Null evidence for linkage of familial breast and colon cancer to CHEK2. H. Ochs-Balcom^1,2, D. Daley^{1, 3}, R. Elston^1,2, G. Wiesner^2,4. 1) Department of Epidemiology & Biostatistics, Case Western Reserve University, Cleveland, OH, USA; 2) Ireland Comprehensive Cancer Center at University Hospitals of Cleveland and CWRU, Cleveland, OH, USA; 3) The James Hogg-iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia, St. Pauls Hospital, Vancouver, British Columbia, Canada; 4) Department of Genetics and Center for Human Genetics, CWRU, Cleveland, OH, USA.
   CHEK2, a gene important in the cell cycle and DNA repair, is hypothesized to be important in breast cancer etiology and perhaps also in other cancers. Families with both breast and colon cancer have been reported to have mutations in the CHEK2 gene, leading to the hypothesis that this gene may be a susceptibility factor for both of these cancers. A total of 159 sibling pairs in 33 nuclear families, each containing two cases of advanced polyps or colon cancer and at least one primary breast cancer in a sibling or mother, were genotyped for 6 markers on chromosome 22. Model-free linkage analysis was performed to determine whether the CHEK2 region is linked to familial breast and colon cancer. Allele sharing identical by descent for concordantly affected sibling pairs at D22S689, 0.02 cM centromeric of CHEK2, was 0.47 (SE 0.05; p=0.76), and at D22S685, 3.74 cM telomeric of CHEK2, was 0.46 (SE 0.05; p=0.77). Similarly, there was no statistically significant evidence for linkage using Haseman-Elston regression. The study had 90% power at the 5% level to detect a locus-specific sibling relative recurrence risk of 1.4 and therefore suggests that CHEK2 is an unlikely susceptibility locus in kindreds with breast and colon neoplasia. We further plan to investigate epistatic interaction of CHEK2 with BRCA1 and 2 because both are candidate genes for breast cancer that may jointly influence risk.