Dataset Information

Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.

ABSTRACT:

Background

Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations of mismatch repair genes, usually in hMLH1 or hMSH2. All earlier studies on penetrance except one population based study were conducted in HNPCC families and did not correct for the way in which these families were ascertained.

Objective

To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 genes.

Methods

Families with known germline mutations of hMLH1 (n = 39) and hMSH2 (n = 45) were extracted from the Dutch HNPCC cancer registry. Ascertainment-corrected maximum likelihood estimation was carried out on a competing risks model for cancer of the colorectum and endometrium.

Results

Both loci were analysed jointly as there was no significant difference in risk (p = 0.08). At age 70, colorectal cancer risk for men was 26.7% (95% confidence interval, 12.6% to 51.0%) and for women, 22.4% (10.6% to 43.8%); the risk for endometrial cancer was 31.5% (11.1% to 70.3%).

Conclusions

Current estimates of the CRC risk of mutations to the hMLH1 and hMSH2 locus should be replaced by considerably lower risks which account for the selection of the families.

SUBMITTER: Quehenberger F

PROVIDER: S-EPMC1736072 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

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Publications

Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.

Quehenberger F F Vasen H F A HF van Houwelingen H C HC

Journal of medical genetics 20050601 6

<h4>Background</h4>Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations of mismatch repair genes, usually in hMLH1 or hMSH2. All earlier studies on penetrance except one population based study were conducted in HNPCC families and did not correct for the way in which these families were ascertained.<h4>Objective</h4>To obtain estimates of the risk of colorectal cancer (CRC) and endometrial cancer (EC) for carriers of disease causing mutations of the hMSH2 and hMLH1 g ...[more]

PMID: 15937084

Similar Datasets

Project description:BackgroundMutations in the mismatch repair genes hMLH1 and hMSH2 predispose to hereditary non-polyposis colorectal cancer (HNPCC). Genetic screening of more than 350 Danish patients with colorectal cancer (CRC) has led to the identification of several new genetic variants (e.g. missense, silent and non-coding) in hMLH1 and hMSH2. The aim of the present study was to investigate the frequency of these variants in hMLH1 and hMSH2 in Danish patients with sporadic colorectal cancer and in the healthy background population. The purpose was to reveal if any of the common variants lead to increased susceptibility to colorectal cancer.MethodsAssociations between genetic variants in hMLH1 and hMSH2 and sporadic colorectal cancer were evaluated using a case-cohort design. The genotyping was performed on DNA isolated from blood from the 380 cases with sporadic colorectal cancer and a sub-cohort of 770 individuals. The DNA samples were analyzed using Single Base Extension (SBE) Tag-arrays. A Bonferroni corrected Fisher exact test was used to test for association between the genotypes of each variant and colorectal cancer. Linkage disequilibrium (LD) was investigated using HaploView (v3.31).ResultsHeterozygous and homozygous changes were detected in 13 of 35 analyzed variants. Two variants showed a borderline association with colorectal cancer, whereas the remaining variants demonstrated no association. Furthermore, the genomic regions covering hMLH1 and hMSH2 displayed high linkage disequilibrium in the Danish population. Twenty-two variants were neither detected in the cases with sporadic colorectal cancer nor in the sub-cohort. Some of these rare variants have been classified either as pathogenic mutations or as neutral variants in other populations and some are unclassified Danish variants.ConclusionNone of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified.

Dataset Information

Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.

Background

Objective

Methods

Results

Conclusions

Publications

Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment.

Similar Datasets

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