Poster Presentation 31st Lorne Cancer Conference 2019

Genomic analysis of low-grade serous ovarian cancer reveals unique therapeutic vulnerabilities (#343)

Dane Cheasley 1 2 , Abhimanyu Nigam 1 2 , Magnus Zethoven 1 3 , Simone Rowley 1 , Sally Hunter 2 , Colin House 2 , Dariush Etemadmoghadam 2 , Timothy Semple 4 , Prue Allan 5 , Mark Carey 6 7 , Marta Llaurado 6 , Amy Dawson 6 , Martin Köbel 8 9 , David Huntsman 9 10 , Cécile Lepage 9 , Neville Hacker 11 , David Bowtell 12 , Anna deFazio 13 , Kylie Gorringe 2 , Ian Campbell 1 2
  1. Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
  3. Bioinformatics Consulting Core, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  4. Molecular Genomics Core, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. Department of Clinical Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  6. Department of Obstetrics & Gynaecology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  7. Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  8. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada
  9. Centre de recherche du Centre hospitalier de l’Université de Montréal (CRCHUM) and Institut du cancer de Montréal, Montreal, Québec, Canada
  10. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  11. Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  12. Cancer Genetics and Genomics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  13. Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Sydney, New South Wales, Australia

Low-grade serous ovarian carcinomas (LGSOC) are associated with a poor response to chemotherapy and are largely characterised by RAS pathway activation. However, Ras-pathway activating mutations account for just over half of LGSC cases and there is an unmet need to identify other drugable targets for the non-ras mutated LGSC. Utilising whole-exome and targeted sequencing of the largest LGSOC cohort to date, we identified recurrent somatic mutations in cancer driver genes currently under investigation for their clinical utility, including the deubiquitinase USP9X (14%), along with KRAS (27%), BRAF (11%), NRAS (12%), EIF1AX (7%), NF1 (6%), NF2 (4%), MACF1 (8%), ASH1L (4%) and DOT1L (4%). Genome-wide copy number analysis identified low-level aberrations in LGSOC, with recurrent loss on chromosome arm 1p (38%) unique to LGSOC when compared to high-grade serous ovarian carcinomas. Immunohistochemistry further highlighted a subset of LGSOCs with either CDKN2A deletion (10%) or overexpression (6%). Currently, investigation is underway into the role that USP9X plays in the context of LGSOC; functional analysis of USP9X knockdown is being conducted using a panel of LGSOC patient-derived cell lines and analysis of USP9X knockout cell lines will be commencing soon. Proteomic and transcriptomic interrogation of USP9X knockdown/knockout is also being conducted in order to elucidate the pathway that the gene effects in LGSOC.Further study into genomic findings will help inform clinical decision-making of both Ras-pathway positive and negative LGSOC cases.