Correlation Between TNRC9 Polymorphisms and BRCA1 Gene Promoter Methylation Status in Palestinian Breast Cancer Patients رسالة ماجستير

Abstract

Breast cancer continues to be a major public health problem worldwide, with genetic and epigenetic factors playing a major role in its pathogenesis. Inactivation of the BRCA1 gene, mainly due to germline mutations, is a major risk factor for breast cancer. However, BRCA1 mutations are less common in the Palestinian population, suggesting that other mechanisms, such as epigenetic alterations, may play a role. This study investigated the association between single nucleotide polymorphisms (SNPs) in the TNRC9 (TOX3) gene (rs3803662, rs8051542 and rs12443621) and BRCA1 promoter methylation in a cohort of Palestinian breast cancer patients. Genotyping was performed by PCR-RFLP, ARMS and sanger sequencing. Our analysis revealed that rs3803662 is significantly associated with increased BRCA1 promoter methylation, suggesting a possible epigenetic mechanism by which this SNP influences BRCA1 silencing and breast cancer risk. This association was particularly pronounced in younger patients (<50 years), who had a higher frequency of the C allele of rs3803662. In contrast, SNPs rs8051542 and rs12443621 showed no significant correlation with BRCA1 methylation, highlighting the specific role of rs3803662 in epigenetic regulation. Linkage disequilibrium (LD) analysis showed minimal non random association between the SNPs, supporting their independent effects on BRCA1 regulation. Haplotype analysis revealed that haplotype 4 (T-C-G) was significantly associated with reduced BRCA1 methylation, suggesting a possible protective effect. However, other haplotypes showed limited or no significant associations. The observed high prevalence of BRCA1 promoter methylation in the Palestinian cohort compared to other VI populations underscores the critical importance of considering population-specific epigenetic landscapes in breast cancer research. Our results suggest that the rs3803662 SNP in TOX3 may contribute to increased BRCA1 promoter methylation and breast cancer susceptibility in the Palestinian population. This study highlights the importance of considering both genetic and epigenetic factors to understand breast cancer risk in this population. Further research is needed to clarify the underlying mechanisms and their clinical implications. A deeper understanding of these mechanisms has the potential to improve risk assessment strategies and support the development of personalized therapeutic interventions for breast cancer