Coexisting somatic promoter hypermethylation and pathogenic <i>MLH1</i> germline mutation in Lynch syndrome

Rahner, Nils; Friedrichs, Nicolaus; Steinke, Verena; Aretz, Stefan; Friedl, Waltraut; Buettner, Reinhard; Mangold, Elisabeth; Propping, Peter; Walldorf, Constanze

doi:10.1002/path.2263

Cited by 67 publications

(38 citation statements)

References 22 publications

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“…23,25,28 However, we show that MS-MLPA offers a better yield in the routine clinical diagnostic setting, 21 since has been a robust methodology, with low variability and good analytical sensitivity when using the highly degraded DNA extracted from FFPE blocks. The definition of clinically meaningful cutoff values is crucial.…”

Section: Discussionmentioning

confidence: 82%

“…The concomitant existence of BRAF mutations or MLH1 promoter hypermethylation in LS patients has been extensively documented. 10,11,13,16,[18][19][20][21][26][27][28] The clinical usefulness of MLH1 hypermethylation analysis relies, in part, on the low prevalence observed. MLH1 hypermethylation analysis does not only outperform BRAF mutation analysis but it is also more cost-effective, in terms of incremental cost per additional MLH1 mutation carrier detected.…”

Section: Discussionmentioning

confidence: 99%

“…[23][24][25] However, the identification of hypermethylation in a limited number of LS tumors has made its use controversial. 10,[26][27][28] Issues that affect screening include the accuracy, sensitivity, and specificity of the test, the benefit to the patient, the possible negative ramifications of the results, and the cost. 8,[29][30][31] Before routine implementation in the clinical setting, it is critical to assess the analytical and clinical validity and the cost-effectiveness of BRAF mutation and MLH1 promoter hypermethylation.…”

Section: Introductionmentioning

confidence: 99%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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“…81 Furthermore, rare cases of MLH1 promoter hypermethylation with simultaneous MLH1 or MSH2 germ line mutation have been described. 82 These rare phenomena should be considered if unusual staining patterns are encountered, and the addition of MSI testing may be helpful to confirm the immunohistochemical findings. Interpretations of various MMR protein immunostaining patterns and recommendations for further workup are summarized in Table 3.…”

Section: Interpretation Of Mismatch Repair Protein Immunostainsmentioning

confidence: 99%

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas

Wang¹,

Kim²,

Koo³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Objectives.— To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. Data Sources.— Data sources include literature review, authors' research data, and personal practice experience. Conclusions.— Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.

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“…However, hypermethylation has also been identified in Lynch syndrome-associated tumors. 14,29,30 Up to 68% of colorectal cancers with MLH1 promoter hypermethylation have the V600E mutation, so cases without this mutation should receive further workup. 7 If a BRAF V600E mutation is not detected, methylation analysis of the MLH1 promoter can be performed by using methylation-specific multiplex ligation-dependent probe amplification or methylationspecific PCR.…”

Section: Microsatellite Instability and Lynch Syndromementioning

confidence: 99%

Select Biomarkers for Tumors of the Gastrointestinal Tract: Present and Future

Bartley

Hamilton

2014

Archives of Pathology &Amp; Laboratory Medicine

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Context Advances in molecular biomarkers of the gastrointestinal tract have contributed to a decline in the incidence of and mortality from diseases of the gastrointestinal tract. The discovery and clinical validation of new biomarkers are important to personalized cancer therapy, and numerous clinical trials are currently ongoing to help identify individualized therapy affecting these biomarkers and molecular mechanisms they represent. Distinct molecular pathways leading to cancers of the colorectum, esophagus, stomach, small bowel, and pancreas have been identified. Using biomarkers in these pathways to direct patient care, including selection of proper molecular testing for identification of actionable mutations and reporting the results of these biomarkers to guide clinicians and genetic counselors, is paramount. Objective To examine and review select clinically actionable biomarkers of the colon, esophagus, stomach, small bowel, and pancreas, including present and future biomarkers with relevant clinical trials. Data Sources Extensive literature review and practical and consultation experience of the authors. Conclusions Although numerous biomarkers have been identified and are currently guiding patient therapy, few have shown evidence of clinical utility in the management of patients with gastrointestinal cancers. Inconsistent results and discordant proposed algorithms for testing were identified throughout the literature; however, the potential for biomarkers to improve outcomes for patients with gastrointestinal cancer remains high. Continued advances through high-quality studies are needed.

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Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome

Cited by 67 publications

References 22 publications

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas

Select Biomarkers for Tumors of the Gastrointestinal Tract: Present and Future

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