A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Abstract

Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7).

Association of low-penetrance alleles with male breast cancer risk and clinicopathological characteristics: results from a multicenter study in Italy

“…and ER-disease [25,27]. On the other hand, variants in ESR1 and 19p13 show evidence of an association primarily with ER-BCs [20,[29][30][31]. At present, there are no data on possible correlations between clinicopathological characteristics and common low-penetrance BC susceptibility alleles in MBC.…”

“…Genome-wide association studies (GWAS) have identified associations between single nucleotide polymorphisms (SNPs), acting as common lowpenetrance variant alleles, and BC risk in women [13][14][15][16][17][18][19][20][21]. An involvement of some of the SNPs found to be associated with FBC has been suggested in MBC susceptibility [22], and by GWAS we could recently identify a novel common variant associated with MBC [23].…”

CAG repeat size in Huntingtin alleles is associated with cancer prognosis

“…GEMO is the French branch of the international initiative CIMBA (Consortium of Investigators of Modifiers of BRCA1 and BRCA2), which aims at identifying modifiers of breast cancer risk through the collection of DNA and clinical data from a large number of BRCA1 and BRCA2 mutation carriers. [12][13][14] Participation in the GEMO cohort was proposed during the cancer clinic in which patients were informed of a positive BRCA1/2 test result. Their written informed consent was obtained.…”

Unravelling modifiers of breast and ovarian cancer risk forBRCA1andBRCA2mutation carriers: update on genetic modifiers

“…[75]. These are the same SNPs that provided independent evidence of association with breast cancer risk for BRCA1 mutation carriers, identified through the BRCA1 GWAS [40]. An analysis of the associations of these SNPs with breast and ovarian cancer risk simultaneously for BRCA1 mutation carriers found no significant evidence of association with ovarian cancer risk in BRCA1 mutation carriers [40].…”