The identification of novel colorectal cancer susceptibility loci

Colorectal cancer (CRC) is the second most common malignancy in developed countries. Germline mutations in a number of genes have been shown to cause CRC, but the Mendelian syndromes associated with these known genes (APC, DNA mismatch repair genes, MYH, SMAD4, ALK3 and STK11) account for less than 5% of the familial clustering. Colorectal tumor families which show evidence against linkage to known disease loci, provide direct evidence for the existence of uncharacterized high/moderate-penetrance CRC genes. Such observations strongly support the continued search for novel CRC predisposition genes through genome-wide linkage. To identify novel CRC susceptibility genes through linkage analyses a series of CRC families in which involvement of known susceptibility genes has been excluded were ascertained. Genome-wide genotyping was performed using high-density SNP arrays to provide maximal power to detect linkage. This study provided statistically significant evidence for a novel predisposition locus for CRC mapping to 3q21-24. Using a series of microsatellite markers the critical interval of linkage was refined to 1 4.4Mb region at 3q22. To further investigate Mendelian susceptibility to CRC, a search for a disease gene at 3q22 was performed by linkage disequilibrium (LD) mapping in 620 familial CRC cases and 960 controls, genotyping 1,676 tagging SNPs and sequencing 30 candidate genes from the region. Signal intensity data from the SNP markers was further evaluated for structural variation within 3q22. On the bases of LD mapping, chromosomal profiling and mutational analyses of genes mapping to 3q22, no causal mutation was identified. Findings are consistent with the hypothesis that variation at 3q22 contributes to a significant proportion of the unexplained genetic risk to CRC, however this is unlikely to be mediated through a restricted set of alleles and is refractory to identification by current analyses strategies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo