Mesothelioma is a rare, aggressive cancer strongly linked to asbestos exposure. In Cappadocia villages, an unusually high incidence has been reported due to environmental asbestos exposure. However, only 50% of the exposed population developed mesothelioma. By examining this population, it was discovered that mesothelioma susceptibility was inherited in an autosomal dominant fashion. However, these cases have not been systematically examined for specific predisposing germline variants.
The BAP1 heterozygous germline mutation is associated familial mesothelioma, longer survival, and less aggressive disease. However, many patients with familial or sporadic mesothelioma remain BAP1WT in the germline, suggesting additional predisposing genes exist. More mesothelioma-associated variants have been discovered (BARD1, BLM) however, none of them has as strong correlation to mesothelioma as BAP1.
The aim of this project is to elucidate the genetic landscape of mesothelioma by integrating data from two populations: (1) Cappadocian patients with unusually high asbestos-associated incidence, and (2) Patients from US, Japan, and Italy, with familial and sporadic mesothelioma. Using WGS and WES, we will identify rare germline variants in select DNA repair and cancer predisposition genes. Cases will be compared to age- and sex-matched healthy controls from UK Biobank to evaluate variant frequency, penetrance, and pathogenicity. Furthermore, to verify the universality of our results, we aim to compare mesothelioma patients registered in the UK biobank with non-cancer controls.
Our objectives are: (1) Discover novel mesothelioma predisposition genes beyond BAP1. (2) Characterize the involved pathways (DNA repair, apoptosis, etc) (3) Assess whether specific variants correlate with clinical features, such as survival.
This work will generate new knowledge on hereditary mesothelioma predisposition and inform future strategies for prevention, surveillance, and therapy.
