Oncogene - Abstract of article: A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer

Oncogene advance online publication 5 December 2011; doi: 10.1038/onc.2011.539

A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer

E S Ratner^1,14, F K Keane^2,14, R Lindner³, R A Tassi⁴, T Paranjape⁵, M Glasgow², S Nallur⁵, Y Deng⁶, L Lu⁶, L Steele⁷, S Sand⁸, R-U Muller^9,10, E Bignotti⁴, S Bellone¹, M Boeke⁵, X Yao⁶, S Pecorelli⁴, A Ravaggi⁴, D Katsaros¹¹, D Zelterman⁶, M C Cristea¹², H Yu⁶, T J Rutherford¹, J N Weitzel⁸, S L Neuhausen⁷, P E Schwartz¹, F J Slack¹³, A D Santin¹ and J B Weidhaas⁵

1. ¹Department of Gynecological Oncology, Yale University, New Haven, CT, USA
2. ²Yale University School of Medicine, New Haven, CT, USA
3. ³Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany
4. ⁴Division of Gynecologic Oncology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, Brescia, Italy
5. ⁵Department of Therapeutic Radiology, Yale University, New Haven, CT, USA
6. ⁶Department of Epidemiology and Public Health, Yale University, New Haven, CT, USA
7. ⁷Department of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA
8. ⁸Division of Clinical Cancer Genetics, City of Hope, Duarte, CA, USA
9. ⁹Renal Division, Department of Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
10. ¹⁰Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany
11. ¹¹Department of Gynecological Oncology, University of Turin, Turin, Italy
12. ¹²Department of Medical Oncology, City of Hope, Duarte, CA, USA
13. ¹³Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

Correspondence: Dr JB Weidhaas, Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, USA. E-mail: joanne.weidhaas@yale.edu

¹⁴These authors contributed equally to this work.

Received 27 July 2011; Revised 27 September 2011; Accepted 14 October 2011; Published online 5 December 2011.

 

Abstract

Germline variants in the 3′ untranslated region (3′UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3′UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09–2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31–7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3′UTR lesions, and that direct targeting may be a viable future treatment approach.

Oncogene - Abstract of article: A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer