{
  "abstract": "A minority of asbestos-exposed individuals develop Pleural mesothelioma (PM), suggesting a role for inherited genetic factors. We performed germline whole-exome sequencing of blood from 127 EPIC participants who developed PM and controls. Rare pathogenic/likely pathogenic variants were assessed in 193 cancer-associated genes and were evaluated for association with PM risk and overall survival. Exome-wide gene-based rare-variant aggregation analyses were performed using SKAT-O and Firth logistic regression. A PM polygenic risk score (PRS) was integrated with PTV status and asbestos exposure. PTVs were enriched in cases and associated with increased PM risk (OR=3.5, 95% CI 1.3-11.2, p-value = 0.01). PTV carriers had improved survival and lower mortality after adjustment for age at diagnosis and sex (HR=0.54, 95% CI 0.32-0.92, p-value = 0.023). PTV carriers had lower PRS values, and among individuals with low asbestos exposure, they were associated with increased PM risk (OR=5.75, 95% CI 1.09-58.2, p-value = 0.023). Gene-based analyses identified four novel loci. Rare variants and polygenic background may jointly influence PM risk, however validation in larger cohorts is warranted.",
  "abstract_shown": true,
  "affiliations": [
    "University of Turin"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 20,
  "authors": [
    {
      "name": "E. J. Herman"
    },
    {
      "name": "C. Debernardi"
    },
    {
      "name": "K. S. Hafeez"
    },
    {
      "name": "S. Devito"
    },
    {
      "name": "T. Y. Lim"
    },
    {
      "name": "A. Russo"
    },
    {
      "name": "A. Allione"
    },
    {
      "name": "E. Weiderpass"
    },
    {
      "name": "A. Agudo"
    },
    {
      "name": "M. L. Vecchia"
    },
    {
      "name": "I. Dianzani"
    },
    {
      "name": "N. C. Castro"
    },
    {
      "name": "V. Simeon"
    },
    {
      "name": "R. Tumino"
    },
    {
      "name": "M. Guevara"
    },
    {
      "name": "L. P. Noray"
    },
    {
      "name": "A. J. Zabala"
    },
    {
      "name": "P. Vineis"
    },
    {
      "name": "E. Casalone"
    },
    {
      "affs": [
        0
      ],
      "name": "G. Matullo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/evmsryaq9djnx.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.29.26364318",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1.full",
  "id": "evmsryaq9djnx",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "genetic and genomic medicine"
    ],
    [
      "openalex",
      "2740|Occupational and environmental lung diseases"
    ]
  ],
  "openalex": "W7216528186",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-29",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/evmsryaq9djnx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:55Z",
      "native_id": "10.64898/2026.09.29.26364318",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:genetic and genomic medicine",
      "subfield": "human-genetics"
    }
  ],
  "title": "Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair",
  "title_text": "Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:55Z",
  "url": "https://research.draconitic.com/paper/evmsryaq9djnx",
  "venue": "medRxiv",
  "versions": []
}