A population based cohort study of patients with multiple colon and endometrial cancer: Correlation of microsatellite instability (MSI) status, age at diagnosis and cancer risk

Hereditary non polyposis colorectal cancer, HNPCC, is an autosomal dominant condition predisposing to cancers of primarily the colorectum and the endo metrium. The aim of our study was to identify persons at a high risk of her editary colorectal cancer and to estimate their risk of colon and other HNP CC-associated tumours. Family histories of cancer were obtained on 89 perso ns with double primary (PP) cancers of the colon and the endometrium. The c ancer risks in their 649 first-degree-relatives (FDR) were analysed. The mi crosatellite instability (MSI) status of the tumour of the proband was also analysed and the cancer risks were estimated in relation to MSI status and age at diagnosis in the proband (over or under 50 years). The overall stan dardised incidence ratio (SIR) was 1.69 (95% Cl; 1.39-2.03). In the 50-year -old cohort the SIR was 2.67 (95% Cl; 2.08-3.38), Colon, rectal and uterus cancer exhibited significantly increased risks. This risk was further incre ased in the = 50-year-old MSI positive families. Several 50-year-old MSI ne gative HNPCC-like families with increased risks were also identified. In co nclusion a FDR to a person with a DP cancer of the colorectum or the colon/ endometrium have a significantly increased risk of having a colorectal or o ther HNPCC-associated cancers if the proband is diagnosed with one of the c ancers before age 50. These families are candidates for genetic counselling and colorectal screening programmes. Mutations in mismatch repair genes ca n explain some of the increased risk in these families, but mutations in MS I negative families are probably due to other colon cancer susceptibility g enes not yet described. (C) 2001 Wiley-Liss, Inc.