High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

Abstract

Background BAP1 is a nuclear deubiquitinase that regulates gene expression, transcription, DNA repair, and more. Several findings underscore the apparent “driver” role of BAP1 in malignant mesothelioma (MM). However the reported frequency of somatic BAP1 mutations in MM varies considerably, a discrepancy that appeared related to either methodological or ethnical differences across various studies. Methods To address this discrepancy, we carried out comprehensive genomic and immunohistochemical (IHC) analyses to detect somatic BAP1 gene alterations in 22 frozen MM biopsies from US MM patients. Results By combining Sanger sequencing, Multiplex Ligation-Dependent Probe Amplification, copy number analysis and cDNA sequencing, we found alteration of BAP1 in 14/22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the 8 MM containing wild-type BAP1, while no nuclear staining was detected in the 14 MM biopsies containing tumor cells with mutated BAP1. Thus, IHC results were in agreement with those obtained by genomic analyses. We then extended IHC analysis to an independent cohort of 70 MM biopsies, of which there was insufficient material to perform molecular studies. IHC revealed loss of BAP1 nuclear staining in 47 out of these 70 MM biopsies (67.1%). Conclusions Our findings conclusively establish BAP1 as the most commonly mutated gene in MM, regardless of ethnic background or other clinical characteristics. Our data point to IHC as the most accessible and reliable technique to detect BAP1 status in MM biopsies.

The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma

“…[16][17][18][19][20] Integrative analysis of mutations and somatic copy-number alterations has revealed frequent inactivation in CDKN2A, NF2, and BAP1. Moreover, the status of these three genes has significant prognostic implications.…”

“…[26][27][28] Mutations in the nuclear deubiquitinase, BAP1, result in either complete absence of protein expression or cytoplasmic sequestration of BAP1, which can be detected by immunohistochemistry, in 27-67% of pleural mesotheliomas. 18,29,30 In contrast to CDKN2A and NF2 alterations, loss of BAP1 protein expression portends improved prognosis for patients with pleural mesothelioma. 30,31 Analogous to pleural mesotheliomas, homozygous CDKN2A deletions are also present in peritoneal mesotheliomas and confer an unfavorable outcome after CRS and HIPEC.…”

Mesothelioma families without inheritance of a BAP1 predisposing mutation

“…The majority are benign polymorphisms (SNPs) or variants of unknown significance (VUS) [4,5,23]. Those of pathogenic significance have been described in association with BAP1-TPDS malignancies [4,21,[24][25][26][27][28]. On the other hand, somatic mutations of BAP1 are a frequent event in MM [26,28,29], with a variable rate of occurrence depending on the molecular assay used.…”

Novel systemic therapy against malignant pleural mesothelioma

“…Familial variants of mesothelioma exist as well: for example, two families with strong family history of mesothelioma without an associated history of exposure to asbestos or other mineral fibers were found to have familial mutations in BRCA associated protein 1 (BAP1), a tumor suppressor gene, that either affects the gene's promoter or forms a premature stop codon (16). Somatic mutations of BAP-1 have also been identified in 57-63% of cases (17).…”