A multistage genetic association study identifies breast cancer risk loci at 10q25 and 16q24.

Higginbotham KS, Breyer JP, McReynolds KM, Bradley KM, Schuyler PA, Plummer WD, Freudenthal ME, Trentham-Dietz A, Newcomb PA, Parl FF, Sanders ME, Page DL, Egan KM, Dupont WD, Smith JR
Cancer Epidemiol Biomarkers Prev. 2012 21 (9): 1565-73

PMID: 22806168 · PMCID: PMC3707501 · DOI:10.1158/1055-9965.EPI-12-0386

BACKGROUND - Heritable risk for breast cancer includes an increasing number of common, low effect risk variants. We conducted a multistage genetic association study in a series of independent epidemiologic breast cancer study populations to identify novel breast cancer risk variants.

METHODS - We tested 1,162 SNPs of greatest nominal significance from stage I of the Cancer Genetic Markers of Susceptibility breast cancer study (CGEMS; 1,145 cases, 1,142 controls) for evidence of replicated association with breast cancer in the Nashville Breast Cohort (NBC; 599 cases, 1,161 controls), the Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls), and BioVU Breast Cancer Study (BioVU; 1,172 cases, 1,172 controls).

RESULTS - Among these SNPs, a series of validated breast cancer risk variants yielded expected associations in the study populations. In addition, we observed two previously unreported loci that were significantly associated with breast cancer risk in the CGEMS, NBC, and CBCS study populations and had a consistent, although not statistically significant, risk effect in the BioVU study population. These were rs1626678 at 10q25.3 near ENO4 and KIAA1598 (meta-analysis age-adjusted OR = 1.13 [1.07-1.20], P = 5.6 × 10(-5)), and rs8046508 at 16q23.1 in the eighth intron of WWOX (meta-analysis age-adjusted OR = 1.20 [1.10-1.31], P = 3.5 × 10(-5)).

CONCLUSIONS - Our data supports the association of two novel loci, at 10q25.3 and 16q23.1, with risk of breast cancer.

IMPACT - The expanding compendium of known breast cancer genetic risk variants holds increasing power for clinical risk prediction models of breast cancer, improving upon the Gail model.

©2012 AACR

MeSH Terms (16)

Adolescent Adult Aged Aged, 80 and over Breast Neoplasms Chromosome Mapping Chromosomes, Human, Pair 10 Chromosomes, Human, Pair 16 Female Genetic Association Studies Genetic Loci Genetic Predisposition to Disease Humans Middle Aged Polymorphism, Single Nucleotide Risk

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