Universität zu Köln

Ratner, E. S., Keane, F. K., Lindner, R., Tassi, R. A., Paranjape, T., Glasgow, M., Nallur, S., Deng, Y., Lu, L., Steele, L., Sand, S., Muller, R-U, Bignotti, E., Bellone, S., Boeke, M., Yao, X., Pecorelli, S., Ravaggi, A., Katsaros, D., Zelterman, D., Cristea, M. C., Yu, H., Rutherford, T. J., Weitzel, J. N., Neuhausen, S. L., Schwartz, P. E., Slack, F. J., Santin, A. D. and Weidhaas, J. B. (2012). A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer. Oncogene, 31 (42). S. 4559 - 4567. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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Abstract

Germline variants in the 30 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 = 25) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Ratner, E. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Keane, F. K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lindner, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tassi, R. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Paranjape, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Glasgow, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nallur, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deng, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lu, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Steele, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sand, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Muller, R-U UNSPECIFIED UNSPECIFIED UNSPECIFIED Bignotti, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bellone, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boeke, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yao, X. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pecorelli, S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ravaggi, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Katsaros, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zelterman, D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Cristea, M. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Yu, H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rutherford, T. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weitzel, J. N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhausen, S. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwartz, P. E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Slack, F. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Santin, A. D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Weidhaas, J. B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-481498
DOI:	10.1038/onc.2011.539
Journal or Publication Title:	Oncogene
Volume:	31
Number:	42
Page Range:	S. 4559 - 4567
Date:	2012
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LET-7 MICRORNA-BINDING; 3'-UNTRANSLATED REGION; EXPRESSION; CARBOPLATIN; PACLITAXEL; SURVIVAL; MODELS; MARKER; SITE Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/48149