title: A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer.
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.
authors.affiliation: Department of Gynecological Oncology, Yale University, New Haven, CT, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Ratner
authors.forename: F K
authors.initials: FK
authors.lastname: Keane
authors.forename: R
authors.initials: R
authors.lastname: Lindner
authors.forename: R A
authors.initials: RA
authors.lastname: Tassi
authors.forename: T
authors.initials: T
authors.lastname: Paranjape
authors.forename: M
authors.initials: M
authors.lastname: Glasgow
authors.forename: S
authors.initials: S
authors.lastname: Nallur
authors.forename: Y
authors.initials: Y
authors.lastname: Deng
authors.forename: L
authors.initials: L
authors.lastname: Lu
authors.forename: L
authors.initials: L
authors.lastname: Steele
authors.forename: S
authors.initials: S
authors.lastname: Sand
authors.forename: R-U
authors.initials: RU
authors.lastname: Muller
authors.forename: E
authors.initials: E
authors.lastname: Bignotti
authors.forename: S
authors.initials: S
authors.lastname: Bellone
authors.forename: M
authors.initials: M
authors.lastname: Boeke
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.forename: S
authors.initials: S
authors.lastname: Pecorelli
authors.forename: A
authors.initials: A
authors.lastname: Ravaggi
authors.forename: D
authors.initials: D
authors.lastname: Katsaros
authors.forename: D
authors.initials: D
authors.lastname: Zelterman
authors.forename: M C
authors.initials: MC
authors.lastname: Cristea
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.forename: T J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: J N
authors.initials: JN
authors.lastname: Weitzel
authors.forename: S L
authors.initials: SL
authors.lastname: Neuhausen
authors.forename: P E
authors.initials: PE
authors.lastname: Schwartz
authors.forename: F J
authors.initials: FJ
authors.lastname: Slack
authors.forename: A D
authors.initials: AD
authors.lastname: Santin
authors.forename: J B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D016190:Carboplatin / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D034622:RNA Interference; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016190:Carboplatin; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D017239:Paclitaxel