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

Abstract

Mutations of the tumor-suppressor gene ARID1A result in the loss of protein expression of the BRG-associated factor 250a (BAF250a), a large subunit of transcription-regulating Human SWI/SNF complexes, which have an important role in the control of cell proliferation and tumor suppression. ARID1A mutations are particularly frequent in endometriosis-associated ovarian clear cell and endometrioid carcinomas, and were recently described as a possible key mechanism and early step in the transformation of endometriosis into cancer. Here, we examined the immunohistochemical expression pattern of BAF250a in a tissue microarray including 74 endometriosis and 30 endometrium samples. Ovarian cancer samples (n ¼ 136) served as a control. Epithelial BAF250a expression was assessable in 90/104 (87%) and stromal BAF250a expression in 95/104 (91%) of the endometriosis, and endometrium cases due to lack of adequate tissue in some spots. Complete lack of BAF250a expression was observed in three endometriomas (n ¼ 3/20, 15%) and one deep-infiltrating endometriosis sample (n ¼ 1/22, 5%), but in none of the peritoneal endometriosis (n ¼ 0/16) and eutopic endometrium samples (n ¼ 0/30). A comparison of the mean immunoreactivity scores revealed a significantly lower expression rate of BAF250a in endometriomas compared with normal endometrium (Po0.0005), as well as peritoneal (P ¼ 0.003) and deep-infiltrating endometriosis (P ¼ 0.02). Our data demonstrates that a complete loss of BAF250a expression is observable in some endometriotic lesions, especially in endometriomas. In addition, we report that a partial loss of BAF250a expression is occurring in the form of cell clusters indicating a clonal loss of BAF250a expression in these cells. The loss of expression of the tumor-suppressor protein BAF250a in some endometriomas possibly indicates a risk of malignant transformation in these cases, which could be of importance in the determination of individual treatment strategies. However, its role and value as a prognostic parameter in endometriosis needs to be further studied.

SWI/SNF complex in disorder

“…Zhang et al 22 recently showed that inactivating mutations in ARID1A are a common feature of gastric cancer. Similarly, others previously identified (mostly truncating) somatic mutations in endometriosis-associated ovarian clear cell and endometrioid carcinomas 23 . As the ARID1A and ARID1B proteins are mutually exclusive in SWI/SNF complexes, 24 it seems that a distortion of the balance of these proteins may be the driver of further pathophysiological processes.…”

Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition

“…A dependency of ARID1A -mutated tumors on activation of the PI3K/AKT pathway is further supported by a study in ARID1A-knockout and ARID1A/PTEN-double-knockout mice, where it was observed that only mice with simultaneous loss of ARID1A and PTEN expression developed poorly differentiated ovarian tumors, in contrast to mice with loss of only ARID1A that did not develop ovarian tumors [29]. This indicates that ARID1A-mutated cell clones require a second-hit mutation in order to transform into cancer, which may explain why loss of ARID1A expression was observable in a subset of non-atypical benign endometriosis in one of our previous studies [30]. …”

Endometriosis: where are we and where are we going?

“…Mutations in ARID1A , involved in chromatin remodeling, are present in both clear cell (15-75%) and endometrioid carcinomas (30-55%) (Wiegand et al 2010, Gadducci et al 2014). Associated with malignant transformation, mutations in ARID1A lead to the loss of its product, BAF250a, which correlates strongly with ovarian clear-cell carcinoma and endometrioid carcinoma subtypes, as well as with high-grade endometrial carcinomas (Wiegand et al 2010, Wiegand et al 2011, Ayhan et al 2012, Lowery et al 2012, Samartzis et al 2012, Chene et al 2015). ARID1A mutations and BAF250a loss are also observed in tumors and contiguous atypical endometriosis, but not in distant endometriotic lesions.…”