Colorectal Cancer Risks in Relatives of Young Onset Cases: Greater in Sibs Than in Parents. S.K. Nigon¹, L.A. Boardman¹, B.W. Morlan¹, K.G. Rabe¹, G.M. Petersen¹, J. Goldberg³, S. Gallinger², N.M. Lindor¹. 1) Mayo Clinic College of Medicine, Rochester, MN USA; 2) Mount Sinai Hospital, University of Toronto, Toronto CANADA; 3) Tufts University, Boston MA.
   Background: Several single-gene Mendelian disorders have been discovered that account for some of the familial aggregation detected in large population studies of CRC. Mutations in the DNA Mismatch Repair (MMR)genes cause HNPCC-Lynch Syndrome, the most common of the recognized CRC-predisposition syndromes. It is unclear how fully this recognized syndrome accounts for observed familial aggregation particularly among first degree relatives of younger onset CRC patients. Aim: To assess familial risk, we studied cases with CRC diagnosed under age 50 years identified through Minnesota Cancer Surveillance System (MCSS) and Mayo Clinic, Rochester, MN. CRC patients were excluded if there was evidence of DNA MMR deficiency by tumor microsatellite instability. A total of 278 probands (131 from MCSS; 147 from Mayo Clinic) were included in this study. Data on a total of 1862 relatives was collected, of whom 68 had had CRC, and an additional 165 had had primary cancers of other types. Standardized incidence ratios (SIR) were estimated by comparing to the Surveillance Epidemiology and End Results (SEER) database. MYH gene mutations were tested in probands with affected siblings. Results: Compared to SEER data, relatives of young onset CRC probands had increased risks for developing CRC. The SIR for CRC was increased among first degree relatives (SIR=1.65; 95% C.I. =1.29-2.07), and this risk was greater for siblings (SIR = 2.67; 95% C.I=1.50-4.41) than for parents (SIR= 1.5; 95% C.I. =1.14-1.94). No mutations were found in the MYH gene in the probands who had siblings diagnosed with CRC. Conclusions: While the risk of CRC among relatives of young onset probands is significantly higher than the general population, and was elevated in parents, the risk was much greater among siblings. This increased sibling risk was not accounted for by MYH gene mutations. This work was supported in part by the National Cancer Institute of the National Institute of Health under RFA #CA-95-011..