P20.014.A. Regulatory polymorphisms of MSH6, MSH2 and PPP1R21 genes affect survival of immunotherapy-treated lung cancer patients

Background: Immune checkpoint inhibitors (ICIs) have improved survival in non-small cell lung cancer (NSCLC) patients, however many patients do not respond to treatment. Identifying markers for of ICI response remains an unmet clinical need. This study hypothesizes that host genetics influences the response to ICIs, contributing to the variability in efficacy among individuals. Material and Methods: We conducted a genome-wide association study (GWAS) in patients with NSCLC receiving ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab, to identify germline variants associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) at 24 months after initiation of ICI therapy. Association analyses were performed for ORR (logistic regression using PLINK2 software) and survival (Cox proportional hazards model, using GenAbel package in R environment), with appropriate covariates. Results: We identified a locus on chromosome 2 (comprising more than 250 variants) associated with OS, with the top ten variants having a hazard ratio >1 and P-value = 6.3 x 10-8. The most significant polymorphisms were regulatory variants of genes at the locus, such as MSH2, MSH6, and PPP1R21, which play a role in the mismatch repair and endosomal trafficking, and may influence response to immunotherapy. Conclusions: This study identifies an association between a genomic locus on chromosome 2 and OS in NSCLC patients treated with ICI. Although these results require validation in larger cohorts and functional studies to elucidate the underlying mechanisms, they highlight the potential of germline variants as predictive biomarkers of response to ICI. Grant References: European Union – Next Generation EU (Missione 4 Componente 1) with Italian Ministry of University and Research (MUR) for “Fondo per il Programma Nazionale di Ricerca e Progetti di Rilevante Interesse Nazionale (PRIN)”- PRIN2022 Life Sciences_LS2 Integrative Biology: from Genes and Genomes to Systems – Project ID 2022ARXHR2, CUP B53D23007910006.