SWI/SNF Complexes in Ovarian Cancer: Mechanistic Insights and Therapeutic Implications.

Abstract

Ovarian cancer remains the most lethal gynecologic malignancy in the developed world. Despite the unprecedented progress in understanding the genetics of ovarian cancer, cures remain elusive due to a lack of insight into the mechanisms that can be targeted to develop new therapies. SWI/SNF chromatin remodeling complexes are genetically altered in approximately 20% of all human cancers. SWI/SNF alterations vary in different histologic subtypes of ovarian cancer, with ARID1A mutation occurring in approximately 50% of ovarian clear cell carcinomas. Given the complexity and prevalence of SWI/SNF alterations, ovarian cancer represents a paradigm for investigating the molecular basis and exploring therapeutic strategies for SWI/SNF alterations. This review discusses the recent progress in understanding SWI/SNF alterations in ovarian cancer and specifically focuses on: (i) ARID1A mutation in endometriosis-associated clear cell and endometrioid histologic subtypes of ovarian cancer; (ii) SMARCA4 mutation in small cell carcinoma of the ovary, hypercalcemic type; and (iii) amplification/upregulation of CARM1, a regulator of BAF155, in high-grade serous ovarian cancer. Understanding the molecular underpinning of SWI/SNF alterations in different histologic subtypes of ovarian cancer will provide mechanistic insight into how these alterations contribute to ovarian cancer. Finally, the review discusses how these newly gained insights can be leveraged to develop urgently needed therapeutic strategies in a personalized manner.