The role of KRAS rs61764370 in invasive epithelial ovarian cancer: implications for clinical testing.

Abstract

PURPOSE:

An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association.

EXPERIMENTAL DESIGN:

Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data.

RESULTS:

No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52).

CONCLUSIONS:

These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.

• Authors: Paul D P Pharoah, Rachel T Palmieri, Susan J Ramus, Simon A Gayther, Irene L Andrulis, Hoda Anton-Culver, Natalia Antonenkova, Antonis C Antoniou, David Goldgar, BCFR Investigators, Mary S Beattie, Matthias W Beckmann, Michael J Birrer, Natalia Bogdanova, Kelly L Bolton, Wendy Brewster, Angela Brooks-Wilson, Robert Brown, Ralf Butzow, Trinidad Caldes, Maria Adelaide Caligo, Ian Campbell, Jenny Chang-Claude, Y Ann Chen, Linda S Cook, Fergus J Couch, Daniel W Cramer, Julie M Cunningham, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Diana M Eccles, Arif B Ekici, Douglas Easton, EMBRACE Investigators, Peter A Fasching, Anna de Fazio, David A Fenstermacher, James M Flanagan, Brooke L Fridley, Eitan Friedman, Bo Gao, Olga Sinilnikova, GEMO Study Collaborators, Aleksandra Gentry-Maharaj, Andrew K Godwin, Ellen L Goode, Marc T Goodman, Jenny Gross, Thomas V O Hansen, Paul Harnett, Matti Rookus, HEBON Investigators, Tuomas Heikkinen, Rebecca Hein, Claus Høgdall, Estrid Høgdall, Edwin S Iversen, Anna Jakubowska, Sharon E Johnatty, Beth Y Karlan, Noah D Kauff, Stanley B Kaye, Georgia Chenevix-Trench, kConFab Investigators and the Consortium of Investigators of Modifiers of BRCA1/2, Linda E Kelemen, Lambertus A Kiemeney, Susanne Krüger Kjaer, Diether Lambrechts, James P Lapolla, Conxi Lázaro, Nhu D Le, Arto Leminen, Karin Leunen, Douglas A Levine, Yi Lu, Lene Lundvall, Stuart Macgregor, Tamara Marees, Leon F Massuger, John R McLaughlin, Usha Menon, Marco Montagna, Kirsten B Moysich, Steven A Narod, Katherine L Nathanson, Lotte Nedergaard, Roberta B Ness, Heli Nevanlinna, Stefan Nickels, Ana Osorio, Jim Paul, Celeste Leigh Pearce, Catherine M Phelan, Malcolm C Pike, Paolo Radice, Mary Anne Rossing, Joellen M Schildkraut, Thomas A Sellers, Christian F Singer, Honglin Song, Daniel O Stram, Rebecca Sutphen, Annika Lindblom, SWE-BRCA Investigators, Kathryn L Terry, Ya-Yu Tsai, Anne M van Altena, Ignace Vergote, Robert A Vierkant, Allison F Vitonis, Christine Walsh, Shan Wang-Gohrke, Barbara Wappenschmidt, Anna H Wu, Argyrios Ziogas, Andrew Berchuck, Harvey A Risch, Ovarian Cancer Association Consortium
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 11 Pg. 3742-50 (Jun 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21385923 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• 3' Untranslated Regions
• KRAS protein, human
• MicroRNAs
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• 3' Untranslated Regions
• Carcinoma, Ovarian Epithelial
• Disease-Free Survival
• Early Detection of Cancer
• Female
• Genes, BRCA1
• Genetic Predisposition to Disease
• Genotype
• Humans
• MicroRNAs (genetics)
• Neoplasm Invasiveness
• Neoplasms, Glandular and Epithelial (diagnosis, genetics)
• Ovarian Neoplasms (diagnosis, genetics)
• Polymorphism, Single Nucleotide
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Risk
• ras Proteins (genetics)