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Genetic predisposition to adenomas explains a large part of heritable colorectal cancer risk

▸ Carvajal-Carmona LG, Zauber AG, Jones AM, et al. Much of the genetic risk of colorectal cancer is likely to be mediated through susceptibility to adenomas. Gastroenterology 2013;144:53–5.

Genetic association studies have identified a number of single nucleotide polypmorphisms (SNPs) that are associated with increased colorectal cancer (CRC) risk. Since these studies have used CRC cases, it remains uncertain whether or not functional genetic variants associated with CRC increase cancer risk through predisposition to adenomas. Carvajal-Carmona and co-workers set out to address this question by performing a genetic association study utilising 1755 adenoma cases, derived from two chemoprevention studies and one gene-identification study, and controls derived from existing population-based collections. Cases with a personal or family history CRC were excluded. The researchers assessed associations with 18 CRC predisposition SNPs and found that, for 8 out of the 18 SNPs, there were significant associations with adenoma risk, with no interstudy heterogeneity. For all SNPs that were associated with adenoma risk, the direction of the association was the same as that for CRC. For four SNPs (rs6983267, rs3802842, rs4939827, and rs961253), the associations were very strong. The studies used to source the cases resulted in enrichment for early onset, multiple, and advanced adenoma, permitting case-case analyses stratified by clinical features such as adenoma multiplicity and size. In these analyses, rs6983267 appeared to be associated with multiple adenomas, suggesting a role in neoplastic initiation as opposed to progression (where one might imagine a SNP to be associated with high-risk polyps). Although power to detect an association between SNPs and adenoma risk was limited to around 70%, it seems possible that those SNPs that were not associated with adenoma risk may be associated with functional variants that have roles in malignant transformation and invasion. Further studies are required to determine which …

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