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

Oncogene volume 31, pages 4559–4566 (2012)Cite this article

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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.

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Acknowledgements

We thank JL and his group for supplying the cell line-associated chemosensitivity data. We appreciate Greg Wilhoite for performing the TaqMan assay and Josef Herzog for processing samples for the City of Hope. We also appreciate Discovery to Cure at Yale University for samples and Jeff Boyd for supplying the BG1 cell line for targeting studies. ER was supported by a Women's Reproductive Health Research (WRHR) Career Development Program grant (5K12HD047018-08). FS and JW were supported by a Mary Kay Foundation Grant, and an R01 from the NCI (CA131301-01A1). JW also was supported by a K08 grant (CA124484). AS was supported by R01CA122728. SLN is partially supported by the Morris and Horowitz Families Endowed Professorship and NIH R01CA74415. JNW and SS are supported by RC4CA153828 from the National Cancer Institute and the Office of the Director, National Institutes of Health, and also by funding from the Markel Foundation. We also appreciate support from the Shannon Family Foundation, the Segesta family and donations made in memory of Jennifer Casey.

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Author notes

  1. E S Ratner and F K Keane: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Gynecological Oncology, Yale University, New Haven, CT, USA

    E S Ratner, S Bellone, T J Rutherford, P E Schwartz & A D Santin

  2. Yale University School of Medicine, New Haven, CT, USA

    F K Keane & M Glasgow

  3. Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany

    R Lindner

  4. Division of Gynecologic Oncology, Angelo Nocivelli Institute of Molecular Medicine, University of Brescia, Brescia, Italy

    R A Tassi, E Bignotti, S Pecorelli & A Ravaggi

  5. Department of Therapeutic Radiology, Yale University, New Haven, CT, USA

    T Paranjape, S Nallur, M Boeke & J B Weidhaas

  6. Department of Epidemiology and Public Health, Yale University, New Haven, CT, USA

    Y Deng, L Lu, X Yao, D Zelterman & H Yu

  7. D,

    L Steele & S L Neuhausen

  8. epartment of Population Sciences, Beckman Research Institute of the City of Hope, Duarte, CA, USA

    L Steele & S L Neuhausen

  9. Division of Clinical Cancer Genetics, City of Hope, Duarte, CA, USA

    S Sand & J N Weitzel

  10. Renal Division, Department of Medicine and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany

    R-U Muller

  11. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany

    R-U Muller

  12. Department of Gynecological Oncology, University of Turin, Turin, Italy,

    D Katsaros

  13. Department of Medical Oncology, City of Hope, Duarte, CA, USA

    M C Cristea

  14. Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT, USA

    F J Slack

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  1. E S Ratner
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Correspondence to J B Weidhaas.

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Competing interests

JW and FS are co-founders of a company that has licensed IP regarding the KRAS variant from Yale University. They both own stock in this company.

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Ratner, E., Keane, F., Lindner, R. et al. A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer. Oncogene 31, 4559–4566 (2012). https://doi.org/10.1038/onc.2011.539

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