CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer

Purpose: The pathogenic CHEK2 HOOdelC variant is firmly established as a breast cancer susceptibility allele. Dutch CHEK2 HOOdelC breast cancer families frequently also include colorectal cancer cases, and the variant is particularly prevalent among breast cancer families with hereditary breast and colorectal cancer. Yet, it is still unclear whether CHEK2 HOOdelC also confers a colorectal cancer risk independent of its breast cancer risk. Experimental Design: CHEK2 HOOdelC was genotyped in the index cases of 369 Dutch colorectal cancer families that had been excluded for familial breast cancer. The cohort included 132 cases with familial adenomatous polyposis (FAP) and FAP-related disease, and 237 cases with hereditary nonpolyposis colorectal cancer (HNPCC) and HNPCC-related disease. Results: None of the FAP/FAP-related cases carried the CHEK2 HOOdelC variant. In contrast, CHEK2 HOOdelC was present in 10 of 237 (4.2%) HNPCC/HNPCC-related cases that was significantly more prevalent than the 1.0% Dutch population frequency (odds ratio, 4.3; 95% confidence interval, 1.7-10.7; P = 0.002). Nine of the 10 CHEK2 HOOdelC colorectal cancer cases met the revised Amsterdam and/or Bethesda criteria. The 10 CHEK2 HOOdelC colorectal cancer families had a high-risk cancer inheritance pattern, including 35 colorectal cancer cases, 9 cases with polyps, and 21 cases with other tumor types. Conclusion: Our analysis provides strong evidence that the HOOdelC variant of CHEK2 confers a colorectal cancer risk in HNPCC/HNPCC-related families, supporting the hypothesis that CHEK2 is a multiorgan cancer susceptibility gene.