390/cancers17060977 - 13 Mar 2025

Cited by 11 | Viewed by 4951

Abstract

Objectives: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, with HPV-positive cases emerging as a distinct subtype with unique clinical and molecular characteristics. Current diagnostic methods, including tissue biopsy and imaging, face limitations in terms of invasiveness, [...] Read more.

Objectives: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer globally, with HPV-positive cases emerging as a distinct subtype with unique clinical and molecular characteristics. Current diagnostic methods, including tissue biopsy and imaging, face limitations in terms of invasiveness, static disease assessment, and difficulty in distinguishing recurrence from treatment-related changes. This review aimed to assess the potential of liquid biopsy as a minimally invasive tool for the diagnosis, treatment monitoring, and surveillance of HPV-associated HNSCC. Methods: This systematic review analyzed literature from PubMed/MEDLINE, Embase, and Web of Science, focusing on original research and reviews related to liquid biopsy applications in HPV-positive HNSCC. Included studies were evaluated based on the robustness of the study design, clinical relevance, and analytical performance of liquid biopsy technologies. Biomarker types, detection methods, and implementation strategies were assessed to identify advancements and challenges in this field. Results: Liquid biopsy technologies, including circulating HPV DNA, ctDNA, and extracellular vesicles, demonstrated high sensitivity (90–95%) and specificity (>98%) in detecting HPV-positive HNSCC. These methods enabled real-time monitoring of tumor dynamics, early detection of recurrence, and insights into treatment resistance. Longitudinal analysis revealed that biomarker clearance during treatment correlates strongly with patient outcomes. Conclusions: Liquid biopsy is a transformative diagnostic and monitoring tool for HPV-associated HNSCC, offering minimally invasive, real-time insights into tumor biology. While challenges remain in standardization and clinical implementation, ongoing research and technological innovations hold promise for integrating liquid biopsy into personalized cancer care, ultimately improving patient outcomes. Full article

(This article belongs to the Special Issue Advancements in “Cancer Biomarkers” for 2025–2026)

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