Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases

Mueller, James; Gazzoli, Isabella; Bandipalliam, Prathap; Garber, Judy E.; Syngal, Sapna; Kolodner, Richard D.

doi:10.1158/0008-5472.can-09-0358

Cited by 40 publications

(56 citation statements)

References 48 publications

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“…The five single-gate studies 34,[57][58][59][60] that were based on high-risk populations all applied different criteria to select participants for inclusion. For two 34,57 of these studies the participant inclusion criteria were unclear, report data from two distinct samples, a population-based sample and a high-risk sample.…”

Section: Single-gate Studies Recruiting High-risk Populationsmentioning

confidence: 99%

“…The remaining three single-gate studies appeared to include participants who were at high risk because of their family history (see Table 6). These five studies varied in size, with the largest study being that by Poynter et al, 34 which recruited 172 participants, and the smallest being that by Mueller et al, 58 which recruited 48 participants.…”

Section: Assessment Of Test Accuracymentioning

confidence: 99%

“…Five of these studies used a single-gate design. 34,[57][58][59][60] The remaining two studies used variations on a two-gate study design; 61,62 in these two studies participants with positive reference standard results were recruited but no reference standard negatives were recruited, thus resembling half of a two-gate design from which sensitivity estimates could be obtained. These studies do not, therefore, have two gates and from this point forward, for clarity, they will be referred to as reference standard-positive studies.…”

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confidence: 99%

“…The study by Caldes et al 57 followed this with Southern blot analysis to detect large deletions whereas Overbeek et al 60 used DHPLC analysis and direct sequencing but this was followed by multiplex PCR of short fluorescent fragments for the detection of large deletions. The study by Mueller et al 58 provided limited details on the reference standard, although it was clearly specified that MLPA was used.…”

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confidence: 99%

“…All five of the single-gate studies based on high-risk populations investigated mutations in MLH1, MSH2 and MSH6, 34,[57][58][59][60] although, as mentioned above, Poynter et al 34 used only direct sequencing to detect MSH6 mutations in cases with absent IHC staining of MSH6. In addition, Overbeek et al 59 investigated mutations in PMS2 in all cases and Mueller et al 58 investigated mutations in PMS2 only in cases that were negative for mutations in MLH1, MSH2 and MSH6.…”

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confidence: 99%

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Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Snowsill

Coelho

Huxley

et al. 2017

Health Technol Assess

112

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BackgroundInherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests – microsatellite instability (MSI) and MMR immunohistochemistry (IHC) – are used in CRC patients to identify individuals at high risk of LS for genetic testing.MLH1(MutL homologue 1) promoter methylation andBRAFV600E testing can be conducted on tumour material to rule out certain sporadic cancers.ObjectivesTo investigate whether testing for LS in CRC patients using MSI or IHC (with or withoutMLH1promoter methylation testing andBRAFV600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources.Review methodsSystematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors.ResultsTen studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC,BRAFV600E andMLH1promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective.LimitationsMost of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted.ConclusionsSystematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients.Study registrationThis study is registered as PROSPERO CRD42016033879.FundingThe National Institute for Health Research Health Technology Assessment programme.

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Section: Single-gate Studies Recruiting High-risk Populationsmentioning

confidence: 99%

Section: Assessment Of Test Accuracymentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Snowsill

Coelho

Huxley

et al. 2017

Health Technol Assess

112

View full text Add to dashboard Cite

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De novo constitutional MLH1 epimutations confer early‐onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one

Goel

Nguyen

Leung

et al. 2010

Intl Journal of Cancer

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Lynch syndrome is an autosomal dominant cancer predisposition syndrome classically caused by germline mutations of the mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Constitutional epimutations of the MLH1 gene, characterized by soma-wide methylation of a single allele of the promoter and allelic transcriptional silencing, have been identified in a subset of Lynch syndrome cases lacking a sequence mutation in MLH1. We report two individuals with no family history of colorectal cancer who developed that disease at age 18 and 20 years. In both cases, cancer had arisen because of the de novo occurrence of a constitutional MLH1 epimutation and somatic loss-of-heterozygosity of the functional allele in the tumors. We show for the first time that the epimutation in one case arose on the paternally inherited allele. Analysis of 13 tumors from seven individuals with constitutional MLH1 epimutations showed eight tumors had lost the second MLH1 allele, two tumors had a novel pathogenic missense mutation and three had retained heterozygosity. Only 1 of 12 tumors demonstrated the BRAF V600E mutation and 3 of 11 tumors harbored a mutation in KRAS. The finding that epimutations can originate on the paternal allele provides important new insights into the mechanism of origin of epimutations. It is clear that the second hit in MLH1 epimutation-associated tumors typically has a genetic not epigenetic basis. Individuals with mismatch repair–deficient cancers without the BRAF V600E mutation are candidates for germline screening for sequence or methylation changes in MLH1.

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Evidence for presence of mismatch repair gene expression positive Lynch syndrome cases in India

Bashyam

Kotapalli

Ratheesh

et al. 2014

Molecular Carcinogenesis

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Lynch syndrome (LS), the most common form of familial CRC predisposition that causes tumor onset at a young age, is characterized by the presence of microsatellite instability (MSI) in tumors due to germline inactivation of mismatch repair (MMR) system. Two MMR genes namely MLH1 and MSH2 account for majority of LS cases while MSH6 and PMS2 may account for a minor proportion. In order to identify MMR genes causing LS in India, we analyzed MSI and determined expression status of the four MMR genes in forty eight suspected LS patient colorectal tumor samples. Though a majority exhibited MSI, only 58% exhibited loss of MMR expression, a significantly low proportion compared to reports from other populations. PCR-DNA sequencing and MLPA-based mutation and exonic deletion/duplication screening respectively, revealed genetic lesions in samples with and without MMR gene expression. Interestingly, tumor samples with and without MMR expression exhibited significant differences with respect to histological (mucin content) and molecular (instability exhibited by mononucleotide microsatellites) features. The study has revealed for the first time a significant proportion of LS tumors not exhibiting loss of MMR expression.

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Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases

Cited by 40 publications

References 48 publications

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation

De novo constitutional MLH1 epimutations confer early‐onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one

Evidence for presence of mismatch repair gene expression positive Lynch syndrome cases in India

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