Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair
- 1University of Turin
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.
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BibTeX
@misc{herman2026rare,
title = {{Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair}},
author = {E. J. Herman and C. Debernardi and K. S. Hafeez and S. Devito and T. Y. Lim and A. Russo and A. Allione and E. Weiderpass and A. Agudo and M. L. Vecchia and I. Dianzani and N. C. Castro and V. Simeon and R. Tumino and M. Guevara and L. P. Noray and A. J. Zabala and P. Vineis and E. Casalone and G. Matullo},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.26364318},
url = {https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair
AU - E. J. Herman
AU - C. Debernardi
AU - K. S. Hafeez
AU - S. Devito
AU - T. Y. Lim
AU - A. Russo
AU - A. Allione
AU - E. Weiderpass
AU - A. Agudo
AU - M. L. Vecchia
AU - I. Dianzani
AU - N. C. Castro
AU - V. Simeon
AU - R. Tumino
AU - M. Guevara
AU - L. P. Noray
AU - A. J. Zabala
AU - P. Vineis
AU - E. Casalone
AU - G. Matullo
PY - 2026
DA - 2026/09/29
PB - medRxiv
DO - 10.64898/2026.09.29.26364318
UR - https://www.medrxiv.org/content/10.64898/2026.09.29.26364318v1
AB - 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.
ER -