Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers

Sjursen, Wenche; Haukanes, Bjørn Ivar; Grindedal, Eli Marie; Aarset, Harald; Stormorken, Astrid; Engebretsen, Lars; Jonsrud, Christoffer; Bjørnevoll, Inga; Andresen, Per Arne; Ariansen, Sarah; Lavik, Liss Anne S.; Gilde, Bodil; Bowitz-Lothe, Inger Marie; Mæhle, Lovise; Møller, Pål

doi:10.1136/jmg.2010.077677

Cited by 81 publications

(66 citation statements)

References 31 publications

(39 reference statements)

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“…As in the study by Snowsill et al, 4 the proportions for each LS mutation were taken from the supplementary evidence in the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) review, 42 which stated that, for all true LS-positive patients, 32% have a MLH1 mutation, 39% have a MSH2 mutation, 14% have a MSH6 mutation and 15% have a PMS2 mutation ( Table 28). Reported family registry data can differ significantly from these values, particularly with respect to the proportion of PMS2 mutations identified 91,94,95 (see Table 28). This may potentially be because of PMS2 testing having historically occurred less in current practice than in the trials on which the EGAPP review based its values.…”

Section: Prevalence Of Lynch Syndromementioning

confidence: 99%

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: Prevalence Of Lynch Syndromementioning

confidence: 99%

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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“…The clinical criteria are useful for the identification of HNPCC, but only approximately half of the identified HNPCC families' harbor a pathogenic MMR mutation that can be reclassified as Lynch syndrome (Sjursen et al. 2010; Steinke et al. 2014).…”

Section: Introductionmentioning

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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“…SISA was the tool applied by the Mallorca group when demonstrating that ovarian cancer in MMR mutation carriers had better survival than expected [Grindedal et al, 2009b]. Missense mutations in our overview of deleterious mismatch-repair mutations demonstrated in Norway [Sjursen et al, 2010] were considered this way.…”

Section: Discussionmentioning

confidence: 99%

A simplified method for segregation analysis (SISA) to determine penetrance and expression of a genetic variant in a family

2011

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Current clinical criteria for Lynch syndrome are not sensitive enough to identify MSH6 mutation carriers

Cited by 81 publications

References 31 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

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

A simplified method for segregation analysis (SISA) to determine penetrance and expression of a genetic variant in a family

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