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Genome-wide association studies have identified FGFR2 as a breast cancer (BC) susceptibility gene in populations of European and Asian descent, but a causative variant has not yet been conclusively identified. We hypothesized that the weaker linkage disequilibrium across this associated region in populations of African ancestry might help refine the set of candidate-causal single nucleotide polymorphisms (SNPs) previously identified by our group. Eight candidate-causal SNPs were evaluated in 1253 African American invasive BC cases and 1245 controls. A significant association with BC risk was found with SNP rs2981578 (unadjusted per-allele odds ratio = 1.20, 95% confidence interval 1.03–1.41, P_trend = 0.02), with the odds ratio estimate similar to that reported in European and Asian subjects. To extend the fine-mapping, genotype data from the African American studies were analyzed jointly with data from European ( n = 7196 cases, 7275 controls) and Asian ( n = 3901 cases, 3205 controls) studies. In the combined analysis, SNP rs2981578 was the most strongly associated. Five other SNPs were too strongly correlated to be excluded at a likelihood ratio of < 1/100 relative to rs2981578. Analysis of DNase I hypersensitive sites indicated that only two of these map to highly accessible chromatin, one of which, SNP rs2981578, has previously been implicated in up-regulating FGFR2 expression. Our results demonstrate that the association of SNPs in FGFR2 with BC risk extends to women of African American ethnicity, and illustrate the utility of combining association analysis in datasets of diverse ethnic groups with functional experiments to identify disease susceptibility variants.

Homologous recombination (HR) and nonhomologous end-joining (NHEJ) are the two mechanisms responsible for repairing DNA double-strand breaks (DSBs) and act in either a collaborative or competitive manner in mammalian cells. DSB repaired by NHEJ may be more complicated than the simple joining of the ends of DSB, because, if nucleotides were lost, it would result in error-prone repair. This has led to the proposal that a subpathway of precise NHEJ exists that can repair DSBs with higher fidelity; this is supported by recent findings that the expression of the HR gene, BRCA1, is causally linked to in vitro and in vivo precise NHEJ activity. To further delineate this mechanism, the present study explored the connection between NHEJ and the cell-cycle checkpoint proteins, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (Chk2), known to be involved in activating BRCA1, and tested the hypothesis that ATM and Chk2 promote precise end-joining by BRCA1. Support for this hypothesis came from the observations that (a) knockdown of ATM and Chk2 expression affected end-joining activity; (b) in BRCA1-defective cells, precise end-joining activity was not restored by a BRCA1 mutant lacking the site phosphorylated by Chk2 but was restored by wild-type BRCA1 or a mutant mimicking phosphorylation by Chk2; (c) Chk2 mutants lacking kinase activity or with a mutation at a site phosphorylated by ATM had a dominant negative effect on precise end-joining in BRCA1-expressing cells. These results suggest that the other two HR regulatory proteins, ATM and Chk2, act jointly to regulate the activity of BRCA1 in controlling the fidelity of DNA end-joining by precise NHEJ. (Cancer Res 2006; 66(3): 1391-400)

A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; P_trend = 1.0 × 10 ⁻¹⁹ ). The odds ratio was lower than that previously reported ( P = .02) and did not vary by age or ethnicity (all P ≥ .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history ( P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10 ⁻¹⁵ ) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 × 10 ⁻¹⁴ ) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002). The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

The evolutionarily conserved Mre11-Rad50-Nbs1 (MRN) complex, consisting of proteins encoded by the genes Mre11, Rad50, and Nbs1, was recently shown to play a crucial role in DNA double-strand break (DSB) repair by recruiting the nuclear protein kinase ataxia telangiectasia mutated to DSB sites, leading to activation of this DNA repair network. Given the fact that carriers of defective mutation and polymorphic variants of ataxia telangiectasia mutated are at higher risk of developing breast cancer, we hypothesized a role of the MRN genes in determining breast cancer susceptibility. This hypothesis was examined both in a case control study of 559 breast cancer patients and 1,125 healthy women of single-nucleotide polymorphisms in Mre11, Rad50, and Nbs1 and by the in vivo detection of binding between Mre11 and BRCA1, encoded by the breast cancer susceptibility gene BRCA1. We were also interested in defining whether any association between MRN genes and breast cancer was modified by reproductive risk factors reflecting the level of estrogen exposure or susceptibility to estrogen exposure, as estrogen is known to initiate breast cancer development due to its metabolites causing DSB formation. Support for the hypothesis came from the observations that (a) one single-nucleotide polymorphism in Nbs1 was significantly associated with breast cancer risk, and a trend toward an increased risk of developing breast cancer was found in women harboring a greater number of putative high-risk genotypes of MRN genes (an adjusted odds ratio of 1.25 for each additional putative high-risk genotype; 95% confidence interval, 1.10-1.44); (b) this association between risk and the number of putative high-risk genotypes was stronger and more significant in women thought to be more susceptible to estrogen, i.e., those with no history of full-term pregnancy, those older (≥26 years of age) at first full-term pregnancy, or those having had fewer (<2) full-term pregnancies; the risk effect conferred by harboring a higher number of high-risk genotypes of MRN genes was more significant in women without a history of breast feeding; and (c) Mre11 and BRCA1 were shown to form a complex in vivo, and this interaction was increased by irradiation. This study supports the role of the MRN pathway in breast cancer development, further strengthening the suggestion that mechanisms regulating DSB repair may play a mutator role driving breast cancer pathogenesis. (Cancer Epidemiol Biomarkers Prev 2007;6(10):2024–32)