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Genetic Biomarkers in Cancer: From Discovery to Clinical Application
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Genetic Biomarkers in Cancer: From Discovery to Clinical Application

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (5 June 2026) | Viewed by 3209

Editor

Dr. Evangelos Koustas

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Guest Editor
Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece
Interests: cancer; tumor biology; biomarkers; cancer therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genetic biomarkers play a pivotal role in the advancement of precision oncology, enabling early cancer detection, prognosis, and personalized treatment strategies. This review explores the journey of genetic biomarker development, from initial discovery through genomic and transcriptomic profiling to their validation and integration into clinical practice. Key technologies such as next-generation sequencing and bioinformatics tools have accelerated biomarker identification, revealing critical mutations, gene expression patterns, and epigenetic alterations linked to tumorigenesis. Despite significant progress, challenges persist in translating biomarkers from bench to bedside, including issues of reproducibility, cost, and regulatory approval. Notable successes, such as BRCA1/2 in breast cancer and EGFR mutations in non-small-cell lung cancer, highlight the transformative potential of genetic biomarkers in guiding targeted therapies and improving patient outcomes. Continued interdisciplinary collaboration and innovation are essential for expanding the clinical utility of genetic biomarkers across diverse cancer types.

Dr. Evangelos Koustas
Guest Editor

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Keywords

  • cancer
  • tumor biology
  • biomarkers
  • cancer therapy
  • targeted therapy

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Published Papers (3 papers)

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Research

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18 pages, 3410 KB  
Article
Domain-Level Distribution of Pathogenic BRCA1/2 Somatic Mutations Shows No Evidence of Large Subtype-Specific Enrichment in Breast Cancer: A Three-Cohort Analysis Supporting Broad BRCA Testing
by Elif Sertesen Çamöz, Fatih Yıldız, Mutlu Dogan, Yunus Kasım Terzi and Zerrin Yılmaz Çelik
Genes 2026, 17(6), 693; https://doi.org/10.3390/genes17060693 - 13 Jun 2026
Viewed by 395
Abstract
Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic [...] Read more.
Background: Pathogenic BRCA1 and BRCA2 mutations confer a homologous recombination deficiency that underlies PARP inhibitor sensitivity. While BRCA1 mutation carriers more frequently develop triple-negative breast cancer (TNBC) and BRCA2 carriers hormone receptor-positive (HR+) disease, whether the specific protein domain harboring a pathogenic somatic mutation differs systematically between breast cancer subtypes remains uncertain. Apparent domain enrichment in earlier unfiltered analyses may be confounded by missense variants of uncertain significance (VUSs), which lack clinical actionability. Methods: We assembled three independent breast cancer cohorts via cBioPortal: TCGA-BRCA (brca_tcga_pub2015), METABRIC (brca_metabric), and MSK-CHORD (msk_chord_2024). All somatic BRCA1/2 mutations were mapped to UniProt-annotated functional domains and to Rebbeck-defined breast/ovarian cancer cluster regions (BCCR/OCCR). Per ENIGMA/ACMG guidance, pathogenic mutations (nonsense, frameshift, and canonical splice site) were analyzed inferentially, while missense and in-frame variants—predominantly VUSs—were only reported descriptively. Fisher’s exact tests with Benjamini–Hochberg FDR correction were applied across domain × subtype contingencies. Cohort heterogeneity was assessed via Cochran’s Q and I2 statistics; pooled effect estimates were computed using inverse-variance fixed-effects meta-analysis. Results: A total of 394 somatic BRCA1/2 mutations were identified across the three cohorts (BRCA1 n = 166; BRCA2 n = 228), of which 147 (37.3%) met pathogenic criteria. Among 131 pathogenic mutations in HR+/HER2− or TNBC subtypes, 84 (64.1%) occurred in HR+/HER2− disease and 47 (35.9%) in TNBC. Domain-level distributions did not differ significantly between subtypes for any BRCA1 domain (BRCT: TNBC 20.0% vs. HR+ 18.8%, OR = 1.08, 95% CI 0.31–3.78, and FDR-adjusted p = 1.00) or BRCA2 domain (DBD: TNBC 17.6% vs. HR+ 30.8%, OR = 0.48, and FDR-adjusted p = 1.00). Cluster-region analyses (nine Rebbeck BCCR/OCCRs) similarly showed no significant enrichment. Post hoc power analysis indicated that the study could only reliably detect large effects (OR ≥ ~3.0 for the principal BRCT contrast), and formal equivalence testing (TOST) demonstrated equivalence within a prespecified ±20% margin for BRCA1 BRCT (TOST p = 0.031). Heterogeneity across cohorts was minimal (Cochran’s Q = 0.62, I2 = 0.0%). Descriptive analyses of VUSs suggested the apparent enrichment of BRCA1 BRCT-localized missense variants in TNBC (31.8% vs. 17.9% in HR+), but this signal did not extend to pathogenic mutations. Conclusions: Within the statistical power available, our three-cohort analysis shows no evidence of large subtype-specific enrichment of pathogenic BRCA1/2 somatic mutations across protein domains or cluster regions; small to moderate effects cannot be excluded. Notably, the majority (64%) of pathogenic mutations occurred in HR+/HER2− disease, underscoring that BRCA1/2 testing should not be deprioritized in non-TNBC subtypes. The apparent BRCT enrichment observed in earlier unfiltered analyses appears to be driven by VUSs rather than pathogenic variants, highlighting the methodological necessity of pathogenicity filtering for clinically actionable inference. These findings provide cohort-scale supportive evidence for emerging clinical guidelines that recommend broader BRCA1/2 testing across breast cancer subtypes. Full article
(This article belongs to the Special Issue Genetic Biomarkers in Cancer: From Discovery to Clinical Application)
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34 pages, 2111 KB  
Article
In Silico Characterization of Pathogenic ESR2 Coding and UTR Variants as Oncogenic Potential Biomarkers in Hormone-Dependent Cancers
by Hakeemah Al-Nakhle, Zainab Almoerifi, Layan Alharbi, Mashael Alayoubi and Rawan Alharbi
Genes 2025, 16(10), 1144; https://doi.org/10.3390/genes16101144 - 26 Sep 2025
Viewed by 1564
Abstract
Background: The ESR2 gene encodes Estrogen Receptor-β1 (ERβ1), a putative tumor suppressor in hormone-dependent malignancies. Although ERβ biology has been studied extensively at the expression level, the functional impact of nonsynonymous SNPs (nsSNPs) and untranslated-region (UTR) variants in ESR2 remains underexplored. Methods [...] Read more.
Background: The ESR2 gene encodes Estrogen Receptor-β1 (ERβ1), a putative tumor suppressor in hormone-dependent malignancies. Although ERβ biology has been studied extensively at the expression level, the functional impact of nonsynonymous SNPs (nsSNPs) and untranslated-region (UTR) variants in ESR2 remains underexplored. Methods: We retrieved variants from Ensembl and performed an integrative in silico assessment using PredictSNP, I-Mutant, MUpro, HOPE, MutPred2, and CScape for pathogenicity, oncogenicity and structural stability; STRING/KEGG/GO for pathway context; RegulomeDB and polymiRTS for regulatory effects; and cBioPortal for pan-cancer clinical outcomes (breast (BRCA), endometrial (UCEC), and ovarian (OV)). We evaluated effects of nsSNPs on ERβ1 stability, ligand-binding/DNA-binding domains, co-factor recruitment, and post-transcriptional regulation. Results: Across tools, 93 missense nsSNPs were consistently predicted to be deleterious. Notably, several variants were found to destabilize ERβ1, particularly within the ligand-binding domains (LBD) and DNA-binding domains (DBD). Putative oncogenic drivers R198P and D154N showed high CScape scores and very low population frequencies, consistent with pathogenicity. Several substitutions were predicted to impair coactivator binding and disrupt interactions with key transcriptional partners, including JUN, NCOA1, and SP1. At the post-transcriptional level, rs139004885 was predicted to disrupt miRNA binding, while 3′UTR rs4986938 showed strong regulatory potential and comparatively high population frequency; by contrast, most other identified SNPs were rare. Clinically, pan-cancer survival analyses indicated worse overall survival (OS) in BRCA for ESR2-Altered cases (HR ≈ 2.25; q < 0.001), but better OS in UCEC (HR ≈ 0.24; q ≈ 0.014) and OV (HR ≈ 0.29; q < 0.001), highlighting a tumor-type-specific association. Conclusions: This integrative analysis prioritizes high-impact ESR2 variants that likely impair ERβ1 structure and shows context-dependent clinical effects. Despite their generally low frequency (except for rs4986938), prospective validation linking variant class to ERβ expression and survival outcomes is needed to support biomarker development and therapeutic applications. Full article
(This article belongs to the Special Issue Genetic Biomarkers in Cancer: From Discovery to Clinical Application)
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Review

