Abstract
Hereditary non polyposis colorectal cancer (HNPCC) is characterized by the presence of early onset colorectal cancer and other epithelial malignancies. The genetic basis of HNPCC is a deficiency in DNA mismatch repair, which manifests itself as DNA microsatellite instability in tumours. There are four genes involved in DNA mismatch repair that have been linked to HNPCC; these include hMSH2, hMLH1, hMSH6 and hPMS2. Of these four genes hMLH1 and hMSH2 account for the majority of families diagnosed with the disease. Notwithstanding, up to 40 percent of families do not appear to harbour a change in either hMSH2 or hMLH1 that can be detected using standard screening procedures such as direct DNA sequencing or a variety of methods all based on a heteroduplex analysis.In this report we have screened a series of 118 probands that all have the clinical diagnosis of HNPCC for medium to large deletions by the Multiplex Ligation-Dependent Probe Amplification assay (MLPA) to determine the frequency of this type of mutation. The results indicate that a significant proportion of Australian HNPCC patients harbour deletion or duplication mutations primarily in hMSH2 but also in hMLH1.
Highlights
Hereditary non polyposis colorectal cancer (HNPCC; MIM 120435 and 120436) is an autosomal dominantly inherited disorder that predisposes males to an approximate colorectal cancer risk of 80% by 70 years of age and females to a 40% risk of bowel cancer and a 40% risk of endometrial cancer by the same age [1]
The genetic basis of HNPCC has been linked to errors in DNA mismatch repair [2,3,4,5], which leaves a characteristic tumour signature of DNA microsatellite instability (MSI) that can be used as a surrogate marker for this syndrome [6, 7]
At least four genes have been associated with DNA mismatch repair and HNPCC and are hMSH2, hMLH1, hMSH6 and hPMS2; for review see Papadopoulos and Lindblom [8]
Summary
Hereditary non polyposis colorectal cancer (HNPCC; MIM 120435 and 120436) is an autosomal dominantly inherited disorder that predisposes males to an approximate colorectal cancer risk of 80% by 70 years of age and females to a 40% risk of bowel cancer and a 40% risk of endometrial cancer by the same age [1]. At least four genes have been associated with DNA mismatch repair and HNPCC and are hMSH2, hMLH1, hMSH6 and hPMS2; for review see Papadopoulos and Lindblom [8]. Both hMSH2 and hMLH1 account for somewhere between 50% and 60% of all families that adhere to the Amsterdam Criteria (3 relatives with colorectal cancer (CRC); one must be a first degree relative of the other two; cross at least two generations; CRC must be diagnosed in one relative under the age of 50 years and familial adenomatous polyposis (FAP) must be excluded). The contribution of hPMS2 and hMSH6 remains undefined, on current evidence both hPMS2 and hMSH6 appear
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