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Single nucleotide polymorphisms in miRNA binding sites and miRNA genes as breast/ovarian cancer risk modifiers in Jewish high‐risk women
Author(s) -
Kontorovich Tair,
Levy Asaf,
Korostishevsky Michael,
Nir Uri,
Friedman Eitan
Publication year - 2010
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.25065
Subject(s) - microrna , single nucleotide polymorphism , breast cancer , ovarian cancer , gene , genetics , oncology , biology , medicine , cancer , genotype
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 ∼2 fold increased risk for developing breast/ovarian cancer, whereas heterozygotes of the rs895819 SNP had an ∼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.