Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis

Walsh, Michael D.; Buchanan, Daniel D.; Walters, Rhiannon; Roberts, Aedan; Arnold, Sven; McKeone, Diane; Clendenning, Mark; Ruszkiewicz, Andrew; Jenkins, Mark A.; Hopper, John L.; Goldblatt, Jack; George, J.P. St.; Suthers, Graeme; Phillips, Kerry; Young, Graeme P.; Macrae, Finlay; Drini, Musa; Woods, Michael O.; Parry, Susan; Jass, Jeremy R.; Young, Joanne

doi:10.1007/s10689-009-9238-8

Cited by 21 publications

(28 citation statements)

References 39 publications

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“…A single false-negative was identified adding to the increasing number of LS tumors harboring a BRAF mutation. 22 In contrast, its specificity is low. Two factors may account for this observation.…”

Section: Discussionmentioning

confidence: 99%

“…37 This case shares a BRAF mutation and promoter hypermethylation, the expected scenario for a non-LS tumor. 10,11,14,15 Walsh et al 22 reported the presence of a BRAF mutation in a member of a LS family that, also showed predisposition to develop colorectal serrated polyps. Interestingly, some evidence suggests that non-LS MSI-H cases may originate from sessile serrated adenoma.…”

Section: Discussionmentioning

confidence: 99%

“…10,11,[16][17][18][19][20][21] Occasionally, BRAF mutations have been detected in LS patients. 22 Methylation of the MLH1 promoter, leading to a loss of MLH1 expression, is also strongly associated with sporadic MSI-positive CRCs. MLH1 promoter hypermethylation has been also evaluated for the selection of patients that will not be tested for germline mutation.…”

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: 99%

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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“…Although lack of BRAF mutation is highly sensitive for a syndromic tumor, rare BRAF mutations have been described in patients with Lynch syndrome. 14,20 As well, BRAF V600E mutations have been described in Lynch syndrome probands with monoallelic PMS2 mutations. 21 Testing for BRAF mutations can be performed by Sanger sequencing and pyrosequencing, allele-specific reverse transcription-PCR, mass spectrometry-based sequencing, high-resolution melting curve analysis, and next-generation sequencing methods using microfluidics technology, among others.…”

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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“…However, four studies have identified 16! the BRAF V600E mutation and a germline MMR gene mutation in MLH1, MSH2 and PMS2 32,82,260,261 . Therefore the presence of a BRAF V600E mutation in a CRC, while a strong negative predictor of carrying a MMR mutation should not be assumed to exclude positive mutation status for any of the four MMR genes, particularly in the context of a family history suggestive of LS.…”

Section: Mlh1 Promoter Methylation and Braf V600ementioning

confidence: 99%

Interpreting the clinical significance of mismatch repair gene sequence variants

Thompson¹

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The clinical classification of inherited nucleotide sequence variants identified in disease-related genes has a direct impact on the clinical management of patients and their families. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). However, ~30% of MMR gene variants identified in suspected Lynch cases are of uncertain clinical significance, which constitutes a challenge for genetic counselling and clinical management of families. In the past there has been no uniform system to tackle these variants, and mainly ad hoc methods have been utilized to determine if they are disease causing. The multifactorial likelihood model approach was initially developed for the evaluation of sequence variants in the BRCA1/2 cancer predisposition genes. It was adapted for MMR gene variants to provide a quantitative measure of risk in the form of probability of pathogenicity. Estimates of prior probability of pathogenicity based on evolutionary sequence conservation and physicochemical characteristics of predicted alterations were combined with variant segregation information and tumour features. Microsatellite instability (MSI) and somatic BRAF V600E tumour data for unselected colorectal cancer probands of known pathogenic variant status were used to derive likelihood ratios (LR) for tumour characteristics using the Colon Cancer Family Registry resource.The LR in favour of pathogenicity was estimated to be ~12-fold for a MSI and BRAF V600E mutation-negative colorectal tumour. Our findings provide a working multifactorial likelihood model for classifications that carefully considers mode of ascertainment for gene testing.

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Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis

Cited by 21 publications

References 39 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

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

Interpreting the clinical significance of mismatch repair gene sequence variants

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