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The Effects of Common Genetic Variants in Oncogenes on Ovarian Cancer Survival

Authors' Affiliations: ¹ Gynaecological Cancer Research Laboratory, UCL EGA Institute for Women's Health, University College London, London, United Kingdom; ² Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York; ³ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California; ⁴ Institute of Cancer Epidemiology, Danish Cancer Society; and ⁵ The Juliane Marie Centre, Rigshospitalet, University of Copenhagen, Denmark Cancer Research UK, Copenhagen, Denmark; ⁶ Department of Gynaecology and Obstetrics, Aarhus University Hospital, Skejby, DK-8200, Aarhus, Denmark; ⁷ Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory; and ⁸ Cancer Research UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; and ⁹ University of Southern California, Keck School of Medicine, Los Angeles, California

Requests for reprints: Simon Gayther, Gynaecological Oncology Unit, UCL EGA Hospital Institute for Women's Health, University College London, UK. Phone: 44-0-20-3108-2001; Fax: 44-0-20-3108-2010; E-mail: s.gayther{at}ucl.ac.uk.

Purpose: The 5-year survival rate for invasive epithelial ovarian cancer is <35%. It has been suggested that common, germline genetic variation may influence survival after cancer diagnoses, which might enable the prediction of response to treatment and survival in the clinical setting. The aim of this study was to evaluate associations between common germline genetic variants in the oncogenes BRAF, ERBB2, KRAS, NMI, and PIK3CA, and survival after a diagnosis of epithelial ovarian cancer.

Experimental Design: We evaluated the association between 34 tagging single nucleotide polymorphisms and survival in 1,480 cases of invasive epithelial ovarian cancer cases from three different studies. Cox regression analysis, stratified by study, was used to estimate per rare allele hazard ratios (HR).

Results: The minor allele rs6944385 in BRAF was significantly associated with poor survival [HR, 1.19; 95% confidence intervals (95% CI), 1.02-1.39; P = 0.024]. The association remained after adjusting for prognostic factors (adjusted HR, 1.20; 95 CI, 1.03-1.40; P = 0.018). A haplotype of BRAF was also associated with poor survival (HR, 1.24; 95% CI, 1.02-1.51; P = 0.029) and was more significant after adjustment (HR, 1.44; 95% CI, 1.15-1.81; P = 0.001). We also found evidence of an association between a KRAS haplotype and poor survival in serous subtype (HR, 1.69; 95% CI, 1.21-2.38; P = 0.002), but this was no longer significant after adjustment. Finally, when analyses were restricted to the serous histologic subtype, the rare allele rs10842513 in KRAS, was associated with poor survival (HR, 1.40; 95% CI, 1.10-1.78; P = 0.007).

Conclusion: Common genetic variants in the BRAF and KRAS oncogenes may be important in the prediction of survival in patients with invasive epithelial ovarian cancer.