Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

Syngal, Sapna; Fox, Edward A.; Eng, Charis; Kolodner, Richard D.; Garber, Judy E.

doi:10.1136/jmg.37.9.641

Cited by 263 publications

(187 citation statements)

References 23 publications

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“…The same yield of about 50% is found for families with less clinical indications of HNPCC but which, in addition, have MSI-high tumours (Terdiman et al, 2001;Raedle et al, 2001). Among families that only fulfil clinical criteria, usually not as stringent as the Amsterdam criteria, mutations are detected in about 30% of kindreds (Wijnen et al, 1998a;Bapat et al, 1999;Lamberti et al, 1999;Syngal et al, 2000;Wahlberg et al, 2002). Depending on the specific subgroup which is tested, the frequency of mutations may be lower than 10% or higher than 90%.…”

Section: Discussionmentioning

confidence: 78%

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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Section: Discussionmentioning

confidence: 78%

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

et al. 2002

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“…The Amsterdam II criteria were fulfilled by 58% of the mutation positive families, which is in accordance with other studies (Syngal et al. 2000; Sjursen et al. 2010; Steinke et al.…”

Section: Discussionmentioning

confidence: 99%

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Sjursen

McPhillips²,

Scott

et al. 2016

Molec Gen & Gen Med

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BackgroundLynch syndrome, the most frequent hereditary colorectal cancer syndrome, is caused by defects in mismatch repair genes. Genetic testing is important in order to identify mutation carriers who can benefit from intensive surveillance programs. One of the challenges with genetic testing is the interpretation of pathogenicity of detected DNA variants. The aim of this study was to investigate all putative pathogenic variants tested for at the Division of Molecular Medicine, Pathology North, in Newcastle, Australia, to establish whether previous variant classification is in accordance with that recently performed in the InSiGHT collaboration.MethodsPrediction programs and available literature were used to classify new variants or variants without classification.ResultsWe identified 333 mutation positive families, in which 211 different putative pathogenic mismatch repair mutations were found. Most variants with an InSiGHT classification (141 out of 146) were in accordance with our classification. Five variants were discordant, of which one can definitively be reclassified according to the InSiGHT scheme as class 5. Sixty‐four variants had not been classified by InSiGHT, of whom 55 have not been previously reported.ConclusionIn conclusion, we found that our classifications were mostly in accordance with the InSiGHT scheme. In addition to already known MMR mutations, we have also presented 55 novel pathogenic or putative pathogenic mutations.

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“…19,20,[31][32][33][34][35][36] Clearly, mutation analysis cannot be applied at a large scale and should only be offered to patients with substantial risk of having a deleterious mutation. Also, microsatellite analysis and immunohistochemistry, which have been shown to allow effective enrichment of high-risk patients, are presently not recommended for all cases of colorectal tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel

Forberg

Holinski‐Feder

et al. 2005

Intl Journal of Cancer

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Clinical criteria, microsatellite analysis (MSA) and immunohistochemistry (IHC) are important diagnostic tools for identification of hereditary nonpolyposis colorectal cancer (HNPCC) patients who are likely to carry pathogenic germline mutations in mismatch repair genes. Based on MSA and IHC results and subsequent mutation analyses of 1,119 unrelated index patients meeting the Amsterdam II criteria or the classical Bethesda guidelines, we analyzed the value of these tools to predict MLH1 and MSH2 mutations with the aim of establishing optimal strategies for their most efficient sequential use. The overall prevalence of pathogenic germline mutations in our cohort was 20.6% (95% CI 5 18.3-23.0%) and 61.8% (95% CI 5 56.8-66.6%), respectively, after MSA/IHC-based preselection. IHC was highly predictive (99.1%) and specific (99.6%) with regard to MSA. However, 14 out of 230 mutations (6%) escaped detection by IHC. Thus, IHC cannot be recommended to substitute MSA fully. Nonetheless, IHC is important to indicate the gene that is likely to be affected. To combine both methods efficiently, we propose a novel screening strategy that provides 2 alternative ways of sequential IHC and MSA application, either using IHC or MSA in the first place. A logistic regression model based on the age of the index patient at first tumor diagnosis and the number of fulfilled HNPCC criteria is used to allocate individual patients to that alternative pathway that is expected to be least expensive. A cost analysis reveals that about 25% of the costs can be saved using this strategy. ' 2005 Wiley-Liss, Inc.

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Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1

Cited by 263 publications

References 23 publications

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

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

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

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