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  • A Review of Genetic and Epigenetic Alterations Underlying Hereditary and Sporadic Cancer Susceptibility

  • Sina Saadati,1,* Mehrsa Bazdar,2
    1. University of Tabriz
    2. University of Tabriz


  • Introduction: Cancer remains a leading cause of morbidity and mortality worldwide, with both inherited and sporadic forms posing significant challenges for prevention, diagnosis, and treatment. While pathogenic coding variants in canonical susceptibility genes explain a proportion of hereditary cancer cases, a substantial subset of patients meeting clinical criteria lacks identifiable mutations, suggesting alternative molecular mechanisms. Concurrently, sporadic tumors frequently harbor aberrant epigenetic landscapes that drive oncogenesis. However, the relative contributions of DNA methylation, stochastic epigenetic mutations, and homologous recombination deficiencies, and how these interact with classic genetic alterations, remain incompletely understood. This review synthesizes recent evidence on genetic and epigenetic drivers across breast, colorectal, and ovarian cancers, aiming to clarify the mechanisms that underlie cancer susceptibility and treatment response.
  • Methods: A literature search was conducted across the Nature, Wiley, Springer, and BMC databases for English-language articles published up to June 2025. Keywords included cancer epigenetics, Lynch-like syndrome, BRCA1 methylation, stochastic epigenetic mutation, and homologous recombination deficiency. After screening, four articles were selected for this review. The reviewed methodologies primarily encompassed molecular and bioinformatic techniques to investigate how epigenetic silencing and non-canonical genetic variants influence cancer risk and therapeutic response. These approaches included targeted bisulfite sequencing of tumor suppressor promoters, multigene panel sequencing, and homologous recombination deficiency (HRD) scoring to connect promoter hypermethylation with clinical outcomes in breast, colorectal, and ovarian cancers.
  • Results: Across breast, colorectal, and ovarian cancer studies, a consistent theme emerged: epigenetic alterations in DNA repair and tumor suppressor genes often complement or substitute for coding mutations. In hereditary breast cancer criteria patients lacking pathogenic variants, targeted bisulfite sequencing revealed hypermethylation of promoter CpG sites in EPCAM, RAD51C, FANCI, PALB2, and MSH2, with four individual sites (e.g., cg47630224 in MSH2) strongly associated with elevated risk and validated by high AUC values in independent cohorts. Co-methylation patterns suggested coordinated epigenetic regulation of homologous recombination genes. In Lynch-like syndrome, multigene sequencing uncovered monoallelic variants in MUTYH, FANCM, and XPA, while epigenome-wide profiling identified elevated stochastic epigenetic mutations (SEMs) and hypermethylated epivariations in DNA repair genes, most notably FAN1 and MLH1, in patients lacking classic MMR mutations. These findings imply that both subthreshold genetic variants and epigenetic drift contribute to colorectal cancer susceptibility in LLS. Spontaneous colorectal tumors in rhesus macaques illustrated MLH1 promoter hypermethylation as the principal driver of MMR deficiency, MSI-high status, and high tumor mutational burden, mirroring human sporadic MSI-high CRC. In silico modeling, a mechanism whereby methylation-induced alterations in DNA shape hindered transcription factor binding at the MLH1 promoter, resulting in protein loss without coding mutations. In high-grade ovarian cancer, BRCA1 promoter methylation occurred exclusively in BRCA1-wild-type tumors and paralleled the HRD scores of BRCA-mutants, with both genetic and epigenetic BRCA loss-of-function (LOF) predicting platinum sensitivity and improved survival. Conversely, HRD positivity in BRCA-unrelated, unmethylated tumors did not confer therapeutic benefit, underscoring that HRD assays alone may misclassify patients. Collectively, these studies reveal convergent roles for epigenetic silencing and non-canonical genetic variants in driving cancer risk and therapeutic response yet highlight discrepancies in HRD predictive value and the relative weight of stochastic versus locus-specific epimutations.
  • Conclusion: This synthesis underscores that cancer susceptibility and treatment outcomes are governed by a dynamic interplay between genetic variants and epigenetic modifications in DNA repair pathways. Germline promoter hypermethylation emerges as a bona fide alternative to coding mutations in familial breast and CRC, while BRCA1 methylation refines patient stratification for platinum-based therapy beyond conventional HRD metrics. The discordance between HRD positivity and clinical response in BRCA-unrelated contexts highlights the need for integrated genetic-epigenetic diagnostics. Future research should standardize epimutation screening protocols across cohorts, employ longitudinal sampling to delineate the temporal stability of stochastic epigenetic changes, and expand in vivo models, such as the rhesus macaque CRC system, to validate mechanistic insights. Moreover, prospective trials incorporating combined mutation and methylation panels will be essential to implement personalized risk assessment and optimize therapeutic strategies in hereditary and sporadic cancers.
  • Keywords: Cancer epigenetics, Lynch-like syndrome, BRCA1 methylation, stochastic epigenetic mutation

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