Poster Presentation Australasian RNA Biology and Biotechnology Association 2025 Conference

VIRMA amplification drives oncogenesis and chemoresistance in high-grade serous ovarian cancer (#35)

Jessica Tieng 1 2 , Renhua Song 1 2 , Jemma Couillault 1 2 , Alex Cole 3 , Anna DeFazio AM 2 4 5 , Justin JL Wong 1 2
  1. Epigenetics and RNA Biology Laboratory , Charles Perkins Centre, University of Sydney, Camperdown , NSW, Australia
  2. School of Medical Sciences , Faculty of Medicine and Health, University of Sydney , Camperdown, NSW, Australia
  3. Centenary Institute and Faculty of Medicine and Health, Centenary Institute, Sydney, NSW, Australia
  4. The Westmead Institute for Medical Research, Westmead, NSW, Australia
  5. Department of Gynaecological Oncology , Westmead Hospital, Westmead, NSW, Australia

Background: High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of ovarian cancer. Five-year survival rates remain below 50% and there is an urgent need to develop more effective treatments. An emerging therapeutic target in cancer is N6-methyladenosine (m6A), which is the most prevalent RNA modification. m6A is deposited by specific writers (methyltransferases) composed of catalytic and scaffolding proteins. Whilst the catalytic components of the writer complex have been widely studied, the importance of scaffolding proteins such as Vir-like m6A methyltransferase associated protein (VIRMA) is unknown in HGSOC.

Methods: Analysis of DNA copy number variation, gene expression and survival data were performed on HGSOC datasets from The Cancer Genome Atlas Program (TCGA) (Nature 2011, 474, 609–15) and a previously published cohort by Garsed et al (Nat Genet 2022, 54:1853-64). In vitro validation was performed by generating dox-inducible knockdown and overexpression of VIRMA in HGSOC cell lines. Growth curve, clonogenicity and cell cycle analysis were measured.

Results: Garsed et al. (n=124) and TCGA (n=579) datasets showed VIRMA to have the highest frequency of gene amplification (10% and 15% respectively) out of all the writer components of m6A. VIRMA amplification was also associated with a significant increase in VIRMA expression. In the Garsed et al. cohort, which is enriched for long-term survivors, patients with VIRMA amplification had a worse median survival time of 61 months compared to 142 months in those with diploid status (p=0.041). This worse median survival time was consistent in the TCGA cohort (median survival 40 months vs 58 months, p=0.00098). In the Garsed et al. cohort, high expression of VIRMA was significantly associated with resistance to platinum-based chemotherapy in HGSOC. In vitro validation showed overexpression of VIRMA in HGSOC cell lines increased cell growth and colony formation. Conversely, knockdown of VIRMA impaired cell growth and colony formation and resulted in cell cycle arrest.

Conclusion: Amplification of VIRMA is associated with worse survival in HGSOC patients. VIRMA was shown to increase cell growth and clonogenicity in vitro and may contribute platinum-based chemotherapy resistance. These findings suggest VIRMA is a driver of oncogenesis in HGSOC and may be a potential target for new treatments.