• Bioinformatics Analysis of Promoter Region Polymorphisms in the BRCA1 Gene among Patients with Metastatic Breast Cancer
  • Majid Mesgar Tehrani,1,* Seyed Sobhan Mousavi,2
    1. Member of the Core Committee of the National Genomics Hub, Shahid Beheshti University of Medical Sciences, Tehran, Iran
    2. Shahid Chamran university


  • Introduction: Breast cancer remains among the most prevalent malignancies worldwide, with over two million new cases and approximately 600,000 deaths recorded in 2020 (1). Regional epidemiology underscores a rising burden: in Iran and East Azerbaijan Province, breast cancer is the most common cancer, with age-standardized incidence rates of 43.02 and 40.72 per 100,000, respectively, and onset a decade earlier than in many developed countries (2, 3). Clinically, breast cancer is heterogeneous, spanning ER-positive, HER2-amplified, and triple-negative (TNBC) subtypes—each with distinct therapeutic implications (4). TNBC, in particular, shows increased incidence among carriers of BRCA1 germline mutations, linking inherited genomic architecture to tumor phenotype and treatment response (4). Against this backdrop, the BRCA1 gene (17q21) is central to DNA damage repair and genomic stability; pathogenic variants confer substantial lifetime risks for breast and ovarian cancers, earlier onset, and more aggressive clinical courses (5–7). In this study, we focused on BRCA1 polymorphisms and their potential clinical significance. We examined their frequencies in public repositories and in our cohort, identified recurrent variants (rs80357446, rs1800062, rs80359874), and considered how inherited variation informs toxicity risk and drug selection, particularly in the era of PARP inhibitors and precision oncology (8–10).
  • Methods: We performed a structured, multi-step analysis integrating public and cohort-level data. First, we queried the National Center for Biotechnology Information (NCBI) databases to retrieve curated information on BRCA1 polymorphisms and related literature, focusing on sequence variation, allelic frequencies, and previously described functional annotations. We then used Megagene software to support in silico analyses, including variant organization, frequency tallies, and metadata harmonization across sources. Our inclusion criteria prioritized variants within coding exons and canonical splice regions of BRCA1, with supplemental review of selected regulatory elements implicated in repair pathway control. Our analytic emphasis remained on observed frequency and distribution patterns, rather than definitive pathogenicity adjudication. For our cohort set, DNA variants were collated from available sequencing outputs; quality control encompassed conventional read-depth, base-quality, and mapping thresholds. Megagene outputs were used to aggregate counts, estimate relative occurrence, and visualize the most recurrent polymorphisms. All steps were designed to be reproducible via NCBI-sourced records and Megagene project files.
  • Results: Across our compiled dataset, three BRCA1 polymorphisms— rs80357446, rs1800062 and rs80359874—emerged as the most frequently occurring. While functional consequences of polymorphisms can vary from neutral to modulatory, our frequency-based ranking highlights these three loci as candidates for deeper functional and clinical investigation. Descriptively, rs80357446 showed the highest relative occurrence, with rs1800062 and rs80359874following; the trio together accounted for a substantive fraction of all observed BRCA1 variation in our set. In keeping with prior observations that not all BRCA1 variants are equivalently disruptive, we note that polymorphisms may exert weak-to-moderate effects that only manifest under specific biological or therapeutic contexts—e.g., in the presence of co-inherited variants or under genotoxic stress from chemotherapy (5, 8, 9).
  • Conclusion: Importantly, our analysis and the existing literature converge on two clinical implications. First, genes play a pivotal role in the occurrence of treatment-related side effects. Germline variation in DNA-repair pathways—including BRCA1—may modulate sensitivity to DNA-damaging chemotherapies and radiation, thereby influencing toxicity profiles. For instance, carriers with repair deficits can experience heightened myelosuppression, mucosal toxicity, or cutaneous reactions at standard doses, especially when co-medications further stress repair capacity (8, 10). While BRCA1 loss is often leveraged therapeutically (e.g., through PARP inhibition), the same biological vulnerability may raise the risk of adverse events in certain contexts, underscoring the value of pre-treatment risk assessment. Second, genetic testing has direct utility in selecting more effective drugs and dosing strategies. In ER-positive disease, HER2-amplified tumors, and particularly TNBC/BRCA1-mutated cancers, germline and tumor testing can identify homologous recombination deficiency signatures that predict benefit from PARP inhibitors and platinum regimens (4, 5, 8). Beyond efficacy, pharmacogenomic awareness supports mitigation of side effects through alternative regimens, dose adjustments, or prophylactic measures. In practice, integrating genetic testing early—both for high-penetrance mutations and common polymorphisms with plausible functional impact—can sharpen therapeutic selection, improve therapeutic index, and guide surveillance for toxicity. In our dataset, the prominence of rs80357446, rs1800062 and rs80359874provides concrete loci for such translational follow-up: functional assays, co-segregation studies, and prospective toxicity monitoring could clarify which carriers warrant modified dosing or enhanced supportive care (5, 8–10).
  • Keywords: BRCA1; breast cancer; polymorphisms; SNPs; hereditary breast cancer;