Genomic investigation of low grade serous ovarian cancer reveals unique therapeutic vulnerabilities


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Dane Cheasley1,Anna deFazio2,Abhimanyu Nigam1,Martin Kobel3,Kylie Gorringe1,Ian G Campbell1
1Peter MacCallum Cancer Centre,2Australian Ovarian Cancer Study,3University of Calgary

Abstract

Background

Low grade serous ovarian carcinomas (LGSC) are a rare and under-characterised histological subtype of epithelial ovarian tumours, which occur in younger women and are largely chemo-resistant. Somatic RAS-pathway mutations have been described in LGSC by our groups and others. However, RAS-pathway activating mutations only account for about half of LGSC cases. In the emerging era of genome medicine, it is timely to fully characterise the genetic events driving this tumour type. This may influence response to therapy and/or development of drug resistance, and identify novel drugable targets for the non-Ras mutated LGSCs.

Method

We performed whole exome sequencing, genome-wide copy number (CN) analysis, and targeted mutation screening on 57 serous borderline tumours (SBT) and 90 LGSC’s; this study is the largest molecular analysis of LGSC to date. CN aberrations were detected in 61% (35/57) of SBTs, compared to 99% (71/72) of LGSCs. 

Results

Oncogenic RAS/RAF mutations were detected in 82.5% (47/57) of SBTs compared to 53% (38/72) of LGSCs, with concomitant NRAS and EIF1AX mutations detected only in LGSC. Exome and targeted sequencing identified KRAS (25%), BRAF (19%), USP9X (17%), NRAS (13%) and EIF1AX (10%) as the most frequently mutated genes in LGSCs.

USP9X is a ubiquitin specific protease linked to the stability of a diverse range of proteins. As a result of this diversity, USP9X appears quite context-dependent in its function. shRNA knockdown of USP9X resulted in increased proliferation in our LGSC cell lines, suggesting that in USP9X acts as a tumour suppressor in this context. Furthermore, USP9X mutant tumours have a very distinct CN profile compared to the rest of the LGSC cohort

Conclusion

We are currently in the process of investigating the molecular pathway in which USP9X interacts in LGSC.  As there are no clinical molecules that inhibit/activate aberrant USP9X activity, unravelling this pathway will hopefully reveal therapeutically targetable opportunities