Abstract
This review looks back at five decades of research into genetic susceptibility to colorectal cancer (CRC) and the insights these studies have provided. Initial evidence of a genetic basis of CRC stems from epidemiological studies in the 1950s and is further provided by the existence of multiple dominant predisposition syndromes. Genetic linkage and positional cloning studies identified the first high-penetrance genes for CRC in the 1980s and 1990s. More recent genome-wide association studies have identified common low-penetrance susceptibility loci and provide support for a polygenic model of disease susceptibility. These observations suggest a high proportion of CRC may arise in a group of susceptible individuals as a consequence of the combined effects of common low-penetrance risk alleles and rare variants conferring moderate CRC risks. Despite these advances, however, currently identified loci explain only a small fraction of the estimated heritability to CRC. It is hoped that a new generation of sequencing projects will help explain this missing heritability.
Highlights
Colorectal cancer (CRC) is the third most common cancer worldwide with half a million new individuals diagnosed annually [1]
It is an established fact that inherited susceptibility has an important role in predisposition to CRC
Whilst there is growing evidence to suggest that his conclusion is, at least in part, correct, the reasoning behind this statement is flawed as the relative risks associated with first degree relatives (FDRs) are likely to be underestimated
Summary
Colorectal cancer (CRC) is the third most common cancer worldwide with half a million new individuals diagnosed annually [1]. In the UK CRC affects ~40,000 individuals and is responsible for. It is an established fact that inherited susceptibility has an important role in predisposition to CRC. The earliest evidence for this came from epidemiological studies in the 1950s which showed a two- to three-fold increased risk of CRC in first degree relatives of patients [2]. Subsequent studies have identified a number of CRC susceptibility genes. These discoveries have greatly increased our understanding of the mechanisms underlying CRC biology and have provided promising targets for therapeutic intervention. The ability to identify individuals at increased risk of CRC is of important clinical relevance
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