Methylation Analysis of MLH1 Improves the Selection of Patients for Genetic Testing in Lynch Syndrome

Pérez–Carbonell, Lucía; Alenda, Cristina; Payá, Artemio; Castillejo, Adela; Barberá, Víctor Manuel; Guillén, Carmen; Rojas, Estefanía; Acame, Nuria; Gutiérrez-Aviño, Francisco José; Castells, Antoni; Llor, Xavier; Andreu, Montserrat; Soto, José Luís; Jover, Rodrigo

doi:10.2353/jmoldx.2010.090212

Cited by 67 publications

(59 citation statements)

References 25 publications

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“…In agreement with previous reports, the sensitivity of the absence of BRAF mutation is very high in identifying MLH1 mutation carriers 16,18,21,39 (Table 3 and Supplementary Data Table 5). A single false-negative was identified adding to the increasing number of LS tumors harboring a BRAF mutation.…”

Section: Discussionsupporting

confidence: 92%

“…First, the low prevalence of BRAF mutations observed in our selected population (11% of MSI tumors and 20% of those lacking MLH1 protein expression). This is in the lower range of reported series 16,18,21,39 but likely to reflect the experience of referral centers. 21 Second, the significant number of LS cases and MLH1 germline carriers analyzed allows more accurate estimates.…”

Section: Discussionmentioning

confidence: 69%

“…This is in the lower range of reported series 16,18,21,39 but likely to reflect the experience of referral centers. 21 Second, the significant number of LS cases and MLH1 germline carriers analyzed allows more accurate estimates. Sensitivity of methylation of MLH1 promoter was again very high with a single false-negative that also shared a BRAF mutation.…”

Section: Discussionmentioning

confidence: 69%

“…[10][11][12][13][14][15] It has been used to distinguish LS-associated from sporadic MSI-positive tumors. 10,11,[16][17][18][19][20][21] The lack of BRAF mutations identifies with high sensitivity (96-100%) and lower specificity (22-100%) CRC cases associated with LS. 10,11,[16][17][18][19][20][21] Occasionally, BRAF mutations have been detected in LS patients.…”

Section: Introductionmentioning

confidence: 99%

“…10,11,[16][17][18][19][20][21] The lack of BRAF mutations identifies with high sensitivity (96-100%) and lower specificity (22-100%) CRC cases associated with LS. 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.…”

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: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

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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Targeted next‐generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families

et al. 2016

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Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next‐generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single‐nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant.

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Polymerase ɛ (POLE) mutations in endometrial cancer: Clinical outcomes and implications for Lynch syndrome testing

Billingsley

Cohn

Mutch

et al. 2014

Cancer

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Background DNA polymerase epsilon (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with markedly increased somatic mutational burden. POLE mutant tumors were described as a molecular subtype with improved progression-free survival (PFS) by The Cancer Genome Atlas. This study investigates the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations in endometrioid EC patients. Methods PCR amplification and Sanger sequencing was used to test for POLE mutation in 544 tumors. Relationships between demographic, survival, clinicopathologic and molecular features were investigated. Statistical tests were two-sided. Results Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years, P=.001). POLE mutations were detected in microsatellite stable (MSS) and unstable (MSI) tumors at similar frequencies (5.9 v 5.2%, respectively) and were most common in MSI tumors lacking MLH1 methylation (P<.001). There was no association with PFS (HR=0.22, P=.127). Conclusions Our discovery that mutations occur at equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. We show that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of association between POLE mutation and PFS indicates POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic origin of disease. As such, POLE tumor testing might be a valuable exclusionary criterion for Lynch syndrome gene testing.

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Methylation Analysis of MLH1 Improves the Selection of Patients for Genetic Testing in Lynch Syndrome

Cited by 67 publications

References 25 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

Targeted next‐generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families

Polymerase ɛ (POLE) mutations in endometrial cancer: Clinical outcomes and implications for Lynch syndrome testing

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