Genotyping and molecular dynamic simulations reveal the role of MSH2 DNA repair polymorphisms in lung cancer risk

Lung cancer is the leading cause of cancer-related mortality worldwide and arises from a complex interplay of genetic predispositions and environmental exposures. Epidemiological studies have shown that alterations in key DNA repair genes, such as MSH2, can significantly impact an individual's susceptibility to cancer. In the present study, we focused on <i>MSH2</i> polymorphisms and their potential role in increasing the risk of lung cancer. Our analysis revealed that four out of six polymorphisms showed a strong association with increased risk of lung cancer in individuals carrying heterozygous or mutant genotypes, specifically 118 T > C, 1032 G > A, T > C/-6, and Asn127Ser. Among these, the T > C/-6 polymorphism exhibited the strongest effect, conferring a 13-fold increased risk of lung cancer (Pcorr = 0.0006) in patients with the variant allele. Stratified analysis further indicated subtype-specific associations: in adenocarcinoma (ADCC) patients, the T > C/-6 variant was linked to a 12-fold higher risk (Pcorr = 0.0018), while in squamous cell carcinoma (SQCC) and small-cell lung carcinoma (SCLC) patients, the same polymorphism was associated with a 2-fold (Pcorr = 0.0006) and 16.5-fold increased risk, respectively, particularly in carriers of the combined or mutant genotypes. MDR analysis predicted the best interaction model (MSH2 118 T > C, IVS 1 + 9 G > C, T > C/-6) with a maximum CVC of 10/10 and the least prediction error of 0.355, accompanied by a significant p-value. Furthermore, MD simulations reveal that the Gly322Asp polymorphism in MSH2 induces pronounced structural destabilisation, which may compromise DNA binding and repair efficiency.