• cancer predisposition
• early diagnosis
• germline mutation
• Lynch syndromes

Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is a dominantly inherited condition, recognised by Lynch et al¹ in 1966, associated with a major susceptibility to colorectal and endometrial cancer. The use of stringent criteria in the definition of the syndrome led to the initial identification of two genes, MSH2 and MLH1, which when mutated are responsible for the cancer susceptibility. Mutations in these two genes may account for up to two-thirds of all HNPCC cases.² More recently, additional genes such as MSH6, PMS1, PMS2, MLH3, TGFβRII, and EXO1 have also been implicated. Together deleterious mutations of these genes account for less than 10% of the cases.

In addition to the colorectum and endometrium, a variety of different sites have been reported to be at an increased risk of cancer in HNPCC patients. Indeed, studies based on either family history or on small groups of patients with identified mutations suggested that carcinomas of the ureter, stomach, small bowel, ovary, and biliary tract^1,3 were more frequently encountered than in the general population. In addition to this tumour spectrum, the presence of sebaceous skin tumours and keratoacanthomas or of glioblastomas defines two different subsets within the HNPCC syndrome, called Muir-Torre⁴ or Turcot⁵ syndromes, respectively. Finally, more recently, an excess of breast cancer has also been reported but remains controversial.⁶

Following these descriptions, several management and follow up programmes for HNPCC families have been proposed.^7,8 To delineate these procedures more precisely, it would be useful to gain further insight into the associated risks of MSH2 and MLH1 mutations.

Prospective recruitment of 436 consecutive patients referred to a French family cancer clinic enabled the identification of 348 subjects from 163 families with an established deleterious mutation in either MSH2 or MLH1 …