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INTERNATIONAL CONGRESS OF

CancerGenetics

• Polymorphisms in Tumor Suppressor Genes (TP53, BRCA1/2) and Cancer Risk Modulation

• Asal Naghipour-Kordlar,¹ Maryam Radmanfard,^2,*
  1. Faculty of Nursing, Tabriz University of Medical Sciences, Tabriz, Iran
  2. Department of Basic Sciences, Ta.C., Islamic Azad University, Tabriz, Iran
  
  
  
• Introduction: Germline alterations in tumor suppressor genes, particularly BRCA1, BRCA2, and TP53, are central determinants of inherited cancer susceptibility and inform risk-reduction strategies and therapeutic decisions (Cheng et al., 2024). High-throughput functional evaluation and systematic clinical classification of BRCA2 variants have recently advanced the capacity to resolve variants of uncertain significance (VUS), thereby improving diagnostic clarity and clinical decision-making for carriers (Huang et al., 2025). Common polymorphisms in TP53, such as the Arg72Pro variant, have been studied as potential modifiers of cancer risk, producing context-dependent associations that vary by cancer type and population background (Tian et al., 2016). Recent reviews emphasize that translation of variant data into practice requires integration of functional evidence, epidemiologic context, and phenotype correlations to tailor counseling, surveillance, and management (Jakstas et al., 2024; Pastorczak et al., 2024).
• Methods: A narrative review approach was applied. Relevant literature was identified through structured searches in biomedical databases using predefined keywords such as BRCA1, BRCA2, TP53, polymorphisms, variant classification, and cancer risk. Peer-reviewed original studies, functional assays, meta-analyses, and review articles were screened for relevance. Evidence was synthesized thematically to evaluate how BRCA1/2 and TP53 polymorphisms influence cancer susceptibility and to highlight clinical implications.
• Results: BRCA1/2 high-penetrance variants Pathogenic variants in BRCA1 and BRCA2 remain among the most clinically actionable genetic alterations in oncology. Carriers face substantially elevated lifetime risks of breast and ovarian cancer, with additional associations in prostate and pancreatic cancers. These findings underpin the widespread use of BRCA1/2 genetic testing in hereditary cancer screening programs and guide preventive interventions such as risk-reducing surgery and intensified surveillance (Cheng et al., 2024). BRCA2 functional classification Recent large-scale functional assays have redefined the landscape of variants of uncertain significance (VUS) in BRCA2. Experimental pipelines combining multiplexed functional evaluation with standardized clinical classification frameworks have successfully reclassified many ambiguous variants as either benign or pathogenic. This progress reduces diagnostic uncertainty and enhances genetic counseling, with direct implications for patient decision-making and cascade testing in families (Huang et al., 2025). TP53 polymorphisms as risk modifiers Unlike BRCA1/2, common TP53 polymorphisms do not confer high-penetrance risk but may act as risk modifiers that influence cancer susceptibility in interaction with other factors. The Arg72Pro polymorphism has been associated with variable effects across populations and cancer types. Some studies suggest that the Pro allele may impair apoptotic potential, thereby contributing to tumorigenesis, while others report minimal or no effect. Meta-analyses highlight the heterogeneity of findings, indicating that gene–environment interactions and ancestry-specific effects likely modulate these associations (Tian et al., 2016). Translational integration Reviews emphasize that translation of genetic findings into clinical practice requires integrated interpretation frameworks. These must combine functional genomics, epidemiological evidence, and clinical features such as family history, comorbidities, and tumor phenotype. In practice, this means that no single variant should be interpreted in isolation; instead, clinical actionability emerges from the convergence of laboratory evidence, statistical associations, and patient-specific context. Key challenges include underrepresentation of non-European populations, lack of standardized functional pipelines, and limited prospective validation of risk predictions (Jakstas et al., 2024; Pastorczak et al., 2024). Table: Summary of Key Findings on Tumor Suppressor Gene Polymorphisms and Cancer Risk Theme Key Findings Clinical/Translational Implications BRCA1/2 high-penetrance variants Strongly increase lifetime risk of breast, ovarian, prostate, and pancreatic cancers. Guides genetic testing, risk-reducing surgery, enhanced surveillance, and family cascade testing. BRCA2 functional classification High-throughput functional assays reclassify many variants of uncertain significance (VUS) as benign or pathogenic. Reduces diagnostic uncertainty; improves counseling and clinical decision-making. TP53 polymorphisms Common variants (e.g., Arg72Pro) show context-dependent effects on cancer risk, with heterogeneity across populations and tumor types. Acts as risk modifiers rather than deterministic drivers; informs population-specific risk assessment. Translational integration Combining functional genomics, epidemiologic evidence, and clinical features is essential for interpretation. Supports personalized counseling and precision surveillance; highlights need for standardized pipelines and diverse populations. Discussion This review highlights the evolving role of tumor suppressor gene polymorphisms in cancer susceptibility and clinical management. BRCA1/2 pathogenic variants remain highly actionable, directly guiding preventive strategies and therapeutic choices (Cheng et al., 2024). Functional studies of BRCA2 variants have improved classification accuracy, offering clinicians greater certainty in counseling carriers (Huang et al., 2025). By contrast, TP53 polymorphisms are less straightforward. While individual studies suggest associations with certain cancers, meta-analyses reveal heterogeneous results influenced by ancestry, environmental exposure, and population stratification (Tian et al., 2016). These findings suggest TP53 polymorphisms act as risk modifiers rather than deterministic drivers. Clinical translation requires frameworks that integrate experimental validation, epidemiology, and patient-specific information. Recent reviews emphasize the need for broader ancestral representation, standardization of functional pipelines, and prospective validation linking variants to clinical outcomes (Jakstas et al., 2024; Pastorczak et al., 2024).
• Conclusion: Polymorphisms in tumor suppressor genes BRCA1, BRCA2, and TP53 contribute to cancer susceptibility along a spectrum from high-penetrance pathogenic mutations to common variants with modest, context-dependent effects. Advances in functional classification, particularly for BRCA2, are reducing VUS prevalence and strengthening risk prediction. TP53 polymorphisms demonstrate heterogeneous associations that require population-aware interpretation. Integrative approaches that combine genomics, epidemiology, and phenotype data are essential for translating genetic findings into personalized cancer prevention and management strategies.
• Keywords: BRCA1, BRCA2, TP53, Polymorphism, Variant Classification