Screening for Lynch Syndrome

30 June 2005

Hereditary non-polyposis colorectal cancer (HNPCC) or Lynch Syndrome is caused by mutations in DNA mismatch repair (MMR) genes. The genes MLH1, MSH2, MSH3, MSH6, PMS1 and PMS2 have all been implicated in this inherited propensity towards colorectal cancer, although mutations in MSH2 or MLH1 are the most common. Diagnosis of HNPCC is based on clinical criteria; the original Amsterdam criteria were subsequently modified, and followed by the less stringent Bethesda criteria, which are intended to identify colorectal cancer patients for whom molecular genetic testing is appropriate (see Accuracy of Revised Bethesda Guidelines for HNPCC diagnosis journal club, below).

Due to the high cost of testing for mutations in the MMR genes, pre-screening to identify the highest risk patients is desirable. A paper in the New England Journal of Medicine compares the two current techniques of pre-screening, testing for microsatellite instability (MSI) and immunohistochemical analysis of colorectal tumour samples [Hampel H et al. (2005) N Engl J Med. 352, 1851-1860]. A total of 1066 newly diagnosed colorectal cancer patients took part in the study; 208 were found to have MSI, and of these, 23 individuals were found to have Lynch Syndrome. Five of the 23 did not meet the Amsterdam or Bethesda criteria for the diagnosis of HNPCC. MSI testing and immunohistochemical analysis were concluded to perform equally well, on the basis that each method failed to identify two individuals with germline MMR mutations. However, the sensitivity and specificity of the two methods were not determined; it was too expensive to test all the samples by each screening method and genotyping.

The authors conclude that molecular screening methods for Lynch Syndrome are required to identify the maximum possible number of affected individuals. Given the performance of the screening techniques, they propose that immunohistochemical analysis could replace MSI testing without adversely affecting testing, and with the advantage that it can be performed in general pathology laboratories, saving time and money.

Comment: This study reinforces the conclusions of Pinol et al. (below) that immunostaining for abnormal MSH2 or MLH1 protein expression is a valid and probably preferable alternative to MSI testing of colorectal tumours in HNPCC screening. However, their suggestion that molecular screening of all colorectal cancer patients in this manner is justifiable, on the basis of the identification of additional Lynch syndrome patients (and prognostic implications of positive results for either form of test), is open to question. Although molecular screening costs much less than full genetic testing for the MMR mutations, it is nevertheless an expensive strategy, and whether it is truly cost-effective should be evaluated.

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