Although environmental factors are clearly important in the etiology of the disease, there is a significant input from genetic factors. First-degree relatives of colorectal cancer cases are considered to have a 2-4-fold increased risk, with around 20-25% of all colorectal cancer cases being associated with a family history (Bonelli et al., 1988). Early screening studies suggested that cancer susceptibility is due to a predisposition in the development of colorectal adenomas (Cannon-Albright et al., 1988). The population frequency of the ''adenoma-prone'' allele was calculated as 19% but not all adenomas progress to cancer and dietary effects might clearly influence the expression of such an allele in terms of both adenoma and cancer. A North European twin study has now provided good evidence that about 35% of all colorectal cancer cases have a genetic component (Lichtenstein et al., 2000) (Figure 17.1b), which is intriguing as known susceptibility alleles account for only 5% of all cases. The genetic factors involved are poorly understood and it is now clear that colorectal cancer susceptibility is complex. Recent evidence has shown that recessive inheritance of susceptibility alleles can also play a major role in increased colorectal cancer risk (Farrington et al., 2005), and the hunt is on for new risk alleles of moderate to low penetrance, or associated with a marginal increased risk, and for those involved in complex gene-gene and gene-environment interactions.
Of the known genetic factors, there are two autosomal dominant and one autosomal recessive inherited cancer syndromes that account for a significant minority of all colorectal cancer cases
(~5%o). Familial Adenomatous Polyposis (FAP) is a rare syndrome caused by mutations in the Adenomatous Polyposis Coli (APC) gene and characterized by the presence of multiple adenomas. In other multiple adenoma families, bi-allelic mutations of the Base Excision Repair (BER) gene MUTYH were identified as the causative lesions and the gene has been associated with increased colorectal cancer risk. The major colorectal cancer syndrome is hereditary non-polyposis colorectal cancer (HNPCC). Affected kindreds have a high occurrence of colorectal and certain extra-colonic cancers and early age of onset. HNPCC has no pathognomonic features and has traditionally been diagnosed on the basis of family history. However, due to the lack of definitive biomarkers for HNPCC, these diagnostic criteria have been pragmatic and are not inclusive of all cases. Clinical criteria such as the Amsterdam criteria will only identify families where the gene defect is highly penetrant and the families are of sufficient size to allow the appropriate number of cases to arise. Thus there is a bias that tends to exclude small families inappropriately. The underlying defect in the majority of HNPCC has been identified as lesions in the DNA mismatch repair (MMR) pathway.
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