Single nucleotide polymorphisms in miRNA binding sites and miRNA genes as breast/ovarian cancer risk modifiers in Jewish high-risk women.
We hypothesized that aberrant gene silencing by miRNA may affect mutant BRCA penetrance. To test this notion, frequency of single nucleotide polymorphisms (SNPs; n = 42) within predicted miRNA binding sites or miRNA precursors were determined and compared in 363 BRCA1 mutation carriers: asymptomatic (n = 160), breast cancer (n = 140) and ovarian cancer (n = 63) patients, and in 125 BRCA2 mutation carriers: asymptomatic (n = 48), breast cancer (n = 58) and ovarian cancer (n = 19) patients. Overall, 16 of 42 SNPs were polymorphic, 11 had a minor allele frequency greater than 5% and 9 of them maintained the Hardy-Weinberg Equilibrium. Based on Cox regression and Kaplan-Meier analyses, statistically significant differences were noted in BRCA2 mutation carriers by health status in 3 SNPs: CC homozygosity at rs6505162 increased ovarian cancer risk (RR 2.77; p = 0.028; 95% CI, 1.11-6.9); heterozygote SNP carriers of rs11169571 had an approximately 2 fold increased risk for developing breast/ovarian cancer, whereas heterozygotes of the rs895819 SNP had an approximately 50% reduced risk for developing breast/ovarian cancer. This study provides preliminary evidence for another regulatory level of penetrance of deleterious mutations in cancer predisposition genes.
Kontorovich
Tair
T
Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, The Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Levy
Asaf
A
Korostishevsky
Michael
M
Nir
Uri
U
Friedman
Eitan
E
D001665:Binding Sites; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D006801:Humans; D007585:Jews; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D035683:MicroRNAs