Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma.
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.
Jones
Siân
S
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Wang
Tian-Li
TL
Shih
Ie-Ming
IeM
Mao
Tsui-Lien
TL
Nakayama
Kentaro
K
Roden
Richard
R
Glas
Ruth
R
Slamon
Dennis
D
Diaz
Luis A
LA
Vogelstein
Bert
B
Kinzler
Kenneth W
KW
Velculescu
Victor E
VE
Papadopoulos
Nickolas
N
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
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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