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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Apoptosis
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Blotting, Western
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Cell Nucleus / enzymology*
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Cell Nucleus / genetics
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Cell Proliferation
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Chromosomes, Human, Pair 3 / genetics*
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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Female
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Male
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Mesothelioma / genetics*
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Mesothelioma / pathology
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Middle Aged
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Mutation / genetics*
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Pleural Neoplasms / genetics*
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Pleural Neoplasms / pathology
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Polycomb-Group Proteins
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RNA, Messenger / genetics
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / genetics*
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Ubiquitin Thiolesterase / genetics*
Substances
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BAP1 protein, human
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E2F Transcription Factors
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Polycomb-Group Proteins
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RNA, Messenger
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Repressor Proteins
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Tumor Suppressor Proteins
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Ubiquitin Thiolesterase