Emerging architecture of colorectal cancer predisposition


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Richard Houlston

The Institute of Cancer Research, Sutton, UK

Abstract

Emerging architecture of colorectal cancer predisposition

Much of the familial aggregation of colorectal cancer (CRC) results from inherited susceptibility, but highly penetrant mutations in known genes cannot account for most of the excess. Some of the unexplained familial risk is presumably due to high-penetrance mutations in as yet unidentified genes, but polygenic mechanisms are likely to account for a greater proportion. This inference, coupled with technological developments, has led to a renaissance in association studies. Until recently most studies have evaluated small numbers of single-nucleotide polymorphisms (SNPs) in a few candidate genes with varying degrees of success. The availability of high resolution linkage disequilibrium (LD) maps and hence of comprehensive sets of tagging SNPs that capture most of the common sequence variation allows whole genome-wide studies for disease associations to be efficiently conducted. This approach is unbiased and does not depend upon prior knowledge of function or presumptive involvement of any gene in disease causation. Moreover, it minimizes the possibility of failing to identify important variants in hitherto unstudied genes. Using this approach six common variants have recently been identified that influence the risk of developing CRC. While the risk associated with each variant is modest, in concert they can exert a substantive risk on an individuals risk and hence have direct clinical utility. In the longer term, high-throughput re-sequencing will be required to identify the rare pathogenic variants that may constitute the majority of low-penetrance alleles.