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Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies—Therapeutic Vulnerabilities in Treatment-Resistant Subtypes

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posted on 2025-05-11, 21:45 authored by Yue Ma, Natisha R. Field, Kristie-Ann Dickson, Deborah J. Marsh, Tao Xie, Sarina Briscas, Emily G. Kokinogoulis, Tali S. Skipper, Amani Alghalayini, Farhana A. Sarker, Nham Tran, Nikola BowdenNikola Bowden
SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42–67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69–100% of SCCOHT cases and SMARCA2 silencing seen 86–100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

History

Journal title

Cancers

Volume

16

Issue

17

Article number

3068

Publisher

MDPI AG

Language

  • en, English

College/Research Centre

College of Health, Medicine and Wellbeing

School

School of Medicine and Public Health

Rights statement

© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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