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

TL;DR

This study explores the MLH1 −93G>A genetic variant's potential role in breast cancer risk among Azerbaijani women.

Contribution

The study is the first to investigate the MLH1 −93G>A variant in relation to breast cancer in the Azerbaijani population.

Findings

The GA genotype of MLH1 −93G>A was associated with increased breast cancer risk (OR = 1.855).

The A allele was linked to higher risk in the dominant model (OR = 1.747).

Genotype distribution correlated with tumor grade and stage, though not after FDR correction.

Abstract

Background: Breast cancer (BC) is the most common malignancy among women, and genetic predisposition plays a critical role in its development. Among DNA mismatch repair (MMR) genes, MLH1 is essential for maintaining genomic stability, and promoter variants may influence its transcriptional regulation. Variants in MMR genes, including MLH1, have been implicated in cancer susceptibility; however, evidence regarding the promoter polymorphism −93G>A (rs1800734) and its association with BC remains limited and inconsistent across populations. Methods: We conducted a case–control study of 143 breast cancer patients and 161 cancer-free controls of Azerbaijani origin. Genotyping of MLH1 −93G>A was performed using PCR-RFLP and validated by next-generation sequencing (NGS). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under different genetic models by logistic regression, followed by false discovery rate (FDR) correction for multiple testing. Results: The genotype distribution among patients was 25.9% GG, 58.7% GA, and 15.4% AA, compared with 37.9%, 46.6%, and 15.5% in controls. A significant association was observed between the GA genotype and BC risk (OR = 1.855, 95% CI: 1.104–3.085, p = 0.019). In the dominant model (GA + AA vs. GG), carriers of the A allele showed increased breast cancer risk (OR = 1.747, 95% CI: 1.069–2.856, p = 0.026). Genotype distribution was also associated with tumor grade (p = 0.047) and stage (p = 0.013). However, none of the associations remained significant after FDR adjustment. Conclusions: This pilot study provides the first evidence from Azerbaijan suggesting a potential role of the MLH1 −93G>A variant in breast cancer susceptibility. Although the associations were nominal and require validation in larger cohorts, the findings point to a biologically plausible link between MLH1 promoter variation and impaired MMR activity, which may contribute to polygenic breast cancer risk. These preliminary results emphasize the importance of evaluating MMR gene variants in underrepresented populations and support further studies integrating functional assays and broader gene coverage.

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