Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Abstract

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 subtype- and 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.

Results: Proportions 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 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). 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.

Conclusion: These 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.

Fig 1.

CHEK2*1100delC frequency rates per country in legend are shown with 95% confidence intervals and were calculated using a modification of the empirical Bayes approach proposed by Clayton and Kaldor, as described in the methods. Analysis included all controls (44,276 non-carriers and 235 CHEK2*1100delC carriers) and all population- and hospital-based breast cancer patients (38,783 non-carriers and 502 CHEK2*1100delC carriers). When the breast cancer patients from the clinical genetics and familial studies were also included, the rates slightly changed, but not the color of the countries in the map (results not shown).

Fig 2.

Breast cancer relative risk curves for CHEK2*1100delC carriers by age for invasive breast cancer: overall, estrogen receptor (ER)–positive, and ER-negative disease. OR, odds ratio.

Fig 3.

Cumulative breast cancer risks for CHEK2*1100delC carriers and the general female population by attained age. ER, estrogen receptor.

Fig A1.

Data flowchart of inclusion and exclusion of patients with breast cancer and healthy controls from the Breast Cancer Association Consortium (BCAC) database.

Fig A2.

Forest plot of odds ratios (ORs) from a fixed meta-analysis of the association between CHEK2*1100delC and invasive breast cancer by study, using population- and hospital-based studies. ABCFS, Australian Breast Cancer Family Study; ABCS, Amsterdam Breast Cancer Study; BBCC, Bavarian Breast Cancer Cases and Controls; BSUCH, Breast Cancer Study of the University of Heidelberg; CGPS, Copenhagen General Population Study; GENICA, Gene Environment Interaction and Breast Cancer in Germany; GESBC, Genetic Epidemiology Study of Breast Cancer by Age 50; HABCS, Hannover Breast Cancer Study; HEBCS, Helsinki Breast Cancer Study; HMBCS, Hannover-Minsk Breast Cancer Study; KBCP, Kuopio Breast Cancer Project; LMBC, Leuven Multidisciplinary Breast Centre; MCBCS, Mayo Clinic Breast Cancer Study; MCCS, Melbourne Collaborative Cohort Study; NBCS, Norwegian Breast Cancer Study; OFBCR, Ontario Familial Breast Cancer Registry; PBCS, NCI Polish Breast Cancer Study; SASBAC, Singapore and Sweden Breast Cancer Study; SBCS, Sheffield Breast Cancer Study; SEARCH, Study of Epidemiology and Risk factors in Cancer Heredity; UCIBCS, UCI Breast Cancer Study; UKBGS, UK Breakthrough Generations Study.

Fig A3.

CHEK2*1100delC-associated breast cancer risk per age category: all invasive and invasive estrogen receptor (ER)–positive disease. P-value trend for all and ER+ disease: P = .014 and P = .026, respectively (see Table 3).