Original Articles
High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

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Background

Breast cancer 1-associated protein 1 (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 U.S. 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 of 22 biopsies (63.6%). No changes in methylation were observed. IHC revealed normal nuclear BAP1 staining in the eight MM containing wild-type BAP1, whereas 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 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.

Key Words

Sporadic malignant mesothelioma
Somatic BAP1 mutation
multiplex ligation-dependent probe amplification
Malignant mesothelioma
BAP1

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Disclosures: Dr. Carbone was supported by National Institute of Health (grant numbers R01CA106567, P01CA114047, P30CA071789) and by the University of Hawai'i Foundation, which received donations to support mesothelioma research from Honeywell International Inc. Dr. Yang was supported by National Institute of Health (R01CA160715-0A) and received the DoD CDMRP PRCRP Career Development Award. Dr. Yang was supported by the Mesothelioma Applied Research Foundation, the United-4 A Cure, the Hawai'i Community Foundation. Dr. Carbone and Dr. Yang were supported by the V Foundation, the P30CA071789 (UHCC Pathology Shared Resource and UHCC GSR). Dr. Becich and Dr. Pass were supported by the National Mesothelioma Virtual Bank, CDC NIOSH 2U24-OH009077-08. Dr. Carbone has pending patent applications on BAP1, and both Dr. Carbone and Dr. Gazdar provide consultation for mesothelioma expertise and diagnosis. All other authors declare no conflict of interest.