ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas

Abstract

ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene in various, predominantly gynecological cancers. We wanted to investigate the distribution of ARID1A in endometrial hyperplasia, carcinomas and metastatic lesions to elucidate the timing of expression loss of its protein ARID1A in the course of endometrial cancer carcinogenesis. In addition, we wanted to assess the relationship between the loss of ARID1A and clinicopathological variables in endometrial cancer in general and the endometrioid subtype in particular. We analyzed a prospectively collected series of 535 primary endometrial cancers, 77 metastatic lesions, as well as 38 retrospectively collected endometrial hyperplasias with evaluable immunohistochemical staining for ARID1A. Fresh frozen tissue was available for mRNA microarray analysis in 122 primary tumors in parallel. Loss of ARID1A protein expression was noted in none of the hyperplasias without atypia, 16% of hyperplasias with atypia, 19% of primary endometrioid tumors and 28% of metastatic lesions. Loss of ARID1A in primary tumor was significantly associated with endometrioid grade 1 or 2 and clearcell histology, diploid tumor cells, younger patient age and deeper myometrial infiltration, but not survival. ARID1A RNA expression was significantly correlated with ARID1A protein loss. Thus, loss of ARID1A appears to be an early event in the carcinogenesis of endometrioid uterine carcinomas and the association with deep myometrial infiltration may suggest an importance for invasiveness.

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

“…The frequency of ARID1A loss in the primary study set (27%) corresponds to other recent publications 6,25 and argues in favor of a tumor suppressor role for ARID1A in endometrial cancer. We did not test the mutation status of ARID1A gene itself, but others have shown a strong correlation between the presence of ARID1A mutations and loss of ARID1A expression, as established by immunohistochemistry.…”

The emerging roles of ARID1A in tumor suppression

“…71,72 In endometrial cancer, Werner et al found frequent ARID1A loss (16%) in complex endometrial hyperplasia with atypia, the precursor lesion of uterine endometrioid carcinoma. 35 Similarly, Mao et al reported that the percentage of complete ARID1A loss increased from 0% in complex atypical hyperplasia, to 25% in low-grade endometrioid carcinoma, to 44% in high-grade endometrioid carcinoma. 73 These findings suggest that loss of ARID1A expression, presumably due to mutation, plays an important role in tumor progression of uterine endometrioid carcinoma.…”

“…In ovarian clear cell carcinoma, no significant differences in survival between ARID1A-negative and ARID1A-positive cases were observed in four different studies. 25,27,28,37 In endometrial cancer, no association between ARID1A loss and disease-specific survival was observed in three studies on endometrioid carcinoma, 34,35,88 or in one study on clear cell carcinoma. 37 In cervical cancer, ARID1A loss was a predictor of reduced overall survival in one study, 39 but not in another.…”

“…Figure 1 summarizes their mutation frequencies in reported human neoplastic diseases. In addition, studies applying immunohistochemistry have also identified frequent loss of ARID1A expression in several additional tumor types ( Table 1) including ovarian endocervical-type mucinous borderline tumor (33%), 29 cervical adenocarcinoma (24~31%), 38 endometrial clear cell carcinoma (21~26%), 33,[35][36][37] endometrial carcinosarcoma (14%), 33 and anaplastic thyroid carcinoma (14%). 33 Comparative genomic hybridization studies have also detected frequent heterozygous deletions involving ARID1A in pancreatic cancer (36~47%), 53,68 breast cancer (13~35%), 55,69 and clear cell renal cell carcinoma (16%).…”

Differences in the ARID‐1 alpha expressions in squamous and adenosquamous carcinomas of uterine cervix

“…Recent studies have shown the loss of ARID1A expression in various, predominantly gynecological cancers. However, the functional and prognostic significance of ARID1A in most tumors has not been fully understood (7)(8)(9)(10)(11).…”