Molecular genetic analysis of hereditary non-polyposis colorectal cancer syndrome
- Cambridge Univ. (United Kingdom)
- Addenbrooke`s Hospital, Cambridge (United Kingdom); and others
HNPCC is estimated to account for 5-10% of all cases of colorectal cancer. Recently genes for HNPCC have been mapped to chromosomes 2p and 3p and candidate genes (hMSH2 and hMLH1) have been identified. We have investigated the molecular pathology of HNPCC by linkage analysis and direct mutation analysis. 14 HNPCC families were investigated for linkage to hMSH2 and hMLH1 with microsatellite markers at D2S119, D2S123, D2S136, D2S391, D2S378 and D3S1007, D3S1029, D3S1076, D3S1298, D3S1611, respectively. Overall the only significant linkage was obtained with D2S123 (Zmax=3.77 at {theta}=0.0), but locus heterogeneity was confirmed: linkage to hMSH2 and hMLH1 was excluded in 6 and 5 families, respectively. 3 families were uniformative for linkage/exclusion to either candidate gene, but no evidence for a third HNPCC locus could be detected. There was no correlation between clinical phenotype (Lynch type I or II) and the results of linkage analysis. No individual family gave a lod score of >3 with any marker, and only a minority of our HNPCC families have been suitable for genetic linkage analysis. We therefore screened affected individuals from 37 unrelated kindreds for mutations in hMSH2 and exons 3 and 4 of the APC gene. Mutation screening was performed using exon specific primers and SSCP analysis. No abnormalities were found in the APC exons suggesting that mutations in these APC 5{prime} exons are not a common cause of HNPCC. hMSH2 screening is continuing, and one missense mutation in a highly conserved codon 322 in exon 6 has been identified.
- OSTI ID:
- 133498
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0226
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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