{
  "abstract": "Background Immune checkpoint inhibitors (ICI) improved survival of patients with non-small cell lung cancer (NSCLC), yet many patients do not respond to treatment. The identification of markers for ICI response remains an unmet clinical need. This study hypothesizes that host genetics influences the response to ICI, contributing to the variability in efficacy among individuals.Methods We conducted a genome-wide association study (GWAS) in patients with NSCLC on 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 the start of ICI therapy. Genomic DNA was genotyped using Axiom Precision Medicine Research Arrays. Raw data were processed with Axiom Analysis Suite, and quality checked with PLINK software. Imputation to the whole genome was done on the Michigan Imputation Server. Association analyses were performed for ORR (logistic regression with PLINK2 software) and survival (Cox proportional hazards model, with GenAbel package in R environment), with appropriate covariates. Variants were annotated for functional significance using SNPnexus and FUMA. Post-GWAS analyses, including colocalization, were performed to explore the function of the identified variants. Their possible role as expression quantitative trait loci was investigated in different databases (GTEx, eQTLGen, TCGA).Results No genome-wide significant associations were found for ORR or PFS, while a locus on chromosome 2 (lead variant: rs111648355) showed near genome-wide significance (p value=6.3×10⁻⁸) for OS. Patients with minor alleles of these variants exhibited significantly worse OS (HR=5.1, 95% CI: 2.9 to 9.2). Functional annotation linked these variants to regulatory effects on genes including MSH2, MSH6, PPP1R21, FBXO11, and STON1. These genes play a role in mismatch repair, endosomal trafficking, or major histocompatibility complex class II regulation, and might influence the response to immunotherapy.Conclusions This study identifies an association between a genomic locus on chromosome 2 and OS in patients with NSCLC treated with ICI. Although these results need 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.",
  "authors": [
    {
      "affiliations": [
        "Institute for Biomedical Technologies, National Research Council, Segrate, MI, Italy"
      ],
      "name": "Martina Esposito"
    },
    {
      "affiliations": [
        "Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Sara Noci"
    },
    {
      "affiliations": [
        "Institute for Biomedical Technologies, National Research Council, Segrate, MI, Italy",
        "Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy"
      ],
      "name": "Francesca Minnai"
    },
    {
      "affiliations": [
        "Institute for Biomedical Technologies, National Research Council, Segrate, MI, Italy"
      ],
      "name": "Tania Camboni"
    },
    {
      "affiliations": [
        "Institute for Biomedical Technologies, National Research Council, Segrate, MI, Italy"
      ],
      "name": "Eleonora Mangano"
    },
    {
      "affiliations": [
        "Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy"
      ],
      "name": "Manuela Gariboldi"
    },
    {
      "affiliations": [
        "Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy",
        "Cancer Genomics and Systems Biology Lab, Department of Medical Biotechnologies, University of Siena, Siena, Italy"
      ],
      "name": "Elisa Frullanti"
    },
    {
      "affiliations": [
        "SC Medical Oncology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore di Milano Policlinico, Milano, Lombardia, Italy"
      ],
      "name": "Claudia Bareggi"
    },
    {
      "affiliations": [
        "Medical Oncology Unit, ASST Ovest Milanese, Legnano, Lombardy, Italy"
      ],
      "name": "Elena Collovà"
    },
    {
      "affiliations": [
        "Medical Oncology Unit, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy"
      ],
      "name": "Serena Girelli"
    },
    {
      "affiliations": [
        "Medical Oncology Unit, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy"
      ],
      "name": "Sheila Piva"
    },
    {
      "affiliations": [
        "Medical Oncology Unit, Fatebenefratelli Hospital, ASST Fatebenefratelli Sacco, Milan, Italy"
      ],
      "name": "Gabriella Farina"
    },
    {
      "affiliations": [
        "Medical Oncology & Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy"
      ],
      "name": "Arianna Pagliaro"
    },
    {
      "affiliations": [
        "Medical Oncology & Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, MI, Italy"
      ],
      "name": "Luca Toschi"
    },
    {
      "affiliations": [
        "SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy"
      ],
      "name": "Luca Sala"
    },
    {
      "affiliations": [
        "SC Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy",
        "Medical Department, Università degli Studi di Milano-Bicocca, Milano, Italy"
      ],
      "name": "Diego Luigi Cortinovis"
    },
    {
      "affiliations": [
        "Institute for Biomedical Technologies, National Research Council, Segrate, MI, Italy"
      ],
      "name": "Francesca Colombo"
    }
  ],
  "title": "Regulatory polymorphisms of MSH6, MSH2, FBXO11, and PPP1R21 genes affect survival of patients with immunotherapy-treated lung cancer",
  "uid": "6efeb728-d14d-580a-a69c-cd4700d443a9"
}