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Title: Molecular profiling of low grade serous ovarian tumours identifies novel candidate driver genes.
Epworth Authors: Stephens, Andrew
Other Authors: Hunter, Sally
Anglesio, Michael
Ryland, Georgina
Sharma, Raghwa
Chiew, Yoke-Eng
Rowley, Simone
Doyle, Maria
Li, Jason
Gilks, C.
Moss, Phillip
Allan, Prue
Huntsman, David
deFazio, Anna
Bowtell, David
Gorringe, Kylie
Campbell, Ian
Keywords: Borderline
Copy Number
Serous Ovarian Tumours
Epithelial Ovarian Tumours
Serous Borderline Tumours
mTOR Inhibitors
RAF Inhibitors
MEK Inhibitors
Low Grade Serous Carcinomas
Homozygous Deletions
Mutated Genes
Exome Sequencing
Epworth Research Institute, Epworth HealthCare, Victoria, Australia.
Cancer Services Clinical Institute, Epworth HealthCare, Victoria, Australia
Obstetrics and Gynaecology Clinical Institute, Epworth HealthCare, Victoria, Australia
Issue Date: Nov-2015
Publisher: Impact Journals
Citation: Oncotarget. 2015 Nov 10;6(35):37663-77.
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.
DOI: 10.18632/oncotarget.5438
PubMed URL:
ISSN: 1949-2553
Journal Title: Oncotarget
Type: Journal Article
Affiliated Organisations: Centre for Cancer Genomics and Predictive Medicine, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Anatomical Pathology, University of Sydney and University of Western Sydney at Westmead Hospital, Westmead, Australia.
Department of Gynaecological Oncology, Westmead Hospital, Westmead, Australia.
Bioinformatics Core Facility, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Genetic Pathology Evaluation Centre, Vancouver General Hospital, Vancouver, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Anatomical Pathology, Peter MacCallum Cancer Centre, East Melbourne, Australia.
Centre for Cancer Research, MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia.
Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, Australia.
The Department of Pathology, University of Melbourne, Parkville, Australia.
The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia.
Australian Ovarian Cancer Study Group (AOCS)
Appears in Collections:Cancer Services
Women's and Children's

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