Loss of ARID1A Expression Is an Early Molecular Event in Tumor Progression From Ovarian Endometriotic Cyst to Clear Cell and Endometrioid Carcinoma

Abstract

OBJECTIVES ARID1A is a recently identified tumor suppressor participating in chromatin remodeling. Somatic inactivating mutations of ARID1A and loss of its expression occur most frequently in ovarian clear cell and endometrioid carcinomas and uterine endometrioid carcinomas. Since endometriosis is thought to be a precursor of most ovarian clear cell and endometrioid carcinomas, we undertook an analysis of ARID1A expression of these tumors arising within an endometriotic cyst (endometrioma). MATERIALS/METHODS Our immunohistochemical study set consisted of 47 endometriotic cysts containing clear cell carcinoma in 24 cases, well-differentiated ovarian endometrioid carcinoma in 20 and mixed clear cell and endometrioid carcinoma in 3. RESULTS ARID1A loss was observed in 31 (66%) of 47 carcinomas and therefore these cases were informative for determining the temporal sequence of loss of ARID1A expression in tumor progression. In 16 of the 47 cases, ARID1A immunoreactivity was retained in both the endometriotic cyst and the carcinoma and thus these cases were not informative. All of the 31 informative cases showed loss of ARID1A immunoreactivity in the carcinoma and in the endometriotic cyst epithelium in direct continuity with the carcinoma but not in the cyst epithelium that was not adjacent to the tumor. CONCLUSIONS The findings in this study provide cogent evidence that loss of ARID1A function as shown by loss of expression, presumably due to mutations, is an early molecular event, occurring before malignant transformation, in the development of the majority of ovarian clear cell and endometrioid carcinomas arising in endometriomas.

Inactivating ARID1A Tumor Suppressor Enhances TERT Transcription and Maintains Telomere Length in Cancer Cells

“…Loss of ARID1A has been suggested as an early molecular event that contributes to tumor development. As an example, the absence of ARID1A immunoreactivity is observed not only in ovarian clear cell and endometrioid carcinomas but also in their adjacent endometriotic cyst epithelium that is contiguous to the carcinoma (52). Because endometriotic cyst epithelium is the cell of origin in many ovarian clear cell and endometrioid carcinomas, future studies should address whether the cyst epithelium with ARID1A loss has higher levels of TERT expression and longer telomere than those cysts with ARID1A retention.…”

Microarray pathway analysis indicated that mitogen-activated protein kinase/extracellular signal-regulated kinase and insulin growth factor 1 signaling pathways were inhibited by small interfering RNA against AT‑rich interactive domain 1A in endometrial cancer

“…However, previous studies have primarily provided insight into the function of wild-type ARID1A (9,10). Furthermore, in EC, the majority of previous studies have focused on the loss of ARID1A expression as determined by immunohistochemistry or gene sequencing of mutations (7)(8)(9)(10)(11).…”

“…Furthermore, in EC, the majority of previous studies have focused on the loss of ARID1A expression as determined by immunohistochemistry or gene sequencing of mutations (7)(8)(9)(10)(11). Therefore, it remains unclear which signaling pathways are influenced by ARID1A mutations and which pathway molecules are targeted by ARID1A mutations in EC pathophysiology.…”

Immune Checkpoint Inhibitors in Gynecological Cancers: Update of Literature and Perspectives of Clinical Research

“…Alterations of the phosphatidylinositol 3-kinase (PIK3CA)/AKT/mammalian target of rapamycin (mTOR) pathway have been detected in 15%-75% of CCOCs (42)(43)(44)(45)(46)(47)(48)(49) and preclinical data from non-small cell lung cancer have suggested that activation of this pathway correlates with an increased expression of PD-L1 in tumor cells (50).…”