Document Detail

A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.
MedLine Citation:
PMID:  10051005     Owner:  NLM     Status:  MEDLINE    
The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.
N J Froggatt; J Green; C Brassett; D G Evans; D T Bishop; R Kolodner; E R Maher
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of medical genetics     Volume:  36     ISSN:  0022-2593     ISO Abbreviation:  J. Med. Genet.     Publication Date:  1999 Feb 
Date Detail:
Created Date:  1999-05-12     Completed Date:  1999-05-12     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  2985087R     Medline TA:  J Med Genet     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  97-102     Citation Subset:  IM    
Cambridge University, Department of Pathology, UK.
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MeSH Terms
Age Factors
Chromosomes, Human, Pair 2 / genetics
Colorectal Neoplasms / genetics*
Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
DNA-Binding Proteins*
Endometrial Neoplasms / genetics
Founder Effect
Gene Expression
MutS Homolog 2 Protein
North America
Ovarian Neoplasms / genetics
Point Mutation
Polymorphism, Single-Stranded Conformational
Proto-Oncogene Proteins / genetics*
Risk Factors
Sequence Analysis, DNA
Sex Factors
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Proto-Oncogene Proteins; EC protein, human; EC Homolog 2 Protein

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