title: High Incidence of Somatic BAP1 alterations in sporadic malignant mesothelioma.
abstract: 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.
authors: *University of Hawai'i Cancer Center, University of Hawai'i, Honolulu, Hawaii; †Hamon Center for Therapeutic Oncology Research and Department of Pathology, UT Southwestern Medical Center, Dallas, Texas; ‡Department of Biomedical Sciences and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California; §Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, Pennsylvania; and ‖Department of Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York.
authors: Masaki
authors: M
authors: Nasu
authors: Mitsuru
authors: M
authors: Emi
authors: Sandra
authors: S
authors: Pastorino
authors: Mika
authors: M
authors: Tanji
authors: Amy
authors: A
authors: Powers
authors: Hugh
authors: H
authors: Luk
authors: Francine
authors: F
authors: Baumann
authors: Yu-An
authors: YA
authors: Zhang
authors: Adi
authors: A
authors: Gazdar
authors: Shreya
authors: S
authors: Kanodia
authors: Maarit
authors: M
authors: Tiirikainen
authors: Erin
authors: E
authors: Flores
authors: Giovanni
authors: G
authors: Gaudino
authors: Michael J
authors: MJ
authors: Becich
authors: Harvey I
authors: HI
authors: Pass
authors: Haining
authors: H
authors: Yang
authors: Michele
authors: M
authors: Carbone
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D015994:Incidence; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation; D009518:New York / Q000453:epidemiology; D010997:Pleural Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D004273:DNA, Neoplasm; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase