Close linkage to chromosome 3p and conservation of ancestral founding haplotype in hereditary nonpolyposis colorectal cancer families.
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.
Department of Medical Genetics, University of Helsinki, Finland.
M
M
Nyström-Lahti
P
P
Sistonen
J P
JP
Mecklin
L
L
Pylkkänen
L A
LA
Aaltonen
H
H
Järvinen
J
J
Weissenbach
A
A
de la Chapelle
P
P
Peltomäki
D000236:Adenoma / Q000235:genetics; D000483:Alleles; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004276:DNA, Satellite / Q000235:genetics; D005260:Female; D005387:Finland; D008040:Genetic Linkage; D005819:Genetic Markers; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008126:Lod Score; D008297:Male; D010375:Pedigree; D012042:Registries; D012984:Software
D004276:DNA, Satellite; D005819:Genetic Markers