title: BAP1 mutation is a frequent somatic event in peritoneal malignant mesothelioma.
abstract: BACKGROUND
  Malignant mesothelioma (MM) arises from mesothelial cells that line the pleural, peritoneal and pericardial surfaces. The majority of MMs are pleural and have been associated with asbestos exposure. Previously, pleural MMs have been genetically characterized by the loss of BAP1 (40-60%) as well as loss of NF2 (75%) and CDKN2A (60%). The rare peritoneal form of MM occurs in ~10% cases. With only ~300 cases diagnosed in the US per year, its link to asbestos exposure is not clear and its mutational landscape unknown.
  
  
  METHODS
  We analyzed the somatic mutational landscape of 12 peritoneal MM of epitheloid subtype using copy number analysis (N = 9), whole exome sequencing (N = 7) and targeted sequencing (N = 12).
  
  
  RESULTS
  Peritoneal MM display few copy number alterations, with most samples having less than 10 Mbp total changes, mostly through deletions and no high copy number amplification. Chromosome band 3p21 encoding BAP1 is the most recurrently deleted region (5/9), while, in contrast to pleural MM, NF2 and CDKN2A are not affected. We further identified 87 non-silent mutations across 7 sequenced tumors, with a median of 8 mutated genes per tumor, resulting in a very low mutation rate (median 1.3 10(-6)). BAP1 was the only recurrently mutated gene (N = 3/7). In one additional case, loss of the entire chromosome 3 leaves a non-functional copy of BAP1 carrying a rare nonsense germline variant, thus suggesting a potential genetic predisposition in this patient. Finally, with targeted sequencing of BAP1 in 3 additional cases, we conclude that BAP1 is frequently altered through copy number losses (N = 3/12), mutations (N = 3/12) or both (N = 2/12) sometimes at a sub-clonal level.
  
  
  CONCLUSIONS
  Our findings suggest a major role for BAP1 in peritoneal MM susceptibility and oncogenesis and indicate important molecular differences to pleural MM as well as potential strategies for therapy and prevention.
authors.affiliation: Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany. hakan.alakus@uk-koeln.de.|Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA. hakan.alakus@uk-koeln.de.|Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA. hakan.alakus@uk-koeln.de.
authors.forename: Hakan
authors.initials: H
authors.lastname: Alakus
authors.affiliation: Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA. yostshawn@gmail.com.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Yost
authors.affiliation: Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA. b2woo@ucsd.edu.
authors.forename: Brian
authors.initials: B
authors.lastname: Woo
authors.affiliation: Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA. rfrench@ucsd.edu.
authors.forename: Randall
authors.initials: R
authors.lastname: French
authors.affiliation: Department of Pathology, University of California San Diego, La Jolla, CA, USA. g4lin@ucsd.edu.
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Lin
authors.affiliation: Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. kjepsen@ucsd.edu.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.affiliation: Division of Genome Information Sciences, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA, USA. kafrazer@ucsd.edu.|Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA. kafrazer@ucsd.edu.|Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA. kafrazer@ucsd.edu.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
authors.affiliation: Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA. alowy@ucsd.edu.|Division of Surgical Oncology, Department of Surgery, University of California San Diego, La Jolla, CA, USA. alowy@ucsd.edu.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.affiliation: Moores UCSD Cancer Center, 3855 Health Science Drive, Maildrop 0820, 92093, La Jolla, USA. oharismendy@ucsd.edu.|Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA. oharismendy@ucsd.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Harismendy
mesh_terms: D056915:DNA Copy Number Variations / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008654:Mesothelioma / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D009154:Mutation / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase