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

By Siân Jones, Tian-Li Wang, Ie-Ming Shih, T. Mao, K. Nakayama, R. Roden, Ruth Glas, D. Slamon, L. Diaz, Bert Vogelstein and 3 more. Science, 2010

1,258 citations recorded by the source corpus.

Remodeling Gone Awry The identification of genes that are mutated at high frequency in human tumors can provide important clues to the molecular pathways that drive tumor growth, which in turn can potentially lead to more effective therapies. Jones et al. (p. 228, published online 9 September; see the cover) looked for such mutations in ovarian clear cell carcinoma, a rare but particularly lethal form of ovarian cancer. Of 42 tumors examined, 57% were found to harbor inactivating mutations in ARID1A, a gene coding for a subunit of the SWI/SNF chromatin remodeling complex, which functions as a master regulator of transcription factor action and gene expression. Thus, proteins associated with the epigenetic control of gene expression can contribute to the development of human cancer. Genetic analysis of a rare but aggressive form of ovarian cancer implicates a chromatin remodeling defect in disease development. 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.

Subfields: Molecular Biology, Pathology and Forensic Medicine, Reproductive Medicine

View Paper: https://www.semanticscholar.org/paper/38caef910ec66278ab074fbc6463b3e35ca06487

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Citations in the corpus

Cancer epigenetics: from mechanism to therapy. (2012, background): “These efforts have highlighted high-frequency mutations in several SWI/SNF complex members in a range of hematological (Chapman et al., 2011; Morin et al., 2011) and solid malignancies (Gui et al., 2011; Jones et al., 2010; Tan et al., 2011; Varela et al., 2011; Wang et al., 2011).”
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups (2012, neutral): “IntClust1: 74(18) IntClust2: 45(20) IntClust3: 150(19) IntClust4: 164(32) IntClust5: 91(48) IntClust6: 44(14) IntClust7: 109(21) IntClust8: 140(34) IntClust9: 67(24) IntClust10: 96(30)”
The Dualistic Model of Ovarian Carcinogenesis: Revisited, Revised, and Expanded. (2016, background): “Inactivating mutation of ARID1A, a tumor suppressor gene involved in switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling, was detected in up to 50% of clear cell carcinomas and 30% of endometrioid carcinomas.(21,57,58) Moreover, mutation and loss of expression of this gene was found in the”
Lessons from the cancer genome. (2013, neutral): “Similarly, >50%of ovarian clear cell carcinomas carry inactivating mutations in ARID1A, which encodes another BAF protein (Jones et al., 2010; Wiegand et al., 2010).”