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Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies-Therapeutic Vulnerabilities in
Yue Ma1, Natisha R Field1, Tao Xie1
1Translational Oncology Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, NSW 2007, Australia.
Abstract:
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.
Insights
Mutations in the SWI/SNF complex are common in ovarian cancers like OCCC and SCCOHT. Targeting these SWI/SNF pathway alterations offers new therapeutic strategies for these rare cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The SWI/SNF (Switch/Sucrose Non-Fermentable) complex is frequently altered in human cancers, particularly in rare ovarian cancer subtypes.
- Specific SWI/SNF subunit mutations characterize chemoresistant ovarian clear cell carcinoma (OCCC) and small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT).
- Somatic mutations in ARID1A are prevalent in OCCC (42-67%) and endometrioid ovarian cancer (EnOC), and also found in endometriosis, suggesting a precursor role.
Purpose of the Study:
- To investigate the role of SWI/SNF complex mutations in specific ovarian cancer subtypes.
- To highlight the genetic alterations in ARID1A, SMARCA4, and SMARCA2 in OCCC and SCCOHT.
- To explore potential therapeutic vulnerabilities arising from SWI/SNF pathway dysregulation.
Main Methods:
- Analysis of somatic mutations in SWI/SNF complex members across ovarian cancer histopathological subtypes.
- Examination of ARID1A, ARID1B, SMARCA4, and SMARCA2 mutations and epigenetic silencing.
- Review of existing literature on SWI/SNF mutations in ovarian cancer and endometriosis.
Main Results:
- ARID1A mutations are frequent in OCCC and EnOC, and present in endometriosis.
- SMARCA4 mutations (69-100%) and SMARCA2 silencing (86-100%) are characteristic of SCCOHT.
- Mutations in ARID1B, SMARCA2, SMARCB1, and SMARCC1 are observed less frequently in these ovarian cancers.
Conclusions:
- SWI/SNF complex mutations are key drivers in specific ovarian cancer subtypes, including OCCC and SCCOHT.
- Understanding these genetic alterations provides insights into the pathogenesis of endometriosis-associated ovarian cancers.
- Dysregulation of the SWI/SNF pathway presents therapeutic opportunities, including the use of DNA damage repair inhibitors, epigenetic modifiers, and immune checkpoint blockade.
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