Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families

Abstract

A susceptibility to hereditary nonpolyposis colorectal cancer (HNPCC) was recently shown to be due to mutations in the MSH2 gene on chromosome 2p. A second susceptibility locus has been mapped to chromosome 3p in two families. The present report describes the results of a genetic study of Finnish HNPCC kindreds. Of 18 apparently unrelated families living in different parts of the country, 11 could be genealogically traced to a common ancestry dating at least 13 generations back in a small geographic area. Linkage studies were possible in 9 families, revealing conclusive or probable linkage to markers on 3p in 8. Five of these were among those having shared ancestry. The location of the gene was refined by a linkage study comprising 12 marker loci. By analysis of recombinations in such families, the HNPCC locus could be assigned to the 1-centimorgan interval between marker loci D3S1561 and D3S1298. A haplotype encompassing 10 centimorgans around the HNPCC locus was conserved in five of the pedigrees with shared ancestry and present in 2 further families in which linkage analysis was not possible. Our results suggest the presence of a widespread single ancestral founding mutation. Moreover, the map position of the 3p gene for HNPCC susceptibility was greatly refined.