Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome

Morak, Monika; Koehler, Udo; Schackert, Hans K.; Steinke, Verena; Royer‐Pokora, Brigitte; Schulmann, Karsten; Kloor, Matthias; Höchter, W.; Weingart, J; Keiling, C; Massdorf, Trisari; Holinski‐Feder, Elke

doi:10.1136/jmedgenet-2011-100050

Cited by 73 publications

(60 citation statements)

References 36 publications

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“…Heterozygous MUTYH mutations were not identified in the remaining 84 index patients, for which somatic mutations or further germline pathomechanisms, for example, large genomic rearrangements such as inversions in the MMR genes have to be considered. 3,[26][27][28] In the control cohort the MUTYH mutation frequency of 1.24% was comparable to the frequencies of 0%-4.8% reported in the general population. 12,22,29 As MAP can manifest in an extremely variable phenotype, MUTYH mutation analysis should also be considered in patients with a low number of adenomas, early-onset or synchronous or metachronous CRC and in patients with MSS tumours.…”

Section: Discussionsupporting

confidence: 73%

“…However, in 10-15% of our cases clinically suspected of LS, the MSI-H and abnormal IHC results in the tumours cannot be explained by MMR germline mutation analyses. 2,3 Germline mutations in the human Mut Y homolog (MUTYH; MIM# 604933) also lead to a predisposition to CRC and adenomas but with an autosomal recessive inheritance. The clinical picture of MUTYH-associated polyposis (MAP, MIM' 608456) is extremely variable and ranges from severe polyposis coli to attenuated forms with late age of onset or few adenomas or CRC, which creates phenotypic overlap with LS.…”

Section: Introductionmentioning

confidence: 99%

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Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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The hallmarks of Lynch syndrome (LS) include a positive family history of colorectal cancer (CRC), germline mutations in the DNA mismatch repair (MMR) genes, tumours with high microsatellite instability (MSI-H) and loss of MMR protein expression. However, in B10-15% of clinically suspected LS cases, MMR mutation analyses cannot explain MSI-H and abnormal immunohistochemistry (IHC) results. The highly variable phenotype of MUTYH-associated polyposis (MAP) can overlap with the LS phenotype, but is inherited recessively. We analysed the MUTYH gene in 85 'unresolved' patients with tumours showing IHC MMR-deficiency without detectable germline mutation. Biallelic p.(Tyr179Cys) MUTYH germline mutations were found in one patient (frequency 1.18%) with CRC, urothelial carcinoma and a sebaceous gland carcinoma. LS was suspected due to a positive family history of CRC and because of MSI-H and MSH2-MSH6 deficiency on IHC in the sebaceous gland carcinoma. Sequencing of this tumour revealed two somatic MSH2 mutations, thus explaining MSI-H and IHC results, and mimicking LS-like histopathology. This is the first report of two somatic MSH2 mutations leading to an MSI-H tumour lacking MSH2-MSH6 protein expression in a patient with MAP. In addition to typical transversion mutations in KRAS and APC, MAP can also induce tumourigenesis via the MSI-pathway.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Biallelic MUTYH mutations can mimic Lynch syndrome

et al. 2014

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“…[12][13][14][15] However, a handful of familial cases with an MLH1 epimutation have been reported in which transmission of the epimutation between generations has been shown to occur in both non-Mendelian 14 and autosomal dominant patterns, with the latter linked to localized cis-acting genetic anomalies. 16,17 In a Caucasian family from Western Australia (WA Family 16), dominant transmission of a mosaic MLH1 epimutation was demonstrated through three successive generations linked to a particular haplotype bearing two single-nucleotide variants (SNVs) in tandem; promoter substitution c. À27C4A and missense variant c.85G4T (p.A29S) (according to coding reference sequence NM_000249.2). 17 The mosaic nature of the epimutation was observed as variable levels of somatic methylation and partial allelic losses of transcription among different tissues and carriers in the family.…”

Section: Introductionmentioning

confidence: 99%

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

et al. 2013

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Germline mutations of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and deletions affecting the EPCAM gene adjacent to MSH2, underlie Lynch syndrome by predisposing to early-onset colorectal, endometrial and other cancers. An alternative but rare cause of Lynch syndrome is constitutional epimutation of MLH1, whereby promoter methylation and transcriptional silencing of one allele occurs throughout normal tissues. A dominantly transmitted constitutional MLH1 epimutation has been linked to an MLH1 haplotype bearing two single-nucleotide variants, NM_000249.2: c. À27C4A and c.85G4T, in a Caucasian family with Lynch syndrome from Western Australia. Subsequently, a second seemingly unrelated Caucasian Australian case with the same MLH1 haplotype and concomitant epimutation was reported. We now describe three additional, ostensibly unrelated, cancer-affected families of European heritage with this MLH1 haplotype in association with constitutional epimutation, bringing the number of index cases reported to five. Array-based genotyping in four of these families revealed shared haplotypes between individual families that extended across r2.6-r6.4 megabase regions of chromosome 3p, indicating common ancestry. A minimal r2.6 megabase founder haplotype common to all four families was identified, which encompassed MLH1 and additional flanking genes and segregated with the MLH1 epimutation in each family. Our findings indicate that the MLH1 c. À27C4A and c.85G4T variants are borne on a European ancestral haplotype and provide conclusive evidence for its pathogenicity via a mechanism of epigenetic silencing of MLH1 within normal tissues. Additional descendants bearing this founder haplotype may exist who are also at high risk of developing Lynch syndrome-related cancers.

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“…8 Approximately 40 index cases of constitutional MLH1 methylation have been reported. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] However, the prevalence of MLH1 constitutional epimutations is still unknown. Most studies addressing this issue have enriched their sampling with patients affected with CRC showing loss of MLH1 protein expression.…”

Section: Introductionmentioning

confidence: 99%

“…9,14,17,23 In a very few cases genetic alterations in cis (gross rearrangements and variants in the promoter region) have been identified as responsible for the methylation. 13,16,19 In these cases, an autosomal dominant pattern is readily observed. However, in most cases no genetic cause for the epimutation has been identified (reviewed in Hitchins and Ward 5 ).…”

Section: Introductionmentioning

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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Biallelic MLH1 SNP cDNA expression or constitutional promoter methylation can hide genomic rearrangements causing Lynch syndrome

Cited by 73 publications

References 36 publications

Biallelic MUTYH mutations can mimic Lynch syndrome

Biallelic MUTYH mutations can mimic Lynch syndrome

The MLH1 c.-27C>A and c.85G>T variants are linked to dominantly inherited MLH1 epimutation and are borne on a European ancestral haplotype

MLH1 methylation screening is effective in identifying epimutation carriers

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