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fact
sheet
Mismatch
Repair Genes hMLH1 and hMSH2 and Colorectal Cancer
Rory J.
Mitchell
University of Edinburgh
HuGE Review
Published
February 10, 2003
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Gene |
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The
human mutL homologue hMLH1 is located at chromosome 3p21-23, and
the gene product is a component of the DNA mismatch repair pathway. The
gene product of the mutS homologue hMSH2 is another component of
this pathway, and the gene is located at chromosome 2p21. |
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Prevalence of
Gene Variants |
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Thus
far more than 200 different variants have been characterized in each of
the hMLH1 and hMSH2 mismatch repair genes. Variants in hMLH1
and hMSH2 are highly heterogeneous, and classification by
pathogenicity is subject to interpretation based on predicted effect on
protein, segregation with disease, and presence in control subjects where
such data are available. Classification of variants by the authors of the
accompanying HuGE review revealed that 259 pathogenic mutations and 45
polymorphisms have been reported in hMLH1, while 191 pathogenic
mutations and 55 polymorphisms have been identified in hMSH2
(1)
.
However, these figures are affected by substantial publication bias and
the actual number of polymorphic variants is likely to be much higher.
Because of the costs involved in conducting thorough mutation analysis of
these genes, data on prevalence of gene variants are largely confined to
colorectal cancer cases. The only published estimate of the prevalence of
mutations in the population estimated that 1 in 3139 (95% CI = 1:1247,
1:7626) members of the population of Scotland carried a pathogenic
mutation
(2)
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Founder effects, in which many mutation carriers can be traced to a common
ancestor, are known to exist in some populations, notably that of Finland.
Otherwise, available data provide no evidence for ethnic or population
variation. |
Disease
Burden |
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Colorectal
cancer is a major public health problem throughout the world. Several
dietary and environmental risk factors have been identified, and there is
also a significant genetic contribution to the aetiology of the condition.
A small proportion of all colorectal cancer cases cluster in families, or
occur at an unusually young age, and are therefore thought to have a
largely genetic basis. Pathogenic mutations in mismatch repair genes,
particularly hMLH1 and hMSH2, have most often been described
in association with such cases. The actual proportion of colorectal cancer
cases attributable to such mutations has not been determined but is likely
to be around 1%.
Evidence of a causal role for variants of hMLH1 and hMSH2
in a subset of colorectal cancer cases comes from both epidemiological and
molecular studies. However, conventional epidemiological evidence is
lacking because of the expense of mutation analysis in controls. The most
compelling evidence comes from studies demonstrating that mutation
carriers are at a significantly increased risk of developing colorectal
cancer compared with the general population
(3,4,5).
Estimates of lifetime risks from these studies suggest that the penetrance
of pathogenic mutations in hMLH1 and hMSH2 that are related
to colorectal cancer is around 80% in males and 40% in females.
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| Interactions |
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Currently limited evidence exists for interactions
between mismatch repair gene mutations and other known risk factors for
colorectal cancer. Further
exploration is merited for potential interactions with genetic risk
factors such as N-acetyltransferase and p53 and with environmental risk
factors such as smoking.
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| Laboratory
Tests
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A
wide variety of techniques and combinations of techniques have been
employed to identify variations in hMLH1 and hMSH2. These
include genomic sequencing, with an estimated sensitivity of 80%, and the
in vitro synthesized protein assay (IVSP), with a sensitivity of around
69%
(6)
. Other techniques,
such as denaturing gradient gel electrophoresis (DGGE) and single-strand
conformational polymorphism (SSCP), rely on alterations in DNA structure
to indicate the presence of mutations. Sensitivity is comparable to that
of IVSP.
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| Population
Testing |
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Information
regarding the prevalence and penetrance of mismatch repair gene mutations
as well as evidence of effective intervention strategies for mutation
carriers are currently insufficient to recommend population testing
outside of the research context. However, testing of early-onset
colorectal cancer cases and individuals with a significant family history
of colorectal cancer can be justified.
Such targeted testing enables additional mutation carriers to be
identified by “cascade” screening of relatives.
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| References |
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1.
Mitchell RJ et al. Mismatch repair genes hMLH1 and hMSH2 and colorectal
cancer: a HuGE review. Am J Epidemiol 2002;156:885-902.
2.
Dunlop MG et al. Population carrier frequency of hMSH2 and hMLH1
mutations. Br J Cancer 2000;83:1643-5.
3.
Aarnio M et al. Cancer risk in mutation carriers of DNA-mismatch-repair
genes. Int J Cancer 1999;81:214-8.
4.
Dunlop MG et al. Cancer risk associated with germline DNA mismatch repair
gene mutations. Hum Mol Genet 1997;6:105-10.
5.
Vasen HF et al. Cancer risk in families with hereditary nonpolyposis
colorectal cancer diagnosed by mutation analysis. Gastroenterology
1996;110:1020-7.
6. Farrington
SM et al. Systematic analysis of hMSH2 and hMLH1 in
young colon cancer patients and controls. Am J Hum Genet
1998;63:749-59.
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