Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes

// Sally M. Hunter 1 , Michael S. Anglesio 4 , Georgina L. Ryland 1 , Raghwa Sharma 5 , Yoke-Eng Chiew 6, 7 , Simone M. Rowley 1 , Maria A. Doyle 8 , Jason Li 8 , C. Blake Gilks 4, 9 , Phillip Moss 10, 15 , Prue E. Allan 10 , Andrew N. Stephens 11, 12, 13 , David G. Huntsman 4 , Anna deFazio 6, 7 , David D. Bowtell 1, 2, 3 , Australian Ovarian Cancer Study Group 1, 14 , Kylie L. Gorringe 1, 2, 3, * , Ian G. Campbell 1, 2, 3, * 1 Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia 2 The Department of Pathology, University of Melbourne, Parkville, Australia 3 The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia 4 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada 5 Anatomical Pathology, University of Sydney and University of Western Sydney at Westmead Hospital, Westmead, Australia 6 Department of Gynaecological Oncology, Westmead Hospital, Westmead, Australia 7 Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, Australia 8 Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 9 Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, Canada 10 Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia 11 Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia 12 Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia 13 Epworth Research Institute, Epworth HealthCare, Richmond, Victoria, Australia 14 The full Australian Ovarian Cancer Study Group can be found at http://www.aocstudy.org 15 Current address: Saint John Regional Hospital, NB, Canada * These authors have contributed equally to this work Correspondence to: Ian G. Campbell, e-mail: Ian.Campbell@petermac.org Keywords: exome, borderline, serous ovarian tumor, genomics, copy number Received: August 14, 2015      Accepted: August 22, 2015      Published: October 19, 2015 ABSTRACT Low grade serous ovarian tumours are a rare and under-characterised histological subtype of epithelial ovarian tumours, with little known of the molecular drivers and facilitators of tumorigenesis beyond classic oncogenic RAS/RAF mutations. With a move towards targeted therapies due to the chemoresistant nature of this subtype, it is pertinent to more fully characterise the genetic events driving this tumour type, some of which may influence response to therapy and/or development of drug resistance. We performed genome-wide high-resolution genomic copy number analysis (Affymetrix SNP6.0) and mutation hotspot screening ( KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53) to compare a large cohort of ovarian serous borderline tumours (SBTs, n = 57) with low grade serous carcinomas (LGSCs, n = 19). Whole exome sequencing was performed for 13 SBTs, nine LGSCs and one mixed low/high grade carcinoma. Copy number aberrations were detected in 61% (35/57) of SBTs, compared to 100% (19/19) of LGSCs. Oncogenic RAS/RAF/ERBB2 mutations were detected in 82.5% (47/57) of SBTs compared to 63% (12/19) of LGSCs, with NRAS mutations detected only in LGSC. Some copy number aberrations appeared to be enriched in LGSC, most significantly loss of 9p and homozygous deletions of the CDKN2A/2B locus. Exome sequencing identified BRAF, KRAS, NRAS, USP9X and EIF1AX as the most frequently mutated genes. We have identified markers of progression from borderline to LGSC and novel drivers of LGSC. USP9X and EIF1AX have both been linked to regulation of mTOR, suggesting that mTOR inhibitors may be a key companion treatment for targeted therapy trials of MEK and RAF inhibitors.