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A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer.
J Med Genet. 1999 Feb; 36(2):97-102.JM

Abstract

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.

Authors+Show Affiliations

Cambridge University, Department of Pathology, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

10051005

Citation

Froggatt, N J., et al. "A Common MSH2 Mutation in English and North American HNPCC Families: Origin, Phenotypic Expression, and Sex Specific Differences in Colorectal Cancer." Journal of Medical Genetics, vol. 36, no. 2, 1999, pp. 97-102.
Froggatt NJ, Green J, Brassett C, et al. A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. J Med Genet. 1999;36(2):97-102.
Froggatt, N. J., Green, J., Brassett, C., Evans, D. G., Bishop, D. T., Kolodner, R., & Maher, E. R. (1999). A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. Journal of Medical Genetics, 36(2), 97-102.
Froggatt NJ, et al. A Common MSH2 Mutation in English and North American HNPCC Families: Origin, Phenotypic Expression, and Sex Specific Differences in Colorectal Cancer. J Med Genet. 1999;36(2):97-102. PubMed PMID: 10051005.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A common MSH2 mutation in English and North American HNPCC families: origin, phenotypic expression, and sex specific differences in colorectal cancer. AU - Froggatt,N J, AU - Green,J, AU - Brassett,C, AU - Evans,D G, AU - Bishop,D T, AU - Kolodner,R, AU - Maher,E R, PY - 1999/3/2/pubmed PY - 1999/3/2/medline PY - 1999/3/2/entrez SP - 97 EP - 102 JF - Journal of medical genetics JO - J Med Genet VL - 36 IS - 2 N2 - 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. SN - 0022-2593 UR - https://www.unboundmedicine.com/medline/citation/10051005/A_common_MSH2_mutation_in_English_and_North_American_HNPCC_families:_origin_phenotypic_expression_and_sex_specific_differences_in_colorectal_cancer_ L2 - https://jmg.bmj.com/lookup/pmidlookup?view=long&amp;pmid=10051005 DB - PRIME DP - Unbound Medicine ER -