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A Multicenter Study of Cancer Incidence in CHEK2 1100delC Mutation Carriers

¹ Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, Cambridge, United Kingdom; ² Cancer Genetics Section, Institute of Cancer Research; ³ Royal Marsden NHS Foundation Trust, Surrey, United Kingdom; ⁴ Departments of Clinical Genetics and Medical Oncology, Erasmus Medical Centre, Rotterdam, the Netherlands; ⁵ Division of Epidemiology, German Cancer Research Centre, Heidelberg, Germany; ⁶ Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom; and ⁷ Department of Hematology/Oncology, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania

Requests for reprints: Douglas F. Easton, Cancer Research UK Genetic Epidemiology Unit, Strangeways Research Laboratories, University of Cambridge, Worts Causeway, Cambridge, CB1 8RN, United Kingdom. E-mail: douglas{at}srl.cam.ac.uk

The CHEK2 1100delC protein-truncating mutation has a carrier frequency of 0.7% in Northern and Western European populations and confers an 2-fold increased risk of breast cancer. It has also been suggested to increase risks of colorectal and prostate cancer, but its involvement with these or other types of cancer has not been confirmed. The incidence of cancer other than breast cancer in 11,116 individuals from 734 non-BRCA1/2 breast cancer families from the United Kingdom, Germany, Netherlands, and the United States was compared with that predicted by population rates. Relative risks (RR) to carriers and noncarriers were estimated by maximum likelihood, via the expectation-maximization algorithm to allow for unknown genotypes. Sixty-seven families contained at least one tested CHEK2 1100delC mutation carrier. There was evidence of underreporting of cancers in male relatives (422 cancers observed, 860 expected) but not in females (322 observed, 335 expected); hence, we focused on cancer risks in female carriers. The risk of cancers other than breast cancer in female carriers was not significantly elevated, although a modest increase in risk could not be excluded (RR, 1.18; 95% confidence interval, 0.64-2.17). The carrier risk was not significantly raised for any individual cancer site, including colorectal cancer (RR, 1.60; 95% confidence interval, 0.54-4.71). However, between ages 20 to 50 years, the risks of colorectal and lung cancer were both higher in female carriers than noncarriers (P = 0.041 and 0.0001, respectively). There was no evidence of a higher prostate cancer risk in carriers than noncarriers (P = 0.26), although underreporting of male cancers limited our power to detect such a difference. Our results suggest that the risk of cancer associated with CHEK2 1100delC mutations is restricted to breast cancer, although we cannot rule out a small increase in overall cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(12):2542–5)

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