Purpose CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtypeand age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and Methods CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population-and hospital-based studies. ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population-and hospital-based studies, and in patients with breast cancer from familial-and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 3 10 220 ). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 3 10 221 ]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 3 10 24 ). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up. INTRODUCTIONSusceptibility to breast cancer is known to be conferred by rare mutations in high-risk genes, notably BRCA1 and BRCA2, by mutations in several moderate-risk genes, and by a large number of common genetic variants. Among moderate-risk genes, one of the best established is CHEK2 (cell-cycle checkpoint kinase 2).1 The protein encoded by CHEK2 is a cell-cycle checkpoint regulator and putative tumor suppressor and it plays a critical role in the DNA damage repair pathway.2-4 The 1100delC germline mutation in CHEK2, which is located at 22q12.1 (NM_007194.3(CHEK2):c.1100del: p.(Thr367Metfs*15)), is the most frequently found protein-truncating variant in populations of European descent.1,5-7 Deletion of a single cytosine at position 1100 in exon 10 introduces a stop codon and results in a kinase-dead CHEK2 protein.Although the evidence that CHEK2*1100delC is associated with increased breast cancer risk is unequivocal, the magnitude of the risk is still uncertain, in part because the variant is relatively uncommon and i...

A B S T R A C T PurposeWe tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and MethodsFrom 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P ϭ .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P Ͻ .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P Ͻ .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P Ͻ .001) in women with estrogen receptor-positive first breast cancer only. ConclusionAmong women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.

A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10−9) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10−39). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.