title: Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.
abstract: Ovarian clear cell carcinoma (OCCC) is an aggressive human cancer that is generally resistant to therapy. To explore the genetic origin of OCCC, we determined the exomic sequences of eight tumors after immunoaffinity purification of cancer cells. Through comparative analyses of normal cells from the same patients, we identified four genes that were mutated in at least two tumors. PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well-known oncoprotein, had previously been implicated in OCCC. The other two mutated genes were previously unknown to be involved in OCCC: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2, and ARID1A encodes adenine-thymine (AT)-rich interactive domain-containing protein 1A, which participates in chromatin remodeling. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor-suppressor gene. In a total of 42 OCCCs, 7% had mutations in PPP2R1A and 57% had mutations in ARID1A. These results suggest that aberrant chromatin remodeling contributes to the pathogenesis of OCCC.
authors.affiliation: Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.forename: Tsui-Lien
authors.initials: TL
authors.lastname: Mao
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Richard
authors.initials: R
authors.lastname: Roden
authors.forename: Ruth
authors.initials: R
authors.lastname: Glas
authors.forename: Dennis
authors.initials: D
authors.lastname: Slamon
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000235:genetics*; D000328:Adult; D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D005260:Female; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D054648:Protein Phosphatase 2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D054648:Protein Phosphatase 2; D014157:Transcription Factors; C112476:ARID1A protein, human; C517191:PPP2R1A protein, human; C484760:PIK3CA protein, human
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