A Subset of Mesotheliomas With Improved Survival Occurring in Carriers of BAP1 and Other Germline Mutations

Abstract

Purpose We hypothesized that four criteria could help identify malignant mesotheliomas (MMs) most likely linked to germline mutations of BAP1 or of other genes: family history of MM, BAP1-associated cancers, or multiple malignancies; or age younger than 50 years. Patients and Methods Over the course of 7 years, 79 patients with MM met the four criteria; 22 of the 79 (28%) reported possible asbestos exposure. They were screened for germline BAP1 mutations by Sanger sequencing and by targeted next-generation sequencing (tNGS) for germline mutations in 55 additional cancer-linked genes. Deleterious mutations detected by tNGS were validated by Sanger sequencing. Results Of the 79 patients, 43 (16 probands and 27 relatives) had deleterious germline BAP1 mutations. The median age at diagnosis was 54 years and median survival was 5 years. Among the remaining 36 patients with no BAP1 mutation, median age at diagnosis was 45 years, median survival was 9 years, and 12 had deleterious mutations of additional genes linked to cancer. When compared with patients with MMs in the SEER cohort, median age at diagnosis (72 years), median survival for all MM stages (8 months), and stage I (11 months) were significantly different from the 79 patients with MM in the current study ( P < .0001). Conclusion We provide criteria that help identify a subset of patients with MM who had significantly improved survival. Most of these patients were not aware of asbestos exposure and carried either pathogenic germline mutations of BAP1 or of additional genes linked to cancer, some of which may have targeted-therapy options. These patients and their relatives are susceptible to development of additional cancers; therefore, genetic counseling and cancer screening should be considered.

Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

“…A total of 79 patients met these recruitment criteria. Inherited germline mutations were found in 28 of 50 probands (56%) . Patients with mesothelioma who carried germline mutations experienced a significantly prolonged survival of 5 to ≥10 years, only 28% reported possible asbestos exposure, and the M:F and pleural vs peritoneum ratios were 1:1, underscoring the uniqueness of this subgroup of patients.…”

“…Similar to mesotheliomas caused by environmental exposure, those linked to inherited germline mutations occur at a younger age and with a M:F ratio close to 1:1 . Thus, the combined presence of 1) clusters of mesotheliomas in young individuals, and 2) a M:F ratio of 1:1 is an indication of either environmental exposure, or genetic predisposition, or both.…”

“…The concepts outlined above also apply also to mesothelioma, a cancer caused predominantly by occupational or environmental exposure to asbestos and to other carcinogenic fibers . In addition, the discovery that susceptibility to mesothelioma was transmitted in a Mendelian fashion in some families, and the subsequent discovery of a very high mesothelioma risk in family members who are heterozygous for inherited/germline BAP1 mutations, underscore the role of genetics in mesothelioma . Homozygous germline BAP1 mutations are embryonic lethal in mice, and they are probably also lethal in humans because they have never been described .…”

“…In addition to BAP1 , other tumor suppressor genes have recently been found to cause a hereditary predisposition to mesothelioma—and to other cancers—in several families in the United States and abroad: overall, at least 12% of mesotheliomas occur in carriers of genetic mutations . Most of these heterozygous germline mutations occur in genes that regulate DNA repair, such as MLH1 , MLH3 , TP53 , BRCA2, etc. The penetrance and prevalence of different tumor types vary, depending on the gene involved: for example, approximately 100% of carriers of BAP1 and TP53 germline mutations developed one and often multiple cancers during their lifetime.…”

“…Patients with mesothelioma who carried germline mutations experienced a significantly prolonged survival of 5 to ≥10 years, only 28% reported possible asbestos exposure, and the M:F and pleural vs peritoneum ratios were 1:1, underscoring the uniqueness of this subgroup of patients. Among them, 43 of 79 patients had deleterious germline BAP1 mutations: their median age at diagnosis was 54 years, and the median survival was 5 years . Among the remaining 36 patients with no BAP1 mutation, the median age at diagnosis was 45 years, the median survival was 9 years, and 12 of 36 patients (33%) had deleterious mutations of other tumor suppressors, such as MLH1 (Lynch syndrome), TP53 (Li‐Fraumeni syndrome), and/or mutations in genes that regulate DNA repair or that were previously found mutated in mesothelioma .…”