title: BAP1 Is Altered by Copy Number Loss, Mutation, and/or Loss of Protein Expression in More Than 70% of Malignant Peritoneal Mesotheliomas.
abstract: Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene (BAP1) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma.
  
  
  
  Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples.
  
  
  
  We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations (p = 0.04), protein expression loss (p = 0.016), or at least one of these alterations (p = 0.007) independently of tumor histological subtype, age, and sex.
  
  
  
  As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Leblay
authors.affiliation: Structural and Functional Genomics Core Facility, University of Lille, Lille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Leprêtre
authors.affiliation: Department of Biopathology, Cancer Center Lyon Leon Berard, Lyon, France; National Cancer Institute, Research Unit 1086, Caen, France.
authors.forename: Nolwenn
authors.initials: N
authors.lastname: Le Stang
authors.affiliation: National Cancer Institute, Research Unit 1213, Lyon, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Gautier-Stein
authors.affiliation: Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; University Hospital of Lyon, Lyon, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Villeneuve
authors.affiliation: Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; Department of Pathology, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Isaac
authors.affiliation: Department of Oncology, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Maillet
authors.affiliation: Department of Biopathology, Cancer Center Lyon Leon Berard, Lyon, France; National Cancer Institute, Research Unit 1086, Caen, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Galateau-Sallé
authors.affiliation: Structural and Functional Genomics Core Facility, University of Lille, Lille, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Villenet
authors.affiliation: Structural and Functional Genomics Core Facility, University of Lille, Lille, France.
authors.forename: Shéhérazade
authors.initials: S
authors.lastname: Sebda
authors.affiliation: Department of Radiology, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Goracci
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.affiliation: Structural and Functional Genomics Core Facility, University of Lille, Lille, France; Sequencing Platform, Research Cancer Institute, Lille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Figeac
authors.affiliation: Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; Department of Surgery, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Glehen
authors.affiliation: Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; Department of Surgery, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: François-Noël
authors.initials: FN
authors.lastname: Gilly
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Foll
authors.affiliation: International Agency for Research on Cancer, Lyon, France. Electronic address: fernandezcuestal@iarc.fr.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.affiliation: Faculty of Medicine, Research Team 3738, Lyon1 University, Oullins, France; French National Network for the Treatment of Rare Peritoneal Surface Malignancies, University Hospital of Lyon and Lyon1 University, Lyon, France; Department of Pathology, University Hospital of Lyon and Lyon1 University, Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Brevet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D056915:DNA Copy Number Variations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C400134:BAP1 protein, human; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: Malignant, BAP1; Mesothelioma; Peritoneal