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Family History, Genetic Testing, and Clinical Risk Prediction: Pooled Analysis of CHEK2*1100delC in 1,828 Bilateral Breast Cancers and 7,030 Controls

¹ Breakthrough Breast Cancer Research Centre, Institute of Cancer Research and ² Non-communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, London United Kingdom; Departments of ³ Obstetrics and Gynaecology, ⁴ Clinical Genetics, and ⁵ Oncology, Helsinki University Central Hospital, Helsinki, Finland; ⁶ Department of Medical Oncology, Josephine Nefkens Institute, Erasmus Medical Centre, Rotterdam, the Netherlands; ⁷ Afdeling Klinische Genetica and ⁸ Netherlands Cancer Institute (NKI-AVL), Amsterdam, the Netherlands; Departments of ⁹ Radiation Oncology and ¹⁰ Gynaecology, Hannover Medical School, Hannover, Germany; ¹¹ N.N. Petrov Institute of Oncology, St. Petersburg, Russia; ¹² Deutsches Krebsforschungszentrum, Heidelberg, Germany; ¹³ Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan; ¹⁴ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Tübingen, Germany; and ¹⁵ Cancer Research UK Epidemiology and Genetics Unit, Institute of Cancer Research, Sutton, Surrey, United Kingdom

Requests for reprints: Julian Peto, Non-Communicable Disease Epidemiology Unit, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom. Phone: 207-927-2455; Fax: 207-580-6897. E-mail: julian.peto{at}lshtm.ac.uk

If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2*1100delC should be 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2*1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P_trend = 0.0003) and Finland (P_trend = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2*1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2*1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2*1100delC and other moderate penetrance alleles in women with a family history of breast cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(1):230–4)