The continuing search for predisposing colorectal cancer variants.

High-penetrance mutations in a small group of genes have been identified as the causal agent of colorectal cancer (CRC) in high-risk families. Our understanding of the sporadic cases is, however, much more limited and only in the past two years have multicentric genome-wide association studies (GWAS) started to unravel the complex genetic architecture behind this common forms. To date, ten loci have been associated with an increased risk of CRC. Environmental factors play a role as well as other genetic factors yet to be discovered. The search for common variants with a low penetrance has come to an end, at least in the European population, and the focus now moves to less common variants (with higher penetrance) and to unclassified variants of unknown significance. As yet, less than 10% of the 35% genetic contribution to CRC is known.