Inherited Risk of Malignant Pleural Mesothelioma in Familial Clusters

Abstract

Malignant pleural mesothelioma (MPM) is a rare form of cancer which is typically caused by exposure to asbestos. Previous studies have identified some genes passed through the family germline involved in tumor suppression, DNA damage response, and inflammation which lead to an increased risk of developing MPM. We sought to identify additional germline variants or identify previously described variants in a cohort of 24 individuals with familial pattern MPM. In addition, two and three samples of the cohort were taken from a pair of brothers (Family A) and a trio of sisters (Family B), respectively, who were previously diagnosed with MPM. I processed, aligned, and analyzed the whole exome sequences of the cohort for novel germline mutations and any somatic mutations which may occur near those germline mutations. Of the 13,773 germline variants discovered, 1,752 which were both rare and deleterious were discovered representing a foundational list of genes putatively associated with the risk of developing MPM. Variants previously associated with elevated risk of MPM were discovered in the RYR2, PTCH1, and PBRM1 genes of both members of Family A while variants in the BAP1 and LATS2 genes were found in all members of Family B. Several variants, including the BAP1 variant identified in Family B, had corresponding somatic mutations in parallel tumor sample mutation analysis. Several previously undescribed variants were identified, including the GRWD1 gene of both members of Family A. This variant directly interacts with the p53 tumor suppressor protein and was among several genes with identified rare and deleterious variants that associated with the prototypical tumor suppressor protein p53.