Diagnosing Lynch syndrome

R isk stratification is essential for designing efficacious and cost effective colon cancer screening programmes. One of the most important risk factors for colorectal cancers (CRC) is an inherited predisposition, implicated in 20% of all cases. The spectrum of genetic susceptibility ranges from the low penetrance mutations that modestly increase the colon cancer risk (for example, I 1307K) to the much more dramatic phenotypes (for example, multiple colonic adenomas in familial adenomatous polyposis) that engender an extraordinarily high risk of cancer. Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) is a case in point. This autosomal dominant condition results from a germline mutation in a DNA mismatch repair (MMR) gene (most commonly hMLH1, hMSH2, and hMSH6 with the rare occurrence in hMLH3, PMS1, and PMS2). Clinically, Lynch syndrome, the most common hereditary disorder predisposing to CRC, is characterised by a greater than 80% lifetime risk of CRC in concert with an excess of several extracolonic cancers namely, endometrial, gastric, pancreatic, small bowel, ovarian, and transitional cell carcinoma of the upper uroepithelial tract (ureter and renal pelvis). Thus diagnosing Lynch syndrome is of considerable importance in order to institute a wide range of cancer surveillance strategies for affected subjects. However, establishing the diagnosis is challenging and requires both considerable knowledge and vigilance. The potential reasons for overlooking the diagnosis of HNPCC include: