Loss of ARID1A expression and its relationship with PI3K-Akt pathway alterations, TP53 and microsatellite instability in endometrial cancer

Abstract

The switch/sucrose non-fermentable (SWI/SNF) subunit ARID1A (AT-rich interactive domain 1A gene) has been recently postulated as a novel tumor suppressor of gynecologic cancer and one of the driver genes in endometrial carcinogenesis. However, specific relationships with established molecular alterations in endometrioid endometrial cancer (EEC) are currently unknown. We analyzed the expression of ARID1A in 146 endometrial cancers (130 EECs and 16 non-EECs) in relation to alterations in the PI3K-Akt pathway (PTEN expression/KRAS/PIK3CA mutations), TP53 status (TP53 immunohistochemistry) and microsatellite instability. To discriminate between microsatellite instability due to somatic MLH1 promoter hypermethylation or germline mutations in one of the mismatch repair genes (Lynch syndrome), we included a 'Lynch syndrome set'. This set included 21 cases with confirmed germline mutations and 15 cases that were suspected to have a germline mutation. Loss of ARID1A expression was exclusively found in EECs in 31% (40/130) of the EEC cases. No loss of expression of the other subunits of the SWI/SNF complex, SMARCD3 and SMARCB1, was detected. Alterations in the PI3K-Akt pathway were more frequent when ARID1A expression was lost. Loss of ARID1A and mutant-like TP53 expression was nearly mutually exclusive (P ¼ 0.0004). In contrast to Lynch-associated tumors, a strong association between ARID1A loss and sporadic microsatellite instability was found. Only five cases (14%) of the 'Lynch syndrome set' as compared with 24 cases (75%, Po0.0001) of the sporadic microsatellite-unstable tumors showed loss of ARID1A. These observations suggest that ARID1A is a causative gene, instead of a target gene, of microsatellite instability by having a role in epigenetic silencing of the MLH1 gene in endometrial cancer. Keywords: ARID1A; endometrial cancer; Lynch syndrome; microsatellite instability Recent genome-wide sequencing studies have demonstrated that the AT-rich interactive domain 1A (ARID1A) gene is frequently mutated in a wide variety of cancer types 1 including a subset of gynecological cancers. 2 In ovarian cancer, near half of the clear-cell subtype and 30% of the endometrioid subtype showed ARID1A mutations, 3 particularly those that are related to endometriosis. 4,5 In endometrial cancer, mutations in the ARID1A gene have been reported in approximately 30% of both low-and high-grade endometrioid endometrial cancers (EECs) but not in serous endometrial carcinomas. [6][7][8] ARID1A encodes a large nuclear protein involved in chromatin remodeling and interacts with several other proteins, including the core protein

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

“…1C). Consistent with this interpretation, mutual exclusivity of ARID1A and TP53 is commonly observed in ovarian and endometrial malignancies (33,34).…”

Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract

“…The common mutations in mesonephric carcinoma are significantly different from those reported in other cervical and endometrial adenocarcinomas 19,20,28,29 and in the TCGA datasets by accessing the cBioPortal for Cancer Genomics, 30,31 (www.cbioportal.org). For example, KRAS/NRAS mutations are the most common molecular aberration detected in mesonephric carcinoma (81%); in contrast, these mutations are less common in other cervical and endometrial adenocarcinomas (less than 30%), [32][33][34] particularly in the microsatellite stable endometrioid adenocarcinomas and the serous endometrial carcinomas. The chromatin remodeling genes ARID1A, ARID1B, and SMARCA4 are frequently mutated in mesonephric carcinoma (31,19, 12%, respectively; overall 62%).…”

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

“…22 ARID1a was scored as negative, weak positive, or strong positive nuclear staining or as 'clonal loss'. 23 In the final analyses, 'clonal loss' was reclassified as 'loss of expression' as this pattern has been indicated to correspond with ARID1a mutations. 24 The ER, PR, and MLH1 scores for all three tissue microarray tumor cores were determined.…”