Various Mutation Screening Techniques in the DNA Mismatch Repair Genes hMSH2 and hMLH1

Wahlberg, Siobhan; Liu, Tao; Lindblom, Per Henrik; Lindblom, Annika

doi:10.1089/109065799316563

Cited by 41 publications

(21 citation statements)

References 25 publications

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“…17 18 Methods used for mutation screening were denaturant gradient gel electrophoresis, protein truncation test, Southern blot, and direct sequencing. 19 …”

Section: Methodsmentioning

confidence: 99%

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer

Lindgren

Liljegren²,

Jaramillo³

et al. 2002

Gut

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Background and aims: Polypectomy in the colon has been shown to prevent colorectal cancer in both the general population and in familial colorectal cancer. Individuals with a family history of colorectal cancer have an increased risk of the disease. Over a period of 10 years, 304 subjects at risk were included in ongoing surveillance with regular colonoscopies. To compile the medical findings and experience generated during this period, a retrospective cross sectional study was performed. Subjects: Subjects were classified into three family groups: families with hereditary non-polyposis colorectal cancer (HNPCC); families with hereditary colorectal cancer (HCC, non-Lynch syndrome); and a third group of families with only empirical risk estimates based on a family history of two close relatives (TCR) with colorectal cancer. Methods: The risk population was studied with regard to age at onset, prevalence, number, cancer risk, size, dysplasia, and distribution of adenomas. A comparison was made within the family groups and with a reference group representing the general population. Results: In total, 195 adenomas and six cancers were detected among 85 individuals. The relative risk of having an adenoma in the whole risk population compared with the general population was 2.6. Subjects from TCR families had most adenomas and HNPCC subjects had the least. A shift from proximal adenomas to distal carcinomas in families with HCC and TCR suggested a higher cancer risk in distal adenomas in these syndromes. HNPCC families showed a younger age at onset and adenomas with a higher degree of dysplasia. In HNPCC, there was a similar localisation of adenomas and carcinomas, suggesting a high risk of cancer in all adenomas. Conclusions: There was clear overrepresentation of adenomas in all three family types compared with the reference population. In HNPCC, we found earlier onset of adenomas and faster progression to cancer. Families with HCC, and even more so TCR subjects, had a later onset and lower risk of cancer from proximal adenomas. Based on these results, surveillance protocols in Sweden have been revised.

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“…17 18 Methods used for mutation screening were denaturant gradient gel electrophoresis, protein truncation test, Southern blot, and direct sequencing. 19 …”

Section: Methodsmentioning

confidence: 99%

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer

Lindgren

Liljegren²,

Jaramillo³

et al. 2002

Gut

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“…These techniques are highly sensitive and specific for the detection of mutations in the coding regions of these genes (Wahlberg et al, 1999). Mutations in the promoter regions of MSH2 and MLH1 will not be detected by these methods; however, they seem to play a limited role (Shin et al, 2002).…”

Section: Genetics and Genomicsmentioning

confidence: 99%

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

et al. 2002

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Hereditary non-polyposis colorectal cancer is an autosomal dominant condition due to germline mutations in DNA-mismatchrepair genes, in particular MLH1, MSH2 and MSH6. Here we describe the application of a novel technique for the detection of genomic deletions in MLH1 and MSH2. This method, called multiplex ligation-dependent probe amplification, is a quantitative multiplex PCR approach to determine the relative copy number of each MLH1 and MSH2 exon. Mutation screening of genes was performed in 126 colorectal cancer families selected on the basis of clinical criteria and in addition, for a subset of families, the presence of microsatellite instability (MSI-high) in tumours. Thirty-eight germline mutations were detected in 37 (29.4%) of these kindreds, 31 of which have a predicted pathogenic effect. Among families with MSI-high tumours 65.7% harboured germline gene defects. Genomic deletions accounted for 54.8% of the pathogenic mutations. A complete deletion of the MLH1 gene was detected in two families. The multiplex ligation-dependent probe amplification approach is a rapid method for the detection of genomic deletions in MLH1 and MSH2. In addition, it reveals alterations that might escape detection using conventional diagnostic techniques. Multiplex ligation-dependent probe amplification might be considered as an early step in the molecular diagnosis of hereditary non-polyposis colorectal cancer.

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“…Thirty-one tumors from 15 HNPCC families, with known germline mutations in hMLH1 or hMSH2, were investigated (Liu et al, 2000;Wahlberg et al, 1999). In addition, 19 MSI-positive sporadic colorectal cancer cases selected from 191 consecutively collected tumors also were examined.…”

Section: Tumorsmentioning

confidence: 99%

Microsatellite Instability and hMLH1 and hMSH2 Expression Analysis in Familial and Sporadic Colorectal Cancer

Salahshor

Koelble

Rubio

et al. 2001

Laboratory Investigation

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SUMMARY:Immunohistochemical expression analysis of mismatch repair gene products has been suggested for the prediction of hereditary nonpolyposis colorectal cancer (HNPCC) carrier status in cancer families and the selection of microsatellite instability (MSI)-positive tumors in sporadic colorectal cancer. In this study, we aimed to evaluate hMSH2 and hMLH1 immunohistochemistry in familial and sporadic colorectal cancer. We found that immunohistochemistry allowed us to identify patients with germline mutations in hMSH2 and many cases with germline mutations in hMLH1. However, some missense and truncating mutations may be missed. In addition, hMLH1 promoter methylation, commonly occurring in familial and sporadic MSI-positive colorectal cancer, can complicate the interpretation of immunohistochemical expression analyses. Our results suggest that immunohistochemistry cannot replace testing for MSI to predict HNPCC carrier status or identify MSI-positive sporadic colorectal cancer. (Lab Invest 2001, 81:535-541).

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Various Mutation Screening Techniques in the DNA Mismatch Repair Genes hMSH2 and hMLH1

Cited by 41 publications

References 25 publications

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer

Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer

Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach

Microsatellite Instability and hMLH1 and hMSH2 Expression Analysis in Familial and Sporadic Colorectal Cancer

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