B191

Advances in genomics offer new strategies for assessing the association of common genetic variations at multiple loci and risk of many diseases, including colorectal cancer (CRC). Low penetrance alleles of genes in several biological pathways, such as DNA repair, metabolism, inflammation, cell cycle, apoptosis, and Wnt signaling may influence the risk of non-familial CRC. To identify susceptibility genes for CRC we designed a large-scale association study in case-control studies nested within the Nurses' Health Study (190 cases and 190 controls) and the Health Professionals Follow-up Study (168 cases and 168 controls). We used a custom GoldenGate® (Illumina) Oligonucleotide Pool Assay including 1536 SNPs selected in candidate genes from cancer-related pathways which have been sequenced and genotyped in the SNP500Cancer project (http://snp500cancer.nci.nih.gov). 1412 of the 1536 (92%) of the SNPs were genotyped successfully within 388 genes (51% intronic; 32% exonic; 12% promoter region; and 5% serine, threonine, and proline region SNPs genotyped). SNPs in high linkage disequilibrium (LD) with another assayed SNP were excluded from further analyses (Meff value calculated by SNPSpD=1249, corrected Bonferroni p-value 0.00004). As expected by chance, in the additive model 11 SNPs had a p-for-trend <0.01 and 38 SNPs had a p-for-trend ≥0.01 and <0.05). Of note the MGMT Lys178Arg (rs2308237) SNP, in LD with the previously reported MGMT Ile143Val SNP, had an inverse association with CRC risk (MGMT Lys178Arg: OR=0.52, 95% CI: 0.35 - 0.78; p-for-trend =0.0003 for the additive model). The common genetic variants identified in this large-scale evaluation of candidate genes warrant further investigation. The SNP500Cancer database and the Illumina GoldenGate® Assay allowed us to test a larger number of SNPs than previously possible, augmenting our understanding of the role of genetic susceptibility in CRC.

[Fifth AACR International Conference on Frontiers in Cancer Prevention Research, Nov 12-15, 2006]