Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes

Abstract

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1‐TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1‐TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5‐year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer‐predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer‐predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

“…In addition to BAP1, loss of function mutations in BRCA2, CHEK2, MLH1, MRE11A, PALB2, and POT1 were more frequent among patients with mesothelioma than among controls. Most significantly for patient care, the data suggests that patients with pleural mesothelioma with inherited mutations in these genes have better overall survival following platinum-based chemotherapy compared with patients with no germline mutation, consistent with previous reports based on small numbers of patients (17,38). Cisplatin plus pemetrexed is the current front-line standard of care therapy for pleural mesothelioma (19), and response to chemotherapy is associated with improved survival (39).…”

“…A limitation of this study was that history of asbestos exposure was based on patient report rather than on independent measurement. The interaction of asbestos exposure and genetic predisposition has been established (17), but confirmation in this study was inevitably tentative. A second limitation was that although patients were not selected for clinical characteristics, the NCI cohort included a high proportion of female and young patients, who have better survival from the disease, hence our evaluation of the effect of genotype on overall survival after adjusting for effects of age at diagnosis and gender.…”

“…It has been suggested that BAP1 is involved in homologous recombination DNA repair by cleaving ubiquitin from histone 2A at a critical step in the process (15). Inherited loss-of-function mutations in other genes may also predispose to mesothelioma (16)(17)(18) with lifetime risks expected to be much lower than risks to carriers of mutations in BAP1.…”

Asbestos Air Pollution: Description of a Mesothelioma Cluster Due to Residential Exposure from an Asbestos Cement Factory

“…In addition, in relation to an interaction between genetic risk factors and asbestos in the development of MM [53], two family (consanguineous) groups were present in this cluster: a mother and daughter who both resided for 11 years near Fibronit [47] and a mother and son who resided near the factory for more than 24 years.…”

Circulating Epigenetic Biomarkers in Malignant Pleural Mesothelioma: State of the Art and critical Evaluation

“…Indeed, germline mutations in different genes mainly involved in DNA damage repair confer moderate-to-high genetic risk of MPM development (25). The BAP1-tumor predisposition syndrome is the most studied genetic condition associated with MPM development and is caused by mutations in the BRCA1-associated protein 1 (BAP1) gene (14,(26)(27)(28)(29)(30)(31)(32). This new evidence should be taken into account together with environmental/occupational exposures, as it may lead to a different risk stratification.…”