MLH1 Promoter Variant -93G>A and Breast Cancer Susceptibility: Evidence from Azerbaijan

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Breast cancer (BC) is a leading malignancy in women, with genetic factors significantly influencing susceptibility.
• DNA mismatch repair (MMR) genes, particularly MLH1, are crucial for genomic stability.
• The MLH1 -93G>A promoter polymorphism (rs1800734) has been inconsistently linked to BC risk across diverse populations.

Purpose of the Study:

• To investigate the association between the MLH1 -93G>A polymorphism and breast cancer risk in an Azerbaijani cohort.
• To explore potential correlations between this genetic variant and clinical characteristics of breast cancer.

Main Methods:

• A case-control study involving 143 breast cancer patients and 161 cancer-free controls of Azerbaijani origin.
• Genotyping of the MLH1 -93G>A polymorphism using PCR-RFLP and validated by next-generation sequencing (NGS).
• Statistical analysis using logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs), with false discovery rate (FDR) correction.

Main Results:

• The GA genotype of MLH1 -93G>A showed a nominal association with increased breast cancer risk (OR = 1.855, p=0.019).
• A dominant genetic model (GA + AA vs. GG) indicated a higher risk for A allele carriers (OR = 1.747, p=0.026).
• Nominal associations were observed between genotype distribution and tumor grade and stage, but these did not remain significant after FDR adjustment.

Conclusions:

• This pilot study presents preliminary evidence from Azerbaijan suggesting a potential link between the MLH1 -93G>A variant and breast cancer susceptibility.
• The findings suggest a plausible biological mechanism involving MLH1 promoter variation and impaired DNA repair contributing to polygenic risk.
• Further validation in larger cohorts and functional studies are warranted to elucidate the role of MLH1 variants in underrepresented populations.