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Science 330 (6001): 228-231

Copyright © 2010 by the American Association for the Advancement of Science

Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma

Siân Jones,1 Tian-Li Wang,2 Ie-Ming Shih,3 Tsui-Lien Mao,4 Kentaro Nakayama,5 Richard Roden,3 Ruth Glas,6 Dennis Slamon,6 Luis A. Diaz, Jr.,1 Bert Vogelstein,1 Kenneth W. Kinzler,1,* Victor E. Velculescu,1,* Nickolas Papadopoulos1,*

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.

1 Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 Department of Gynecology and Obstetrics and Oncology, Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.
3 Department of Pathology, Oncology, Gynecology, and Obstetrics, Johns Hopkins Medical Institutes, Baltimore, MD 21231, USA.
4 Department of Pathology, National Taiwan University College of Medicine, Taipei 100, Taiwan.
5 Department of Gynecology and Obstetrics, Shimane University School of Medicine, Izumo, Shimane 6938501, Japan.
6 Division of Hematology/Oncology, David Geffen School of Medicine at the University of California, Los Angeles, CA 99095, USA.

* To whom correspondence should be addressed. E-mail: npapado1{at}jhmi.edu (N.P.); kinzlke{at}jhmi.edu (K.W.K.); velculescu{at}jhmi.edu (V.E.V.)


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