<i>MLH1</i> Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Borràs, Ester; Pineda, Marta; Blanco, Ignacio; Jewett, Ethan M.; Wang, Fei; Teulé, Àlex; Caldés, Trinidad; Urioste, Miguel; Martínez-Bouzas, Cristina; Brunet, Joan; Balmañà, Judith; Torres, Alexandra; Cajal, Teresa Ramón y; Sanz, Judit; Pérez-Cabornero, Lucía; Castellví–Bel, Sergi; Alonso, Ángel; Lanas, Ángel; González, Sara; Moreno, Vı́ctor; Gruber, Stephen B.; Rosenberg, Noah A.; Mukherjee, Bhramar; Lázaro, Conxi; Capellà, Gabriel

doi:10.1158/0008-5472.can-10-0570

Cited by 30 publications

(31 citation statements)

References 42 publications

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“…The patient was a carrier of the Spanish pathogenic MLH1 c.1865T4A (L622H) mutation. 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.…”

Section: Discussionmentioning

confidence: 90%

“…Although the tumor displayed the typical molecular profile associated with sporadic MSI tumors, BRAF mutation and MLH1 promoter hypermethylation, the patient was a carrier of the founder Spanish pathogenic MLH1 c.1865T4A (L622H) mutation. 37 Cost-effectiveness analysis Both testing strategies were compared with MLH1 germline testing for all individuals (BRAF-MLH1 mutation analysis (Strategy 1); Hypermethylation -MLH1 mutation analysis (Strategy 2); DNA testing of all individuals (Strategy 3) (Supplementary Data Figure 1). Parameters, base case values and assumptions used to calculate the incremental cost per additional mutation detected are shown in Table 1.…”

Section: Usefulness Of Braf V600e Mutation Analysis In the Identificamentioning

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: 90%

Section: Usefulness Of Braf V600e Mutation Analysis In the Identificamentioning

confidence: 99%

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

et al. 2012

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“…29 To deduce the methylation-associated haplotype, intrafamilial segregation analysis was performed under the assumption that the number of crossovers between adjacent markers was minimal.…”

Section: Haplotype Analysismentioning

confidence: 99%

MLH1 methylation screening is effective in identifying epimutation carriers

et al. 2012

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Recently, constitutional MLH1 epimutations have been identified in a subset of Lynch syndrome (LS) cases. The aim of this study was the identification of patients harboring constitutional MLH1 epimutations in a set of 34 patients with a clinical suspicion of LS, MLH1-methylated tumors and non-detected germline mutations in mismatch repair (MMR) genes. MLH1 promoter methylation was analyzed in lymphocyte DNA samples by MS-MLPA (Methylation-specific multiplex ligation-dependent probe amplification). Confirmation of MLH1 constitutional methylation was performed by MS-MCA (Methylation-specific melting curve analysis), bisulfite sequencing and pyrosequencing in different biological samples. Allelic expression was determined using heterozygous polymorphisms. Vertical transmission was evaluated by MS-MLPA and haplotype analyses. MS-MLPA analysis detected constitutional MLH1 methylation in 2 of the 34 individuals whose colorectal cancers showed MLH1 methylation (5.9%). These results were confirmed by bisulfite-based methods. Both epimutation carriers had developed metachronous early-onset LS tumors, with no family history of LS-associated cancers in their first-degree relatives. In one of the cases, the identified MLH1 constitutional methylation was monoallelic and results in MLH1 and EPM2AIP1 allele-specific transcriptional silencing. It was present in normal somatic tissues and absent in spermatozoa. The methylated MLH1 allele was maternally transmitted and methylation was reversed in a daughter who inherited the same allele. MLH1 methylation screening in lymphocyte DNA from patients with early-onset MLH1-methylated LS-associated tumors allows the identification of epimutation carriers. The present study adds further evidence to the emerging entity of soma-wide MLH1 epimutation and its heritability.

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“…Many founder mutations associated with LS have been reported in the MLH1 gene [10][11][12][13][14][15]. In Italy, a founder MLH1 mutation was found in six Lynch families originating from a relatively small geographic area of Northern Italy [42,43] and three other have been described in Southern Italy [44].…”

Section: Discussionmentioning

confidence: 99%

“…inherited by numerous descendants of a common ancestor, have been reported in the MMR genes associated with LS [10][11][12][13][14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

et al. 2014

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The MLH1 c.2252_2253delAA mutation was\ud found in 11 unrelated families from a restricted area southwest\ud of Turin among 140 families with mutations in the\ud mismatch repair genes. The mutation is located in the highly\ud conserved C-terminal region, responsible for dimerization\ud with the PMS2 protein. Twenty-five tumour tissues from 61\ud individuals with the c.2252_2253delAA mutation were tested\ud for microsatellite instability(MSI) and protein expression.We\ud compared the clinical features of these families versus the rest\ud of our cohort and screened for a founder effect. All but one\ud tumours showed the MSI-high mutator phenotype. Normal,\ud focal and lack of MLH1 staining were observed in 16, 36 and\ud 48 % of tumours, respectively. PMS2 expression was always\ud lost. The mutation co-segregated with Lynch syndrome-related\ud cancers in all informative families. All families but one\ud fulfilled Amsterdam criteria, a frequency higher than in other\ud MLH1 mutants. This was even more evident for AC II (72.7\ud vs. 57.5 %). Moreover, all families had at least one colon\ud cancer diagnosed before 50 years and one case with multiple\ud Lynch syndrome-related tumours. Interestingly, a statistically\ud significant (p = 0.0057) higher frequency of pancreatic\ud tumourswas observed compared to familieswith other MLH1\ud mutations: 8.2 % of affected individuals versus 1.6 %. Haplotype\ud analysis demonstrated a common ancestral origin of the\ud mutation, which originated about 1,550 years ago. The\ud mutation is currently classified as having an uncertain clinical\ud significance. Clinical features, tissue analysis and co-segregation\ud with disease strongly support the hypothesis that the\ud MLH1 c.2252_2253delAA mutation has a pathogenic effec

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MLH1 Founder Mutations with Moderate Penetrance in Spanish Lynch Syndrome Families

Cited by 30 publications

References 42 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

MLH1 methylation screening is effective in identifying epimutation carriers

A founder MLH1 mutation in Lynch syndrome families from Piedmont, Italy, is associated with an increased risk of pancreatic tumours and diverse immunohistochemical patterns

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