Frequency of germline mutations in cancer susceptibility genes in malignant mesothelioma.

Abstract

8564 Background: Malignant mesothelioma (MM) is thought to be largely due to asbestos exposure, but the prevalence and the causative role of germline cancer susceptibility gene mutations in MM is unknown. Methods: Targeted genomic capture and next generation sequencing of 85 cancer susceptibility genes was performed on DNA extracted from peripheral blood or saliva from 198 patients with pleural, peritoneal, or tunica vaginalis MM presenting to The University of Chicago Mesothelioma Clinic. Results: The patient population fit usual MM demographics: the majority were male (n = 136, 69%), had pleural disease (n = 148, 75%), epithelioid histology (n = 157, 79%), and a history of occupational asbestos exposure (n = 129, 65%). The median age at MM diagnosis was 67 years (range 24-88). We identified 24 pathogenic germline mutations in 13 genes in 23/198 (12%) MM patients. BAP1 mutations were the most common (n = 6, 25%). The remaining were in genes involved in cell cycle and DNA repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (OR 0.23; 95% CI 0.10-0.58), asbestos exposure (OR 0.28; 95% CI 0.11-0.72), and older age (OR 0.95, 95% CI 0.92-0.99) were associated with decreased odds of carrying a germline mutation while having a second cancer diagnosis (OR 3.33; 95% CI 1.22-9.07) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR 1658; 95% CI 199-76224), BRCA2 (OR 5; 95% CI 1.0-14.7), CDKN2A (OR 53; 95% CI 6-249), TMEM127 (OR 88; 95% CI 1.7-1105), and VHL (OR 50; 95% CI 1.1-453) were significantly higher in MM cases than in a non-cancer control population. Tumor sequencing identified mutations in a homologous recombination (HR) DNA repair pathway gene in 52% (n = 29/54), including BAP1 (n = 27), FANCA (n = 2), ATM (n = 1), ATR (n = 1), BRCA2 (n = 1), and CHEK2 (n = 1). Conclusions: A significant proportion of MM patients carry germline pathogenic mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for MM patients and provide rationale for a further investigation of the HR pathway in MM.