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20 pages, 321 KB  
Review
Microsatellite Phenotype as a Guide for Immunotherapy in Colorectal Cancer: Current Status and Future Perspectives
by Evangelos Koustas, Eleni-Myrto Trifylli, Vaios Oraiopoulos, Michalis V. Karamouzis and Panagiotis Sarantis
Genes 2026, 17(6), 674; https://doi.org/10.3390/genes17060674 - 9 Jun 2026
Viewed by 368
Abstract
The therapeutic armamentarium for colorectal cancer (CRC) has been significantly expanded with the introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs). However, the response to immunotherapy is strongly dependent on microsatellite instability (MSI) status. Tumors with high MSI (MSI-H) and/or mismatch repair deficiency [...] Read more.
The therapeutic armamentarium for colorectal cancer (CRC) has been significantly expanded with the introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs). However, the response to immunotherapy is strongly dependent on microsatellite instability (MSI) status. Tumors with high MSI (MSI-H) and/or mismatch repair deficiency (dMMR) exhibit high tumor mutational burden (TMB), increased neoantigen load, and enhanced immunogenicity, leading to improved responses to ICIs compared with microsatellite-stable (MSS) and/or mismatch repair-proficient (pMMR) tumors. This has changed the treatment landscape of this small subgroup of metastatic CRC (mCRC), including the approval of pembrolizumab as a first-line option. In contrast, most mCRC cases are MSS/pMMR and are resistant or poorly responsive to ICIs, with no established standard immunotherapy strategy. Therefore, current approaches aim to convert these “cold” tumors into “hot,” immunologically active tumors. This review summarizes the distinct molecular basis of MSI phenotypes and their interaction with the tumor microenvironment, and provides relevant insights into current clinical evidence for prognostic and predictive biomarkers beyond MSI status, as well as novel therapeutic strategies to overcome resistance in MSS disease. Full article
(This article belongs to the Special Issue Genetic Biomarkers in Cancer: From Discovery to Clinical Application)
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