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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.

SUBMITTER: Pharoah PD

PROVIDER: S-EPMC3107901 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Pharoah Paul D P PD Palmieri Rachel T RT Ramus Susan J SJ Gayther Simon A SA Andrulis Irene L IL Anton-Culver Hoda H Antonenkova Natalia N Antoniou Antonis C AC Goldgar David D Beattie Mary S MS Beckmann Matthias W MW Birrer Michael J MJ Bogdanova Natalia N Bolton Kelly L KL Brewster Wendy W Brooks-Wilson Angela A Brown Robert R Butzow Ralf R Caldes Trinidad T Caligo Maria Adelaide MA Campbell Ian I Chang-Claude Jenny J Chen Y Ann YA Cook Linda S LS Couch Fergus J FJ Cramer Daniel W DW Cunningham Julie M JM Despierre Evelyn E Doherty Jennifer A JA Dörk Thilo T Dürst Matthias M Eccles Diana M DM Ekici Arif B AB Easton Douglas D Fasching Peter A PA de Fazio Anna A Fenstermacher David A DA Flanagan James M JM Fridley Brooke L BL Friedman Eitan E Gao Bo B Sinilnikova Olga O Gentry-Maharaj Aleksandra A Godwin Andrew K AK Goode Ellen L EL Goodman Marc T MT Gross Jenny J Hansen Thomas V O TV Harnett Paul P Rookus Matti M Heikkinen Tuomas T Hein Rebecca R Høgdall Claus C Høgdall Estrid E Iversen Edwin S ES Jakubowska Anna A Johnatty Sharon E SE Karlan Beth Y BY Kauff Noah D ND Kaye Stanley B SB Chenevix-Trench Georgia G Kelemen Linda E LE Kiemeney Lambertus A LA Kjaer Susanne Krüger SK Lambrechts Diether D Lapolla James P JP Lázaro Conxi C Le Nhu D ND Leminen Arto A Leunen Karin K Levine Douglas A DA Lu Yi Y Lundvall Lene L Macgregor Stuart S Marees Tamara T Massuger Leon F LF McLaughlin John R JR Menon Usha U Montagna Marco M Moysich Kirsten B KB Narod Steven A SA Nathanson Katherine L KL Nedergaard Lotte L Ness Roberta B RB Nevanlinna Heli H Nickels Stefan S Osorio Ana A Paul Jim J Pearce Celeste Leigh CL Phelan Catherine M CM Pike Malcolm C MC Radice Paolo P Rossing Mary Anne MA Schildkraut Joellen M JM Sellers Thomas A TA Singer Christian F CF Song Honglin H Stram Daniel O DO Sutphen Rebecca R Lindblom Annika A Terry Kathryn L KL Tsai Ya-Yu YY van Altena Anne M AM Vergote Ignace I Vierkant Robert A RA Vitonis Allison F AF Walsh Christine C Wang-Gohrke Shan S Wappenschmidt Barbara B Wu Anna H AH Ziogas Argyrios A Berchuck Andrew A Risch Harvey A HA

Clinical cancer research : an official journal of the American Association for Cancer Research 20110308 11

<h4>Purpose</h4>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.<h4>Experimental design ...[more]

PMID: 21385923

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Project description:Background:The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods:We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results:Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions:Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality.

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

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

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