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ARID1A in Gynecologic Precancers and Cancers

  • Gynecologic Oncology: Review
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Abstract

The highest frequency of genetic alterations in the tumor suppressor ARID1A occurs in malignancies of the female reproductive tract. The prevalence of ARID1A alterations in gynecologic precancers and cancers is summarized from the literature, and the putative mechanisms of tumor suppressive action examined both in benign/precursor lesions including endometriosis and atypical hyperplasia and in malignancies of the ovary, uterus, cervix and vagina. ARID1A alterations in gynecologic cancers are usually loss-of-function mutations, resulting in diminished or absent protein expression. ARID1A deficiency results in pleiotropic downstream effects related not only to its role in transcriptional regulation as a SWI/SNF complex subunit, but also related to the functions of ARID1A in DNA replication and repair, immune modulation, cell cycle progression, endoplasmic reticulum (ER) stress and oxidative stress. The most promising actionable signaling pathway interactions and therapeutic vulnerabilities of ARID1A mutated cancers are presented with a critical review of the currently available experimental and clinical evidence. The role of ARID1A in response to chemotherapeutic agents, radiation therapy and immunotherapy is also addressed. In summary, the multi-faceted role of ARID1A mutation in precancer and cancer is examined through a clinical lens focused on development of novel preventive and therapeutic interventions for gynecological cancers.

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Funding

This work was supported by DOD Ovarian Cancer Research Program Award W81XWH-16-1-0196 to G.S.H. and NCI P30CA016359.

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Authors and Affiliations

  1. Yale College, Yale University, New Haven, Connecticut, USA

    Jaida E. Morgan & Nishah Jaferi

  2. Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven, Connecticut, USA

    Zainab Shonibare & Gloria S. Huang

  3. Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology, Yale School of Medicine, Yale Cancer Center, Yale University, PO Box 208063, New Haven, CT, 06520-8063, USA

    Gloria S. Huang

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  1. Jaida E. Morgan
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Conflicts of Interest

G.S.H. is the Inventor on U.S. Patent 17102992 for Targeting of ARID1A-Deficient Cancers. G.S.H. has received consulting fees from Glaxo Smith Kline and AstraZeneca, outside of the scope of this work.

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The other authors (J. M., N. J., Z.S.) have no relevant financial or non-financial interests to disclose.

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Morgan, J.E., Jaferi, N., Shonibare, Z. et al. ARID1A in Gynecologic Precancers and Cancers. Reprod. Sci. (2024). https://doi.org/10.1007/s43032-024-01585-w

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