Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder that predisposes to predominantly colorectal and endometrial cancers due to germline mutations in DNA mismatch repair genes, mainly MLH1, MSH2 and in families with excess endometrial cancer also MSH6. In this population‐based study, we analysed the mutation spectrum of the MLH1, MSH2 and MSH6 genes in a cohort of patients with microsatellite unstable double primary tumours of the colorectum and the endometrium by PCR, DHPLC and sequencing. Fourteen of the 23 patients (61%) had sequence variants in MLH1, MSH2 or MSH6 that likely affect the protein function. A majority (10/14) of the mutations was found among probands diagnosed before age 50. Five of the mutations (36%) were located in MLH1, 3 (21%) in MSH2 and 6 (43%) in MSH6. MSH6 seem to have larger impact in our population than in other populations, due to a founder effect since all of the MSH6 families originate from the same geographical area. MSH6 mutation carriers have later age of onset of both colorectal cancer (62 vs. 51 years) and endometrial cancer (58 vs. 48 years) and a larger proportion of endometrial cancer than MLH1 or MSH2 mutation carriers. We can conclude that patients with microsatellite unstable double primary cancers of the colorectum and the endometrium have a very high risk of carrying a mutation not only in MLH1 or MSH2 but also in MSH6, especially if they get their first cancer diagnosis before the age of 50. © 2004 Wiley‐Liss, Inc.