Identification of colorectal cancer mutation carriers

11 July 2006

Colorectal cancers are the third most common form of cancer (around 35,000 cases annually) and the second leading cause of cancer deaths (around 16,000 cases annually) in the UK. Although most colorectal cancers occur in individuals with no significant family history of the disease, a small proportion of these are familial cancers. Hereditary non-polyposis colorectal cancer (HNPCC), also known as Lynch Syndrome, is the most common of these, representing 1-5% of all cases. A recent paper in the New England Journal of Medicine presents a new approach to the identification of colorectal cancer patients with HNPCC [Barnetson et al. (2006) NEJM 354(26), 2751-2763]. Finding cases of familial colorectal cancer is important because it allows the identification of affected family members at high risk of the disease; increased levels of surveillance or preventative interventions in this group greatly decrease the mortality rates.

HNPCC is caused by mutations in specific DNA mismatch repair (MMR) genes. Identification of these mutations is a time-consuming and expensive process, and inappropriate for unselected colorectal cancer patients. Instead, specific clinical criteria (the Amsterdam criteria and Bethesda guidelines) are applied to identify those at increased risk, and this stratification, combined with molecular testing techniques, is used to determine which patients should be referred for genetic testing, and which genes should be analysed. Barnetson and colleagues present a new predictive algorithm said to be more effective than the current criteria, which can be used in combination with molecular testing to identify patients who should receive genetic testing for HNPCC. The model was developed using data from a moderate sized cohort of 870 colorectal cancer patients under the age of 55, who were tested for mutations in three key MMR genes. 38 such mutations were identified, representing 4.4% of the cases.

Comment: The new approach to assessing the probability of an underlying familial MMR gene mutation being present in a colorectal cancer patient represents a potentially useful addition to the techniques already in use to identify HNPCC, but there are further complications that need to be considered too, such as the cases caused by rarer mutations in additional genes, and the limitations of genetic testing. However, all moves towards improving the rate of identification of HNPCC are valuable in terms of prevention of further familial cases.

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