Rare Germline Variants and Genetic Susceptibility to Pleural Mesothelioma: Moving Beyond DNA Repair

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.