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Title: Mutator gene and hereditary non-polyposis colorectal cancer

Abstract

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

Inventors:
 [1];  [2];  [2]
  1. Helsingfors, FI
  2. Baltimore, MD
Publication Date:
Research Org.:
ELEANOR ROOSEVELT INSTITUTE
Sponsoring Org.:
USDOE
OSTI Identifier:
983105
Patent Number(s):
7,326,778
Application Number:
08/160,295
Assignee:
The John Hopkins University (Baltimore, MD) CHO
DOE Contract Number:
FG02-91ER61139
Resource Type:
Patent
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

de la Chapelle, Albert, Vogelstein, Bert, and Kinzler, Kenneth W. Mutator gene and hereditary non-polyposis colorectal cancer. United States: N. p., 2008. Web.
de la Chapelle, Albert, Vogelstein, Bert, & Kinzler, Kenneth W. Mutator gene and hereditary non-polyposis colorectal cancer. United States.
de la Chapelle, Albert, Vogelstein, Bert, and Kinzler, Kenneth W. Tue . "Mutator gene and hereditary non-polyposis colorectal cancer". United States. doi:. https://www.osti.gov/servlets/purl/983105.
@article{osti_983105,
title = {Mutator gene and hereditary non-polyposis colorectal cancer},
author = {de la Chapelle, Albert and Vogelstein, Bert and Kinzler, Kenneth W},
abstractNote = {The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.},
doi = {},
journal = {},
number = ,
volume = ,
place = {United States},
year = {Tue Feb 05 00:00:00 EST 2008},
month = {Tue Feb 05 00:00:00 EST 2008}
}

Patent:

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  • 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 excludedmore » 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.« less
  • The diagnosis of HNPCC was made in 16 individuals over three generations in a large kindred from the northwestern region of South Africa, on the basis of clinical, surgical and pathological data and hospital or family records; all affecteds were males. We have excluded potential candidate genes and regions on chromosomes 1, 5, 6, 8, 9, 17 and 22 by linkage analysis. Following reports of two genes underlying HNPCC, namely hMSH2 and hMLH1, on chromsomes 2 and 3 respectively, we have shown that the disorder in the SA HNPCC family cosegregates with a specific hMLH1 gene-associated haplotype on chromosome 3.more » Interestingly, at least one female asymptomatic carrier of the disease-associated haplotype, who is more than 70 years of age, has been identified. Four asymptomatic males who are carriers of the disease-associated haplotype have been identified, but they are all below 40 years of age. Two notable features of the disorder in this family include the extreme sex bias and lack of non-colonic malignancies which might be expected in HNPCC. We are currently investigating the hMLH1 gene for mutations which might explain the unusual phenotype of the disease in this kindred, and looking for an explanation for the apparent sex based difference in the segregation of the disorder.« less
  • A probabilistic analysis has been developed to assist the binary classification and risk assessment of members of familial colon cancer kindreds. The analysis is based on the microautoradiographic observation of (/sup 3/H)thymidine-labeled epithelial cells in colonic mucosa of the kindred members. From biopsies of colonic mucosa which are labeled with (/sup 3/H)thymidine in vitro, the degree of similarity of each subject's cell-labeling pattern measured over entire crypts was automatically compared to the labeling patterns of high-risk and low-risk reference populations. Each individual was then presumptively classified and assigned to one of the reference populations, and a degree of risk formore » the classification was provided. In carrying out the analysis, a linear score was calculated for each individual relative to each of the reference populations, and the classification was based on the polarity of the score difference; the degree of risk was then quantitated from the magnitude of the score difference. When the method was applied to kindreds having either familial polyposis or familial non-polyposis colon cancer, it effectively segregated individuals affected with disease from others at low risk, with sensitivity and specificity ranging from 71 to 92%. Further application of the method to asymptomatic family members believed to be at 50% risk on the basis of pedigree evaluation revealed a biomodal distribution to nearly zero or full risk. The accuracy and simplicity of this approach and its capability of revealing early stages of abnormal colonic epithelial cell development indicate potential for preclinical screening of subjects at risk in cancer-prone kindreds and for assisting the analysis of modes of inheritance.« less
  • Two susceptibility loci for hereditary nonpolyposis colorectal cancer (HNPCC) have been identified, and each contains a mismatch repair gene: MSH2 on chromosome 2p and MLH1 on chromosome 3p. We studied the involvement of these loci in 13 large HNPCC kindreds originating from three different continents. Six families showed close linkage to the 2p locus, and a heritable mutation of the MSH2 gene was subsequently found in four. The 2p-linked kindreds included a family characterized by the lack of extracolonic manifestations (Lynch I syndrome), as well as two families with cutaneous manifestations typical of the Muir-Torre syndrome. Four families showed evidencemore » for linkage to the 3p locus, and a heritable mutation of the MLH1 gene was later detected in three. One 3p-linked kindred was of Amerindian origin. Of the remaining three families studied for linkage, one showed lod scores compatible with exclusion of both MSH2 and MLH1, while lod scores obtained in the other two families suggested exclusion of one HNPCC locus (MSH2 or MLH1) but were uninformative for markers flanking the other locus. Our results suggest that mismatch repair genes on 2p and 3p account for a major share of HNPCC in kindreds that can be evaluated by linkage analysis. 36 refs., 2 figs., 3 tabs.« less
  • Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% ofmore » the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for >20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services. 34 refs., 3 figs., 2 tabs.« less