title: Prevalence of the variant allele rs61764370 T>G in the 3'UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families.
abstract: Recently, a variant allele in the 3'UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, we also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. Importantly, results from the current study suggest that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.
authors.affiliation: Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Erasmus University Medical Center, Rotterdam, The Netherlands. a.hollestelle@erasmusmc.nl
authors.forename: Antoinette
authors.initials: A
authors.lastname: Hollestelle
authors.forename: Cory
authors.initials: C
authors.lastname: Pelletier
authors.forename: Maartje
authors.initials: M
authors.lastname: Hooning
authors.forename: Ellen
authors.initials: E
authors.lastname: Crepin
authors.forename: Mieke
authors.initials: M
authors.lastname: Schutte
authors.forename: Maxime
authors.initials: M
authors.lastname: Look
authors.forename: J Margriet
authors.initials: JM
authors.lastname: Collee
authors.forename: Anja
authors.initials: A
authors.lastname: Nieuwlaat
authors.forename: Lambert C J
authors.initials: LC
authors.lastname: Dorssers
authors.forename: Caroline
authors.initials: C
authors.lastname: Seynaeve
authors.forename: Yurii S
authors.initials: YS
authors.lastname: Aulchenko
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.forename: Ans M W
authors.initials: AM
authors.lastname: van den Ouweland
authors.forename: Joanne B
authors.initials: JB
authors.lastname: Weidhaas
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins