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 novel: PPP2R1A encodes a regulatory subunit of serine/threonine phosphatase 2 and ARID1A encodes 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.

Novel MXD4–NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma

“…We identified a nonsense mutation in PRUNE2 that was reported to be a potentially oncogenic30 but not therapeutically targetable mutated genes at that time. No somatic mutation of cancer‐associated genes frequently mutated in epithelial ovarian cancer—such as TP53, 31 KRAS, 32 PIK3CA ,33 and ARID1A 34—was detected.…”

Une forme « ariditaire » du cancer de l’ovaire

“…Peu étudié au niveau moléculaire, il présente moins d'insconcernaient des mutations de gènes impliqués dans l'oncogenèse en géné-ral (CTNNB1 qui code la -caténine, KRAS, PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit ] et TP53) et l'amplification de la région chromosomique 20q13.2 [5,6]. Deux études récentes basées sur le séquençage du génome tumoral décri-vent des mutations somatiques du gène ARID1A (AT-rich interactive domaincontaining protein 1A), qui jouerait ainsi un rôle de gène suppresseur de tumeurs (GST) [7,8]. Le gène ARID1A code tabilité chromosomique que le CAS de haut grade.…”

Loss of ARID1A/BAF250a-expression in endometriosis: a biomarker for risk of carcinogenic transformation?

“…Using whole-exome sequencing, recurrent mutations in ARID1A were recently reported in ovarian clear cell carcinomas and endometrioid ovarian carcinomas by two independent groups. 7,8 Wiegand et al 7 found mutations in ARID1A in 46% of 119 ovarian clear cell carcinomas and 30% of 33 endometrioid ovarian carcinomas but in none of 76 high-grade serous carcinomas. Likewise, Jones et al 8 observed ARID1A-mutations in 57% of 42 ovarian clear cell carcinomas.…”

“…7,8 Wiegand et al 7 found mutations in ARID1A in 46% of 119 ovarian clear cell carcinomas and 30% of 33 endometrioid ovarian carcinomas but in none of 76 high-grade serous carcinomas. Likewise, Jones et al 8 observed ARID1A-mutations in 57% of 42 ovarian clear cell carcinomas. Using immunohistochemistry it was demonstrated that ARID1A mutations result in the loss of the protein BRG-associated factor 250a (BAF250a), which is a large subunit of transcriptionregulating Human SWI/SNF complexes and has an important role in the control of cell proliferation and tumor suppression.…”

“…7 Loss of BAF250a expression could therefore represent a key mechanism and early step in the transformation of endometriosis into cancer. 7,8 The aim of this study is to examine if loss of BAF250a expression is present in benign endometriotic tissue. Therefore, we examined a large cohort of endometriotic lesions as well as a control cohort of ovarian cancer by immunohistochemistry.…”