title: The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.
abstract: Malignant pleural mesotheliomas (MPMs) often show CDKN2A and NF2 inactivation, but other highly recurrent mutations have not been described. To identify additional driver genes, we used an integrated genomic analysis of 53 MPM tumor samples to guide a focused sequencing effort that uncovered somatic inactivating mutations in BAP1 in 23% of MPMs. The BAP1 nuclear deubiquitinase is known to target histones (together with ASXL1 as a Polycomb repressor subunit) and the HCF1 transcriptional co-factor, and we show that BAP1 knockdown in MPM cell lines affects E2F and Polycomb target genes. These findings implicate transcriptional deregulation in the pathogenesis of MPM.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bott
authors.forename: Marie
authors.initials: M
authors.lastname: Brevet
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shimizu
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ito
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Jenette
authors.initials: J
authors.lastname: Creaney
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lake
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Boris
authors.initials: B
authors.lastname: Reva
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Robert
authors.initials: R
authors.lastname: Delsite
authors.forename: Simon
authors.initials: S
authors.lastname: Powell
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Adam
authors.initials: A
authors.lastname: Olshen
authors.forename: Valerie
authors.initials: V
authors.lastname: Rusch
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000201:enzymology* / Q000235:genetics; D049109:Cell Proliferation; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D043222:Ubiquitin Thiolesterase / Q000235:genetics*
chemical_list: C400134:BAP1 protein, human; D050684:E2F Transcription Factors; D063146:Polycomb-Group Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase