Abstract 1232: Familial mesothelioma: Beyond BAP1

Abstract

Abstract BAP1 germline mutations are associated with some, but not all, familial malignant mesotheliomas. We sought to identify new genetic risk factors from a large cohort of malignant mesotheliomas cases with a family history of cancers but no germline BAP1 mutation. Whole genome sequencing was performed on 15 samples (14 peripheral blood and 1 MM sample). Promising mutated candidate genes were identified in 12 of 14 BAP1 mutation-negative cases, with 3 different candidate genes mutated in 3 cases, 2 different candidates mutated in 5 cases, and 1 candidate mutated in 4 cases. Candidate genes encoded proteins involved in DNA damage repair, DNA polymerase, DNA and histone methytransferase, as well as mitotic control, helicase, and kinase factors. All mutations were confirmed by Sanger sequencing. Mutations included in/dels predicting frameshifts (4), splice site mutations (6), and missense mutations (14). Notably, in addition to being BAP1 mutation-negative, germline mutations were not identified in any of the genes known to be commonly mutated somatically in malignant mesothelioma, i.e., CDKN2A, NF2, TP53, SETD2, or PBRM1. Sequencing of blood and/or tumor DNA from several available affected members of these families validated co-segregation of mutations in candidate genes with the development of various cancers. Malignant mesothelioma specimens from two members of one family showed somatic loss of heterozygosity of the wild-type allele, indicating biallelic inactivation of the candidate gene—a suspected tumor suppressor locus—in these tumors. Citation Format: Mitchell Cheung, Jill A. Ohar, Suzanne E. Howard, Timothy D. Howard, Mary Hesdorffer, Joseph R. Testa. Familial mesothelioma: Beyond BAP1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1232.