Hereditary nonpolyposis colorectal cancer in 95 families: Differences and similarities between mutation-positive and mutation-negative kindreds

Hereditary nonpolyposis colorectal cancer (HNPCC) describes the condition o f a disparate group of families that have in common a predisposition to col orectal cancer in the absence of a premalignant phenotype. The genetic basi s of this disease has been linked to mutations in genes associated with DNA mismatch repair. A large proportion of families harbor changes in one of t wo genes, hMSH2 and hMLH1. Approximately 35% of families in which the diagn osis is based on the Amsterdam criteria do not appear to harbor mutations i n DNA-mismatch-repair genes. In this report we present data from a large se ries of families with HNPCC and indicate that there are subtle differences between families that harbor germline changes in hMSH2 and families that ha rbor hMLH1 mutations. Furthermore, there are differences between the mutati on-positive group (hMSH2 and hMLH1. combined) of families and the mutation- negative group of families. The major findings identified in this study foc us primarily on the extracolonic disease profile observed between the mutat ion-positive families and the mutation-negative families. Breast cancer was not significantly overrepresented in the hMSH2 mutation-positive group but was overrepresented in the hMLH1 mutation-positive group and in the mutati on-negative group. Prostate cancer was not overrepresented in the mutation- positive groups but was overrepresented in the mutation-negative group. In age at diagnosis of colorectal cancer, there was no difference between the hMSH2 mutation-positive group and the hMLH1 mutation-positive group, but th ere was a significant difference between these two groups and the mutation- negative group.