Frequent Mutations of Chromatin Remodeling Gene <i>ARID1A</i> in Ovarian Clear Cell Carcinoma

TLDR

Ovarian clear cell carcinoma is an aggressive, therapy‑resistant cancer in which mutations in PIK3CA and KRAS have been previously implicated. The study aimed to investigate the genetic origins of OCCC by sequencing eight tumors. Exomic sequencing was performed on eight immunoaffinity‑purified tumor samples and compared with matched normal cells. Four genes were recurrently mutated, including PPP2R1A (oncogene) and ARID1A (tumor suppressor), with 7 % and 57 % mutation rates respectively, indicating that aberrant chromatin remodeling drives OCCC pathogenesis.

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.