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Human Molecular Genetics Advance Access originally published online on March 6, 2009
Human Molecular Genetics 2009 18(10):1869-1878; doi:10.1093/hmg/ddp107
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

Lydia Quaye1,{dagger}, Dimitra Dafou1,{dagger}, Susan J. Ramus1,{dagger}, Honglin Song2, Aleksandra Gentry Maharaj1, Maria Notaridou1, Estrid Hogdall4, Susanne Kruger Kjaer4, Lise Christensen5, Claus Hogdall6, Douglas F. Easton3, Ian Jacobs1, Usha Menon1, Paul D.P. Pharoah2 and Simon A. Gayther1,*

1 Gynaecological Oncology Unit, UCL EGA Institute for Women’s Health, University College London, UK 2 CR-UK Department of Oncology 3 Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK 4 Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark 5 Department of Pathology, Bispebjerg Hospital, University of Copenhagen, Denmark 6 The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Denmark

* To whom correspondence should be addressed. Tel: +44 20 7679 9496; Fax: +44 20 7679 9687; Email: s.gayther{at}ucl.ac.uk

Received December 29, 2008; Accepted February 27, 2009

Common germline genetic variation and/or somatic alterations in tumours may be associated with survival in women diagnosed with ovarian cancer. The successful identification of genetic associations relies on a suitable strategy for identifying and testing candidate genes. We used microcell-mediated chromosome transfer approach and expression microarray analysis to identify genes that were associated with neoplastic suppression in ovarian cancer cell lines. Sixty-five tagging single nucleotide polymorphisms (tSNPs) in nine candidate genes were genotyped in ~1700 invasive ovarian cancer cases to look for associations with survival. For two of these genes, loss of heterozygosity (LOH) analysis of tSNPs in 314 ovarian tumours was used to identify associations between somatic gene deletions and survival. We identified significant associations with survival for a tSNP in caspase 5 (CASP5) [hazard ratio (HR) = 1.13 (95% CI: 1.00–1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75–0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71–0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis, both associations in RBBP8 remained significant (P = 0.028 and 0.036). We then genotyped 314 ovarian tumours for several tSNPs in CASP5 and RBBP8 to identify gene deletions by LOH. For RBBP8, 35% of tumours in 101 informative cases showed somatic allelic deletion; LOH of RBBP8 was associated with a significantly worse prognosis [HR = 2.19 (95% CI: 1.36–3.54), P = 0.001]. In summary, a novel in vitro functional approach in ovarian cancer cells has identified RBBP8 as a gene for which both germline genetic variation and somatic alterations in tumours are associated with survival in ovarian cancer patients.

{dagger} These authors contributed equally to the study.


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