Primary constitutional MLH1 epimutations: a focal epigenetic
            event

Dámaso, Estela; Castillejo, Adela; Arias, María del Mar; Canet-Hermida, Júlia; Navarro, Matilde; Valle, Jesús Del; Campos, Olga; Fernández, Anna; Marín, Fátima; Turchetti, Daniela; García-Díaz, Juan de Dios; Lázaro, Conxi; Genuardi, Maurizio; Rueda, Daniel; Alonso, Ángel; Soto, José Luís; Hitchins, Megan P.; Pineda, Marta; Capellà, Gabriel

doi:10.1038/s41416-018-0019-8

Cited by 27 publications

(34 citation statements)

References 31 publications

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“…In addition, about 5%-15% of colorectal carcinomas (CRCs) display reduced MLH1 immunostaining and MMR deficiency due to promoter hypermethylation. In most cases, epigenetic inactivation is a somatic event, but constitutional MLH1 hypermethylation has been reported in several patients [125][126][127][128]. Overall, this mechanism explains 1.5%-10.5% of CRCs associated with abnormal expression of MLH1, and might account for up to 3% of LS [128].…”

Section: Lynch Syndromementioning

confidence: 99%

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DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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DNA methylation in the human genome is largely programmed and shaped by transcription factor binding and interaction between DNA methyltransferases and histone marks during gamete and embryo development. Normal methylation profiles can be modified at single or multiple loci, more frequently as consequences of genetic variants acting in cis or in trans, or in some cases stochastically or through interaction with environmental factors. For many developmental disorders, specific methylation patterns or signatures can be detected in blood DNA. The recent use of high-throughput assays investigating the whole genome has largely increased the number of diseases for which DNA methylation analysis provides information for their diagnosis. Here, we review the methylation abnormalities that have been associated with mono/oligogenic diseases, their relationship with genotype and phenotype and relevance for diagnosis, as well as the limitations in their use and interpretation of results.

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Section: Lynch Syndromementioning

confidence: 99%

“…Therefore, additional approaches should be used, including pyrosequencing and MS-melting curve analysis in cases scoring negatively, but with strong clinical suspicion [131]. Genome-wide approaches have shown that primary epimutations are focal events involving a 1.6 kb region encompassing the shared MLH1/EPM2AIP1 promoter [125].…”

Section: Lynch Syndromementioning

confidence: 99%

DNA Methylation in the Diagnosis of Monogenic Diseases

Cerrato

Sparago

Ariani

et al. 2020

Genes

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“…To ensure consistency of data processing, we only compared our samples with publically accessible samples with raw idat files. GSE68060, GSE68838, GSE77954, GSE77965, GSE81211, GSE101764, GSE107352, and GSE75546 were collected from GEO while E-MTAB-6450 was collected from ArrayExpress [43][44][45][46][47][48] (Additional file 1: Table S6). Some cell line samples and metastatic cancer samples were removed upon further study.…”

Section: Public Datasets and Processingmentioning

confidence: 99%

Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma

Jian

Guo

et al. 2020

Clin Epigenet

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Background: Abnormal DNA methylation is a hallmark of human cancers and may be a promising biomarker for early diagnosis of human cancers. However, the majority of DNA methylation biomarkers that have been identified are based on the hypothesis that early differential methylation regions (DMRs) are maintained throughout carcinogenesis and could be detected at all stages of cancer. Methods: In this study, we identified potential early biomarkers of colorectal cancer (CRC) development by genomewide DNA methylation assay (Illumina infinium450, 450 K) of normal (N = 20) and pre-colorectal cancer samples including 18 low-grade adenoma (LGA) and 22 high-grade adenoma (HGA), integrated with GEO and ArrayExpress datasets (N = 833). Results:We identified 209 and 8692 CpG sites that were significantly hyper-methylated in LGA and HGA, respectively. Pathway analysis identified nervous system-related methylation changes that are significantly associated with early adenoma development. Integration analysis revealed that DNA methylation in the promoter region of ADHFE1 has the most potential for being an early diagnostic biomarker for colorectal adenoma and cancer (sensitivity = 0.96, specificity = 0.95, area under the curve = 0.97).Conclusions: Overall, we demonstrated that DNA methylation have been shown significant changes in the stage of LGA and HGA in the development of colon cancer. Genome-wide DNA methylation to LGA and HGA provided an important proxy to identify promising early diagnosis biomarkers for colorectal cancer.

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“…Most are considered primary, arising apparently de novo and reversible between generations, whereas secondary epimutations are associated with a genetic variant in cis. Recently, we demonstrated that EPM2AIP1-MLH1 CpG island is the sole differentially methylated region in primary MLH1 epimutation carriers [9]. Available evidence suggests that constitutional epimutations cause a severe LS phenotype, including early-onset and multiple primary tumors [5].…”

Section: Introductionmentioning

confidence: 98%

“…Ninety-seven index cases with a constitutional MLH1 epimutation have been reported so far [8][9][10][11][12]. Most are considered primary, arising apparently de novo and reversible between generations, whereas secondary epimutations are associated with a genetic variant in cis.…”

Section: Introductionmentioning

confidence: 99%

Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation

et al. 2019

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Constitutional MLH1 methylation (epimutation) is a rare cause of Lynch syndrome. Low-level methylation (≤ 10%) has occasionally been described. This study aimed to identify low-level constitutional MLH1 epimutations and determine its causal role in patients with MLH1-hypermethylated colorectal cancer. Eighteen patients with MLH1-hypermethylated colorectal tumors in whom MLH1 methylation was previously undetected in blood by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were screened for MLH1 methylation using highly sensitive MS-melting curve analysis (MS-MCA). Constitutional methylation was characterized by different approaches. MS-MCA identified one patient (5.6%) with low-level MLH1 methylation (~1%) in blood and other normal tissues, which was confirmed by clonal bisulfite sequencing in blood. The patient had developed three clonally related gastrointestinal MLH1methylated tumor lesions at 22, 24, and 25 years of age. The methylated region in normal tissues overlapped with that reported for other carriers of constitutional MLH1 epimutations. Low-level MLH1 methylation and reduced allelic expression were linked to the same genetic haplotype, whereas the opposite allele was lost in patient's tumors. Mutation screening of MLH1 and other hereditary cancer genes was negative. Herein, a highly sensitive MS-MCA-based approach has demonstrated its utility for the identification of lowlevel constitutional MLH1 epigenetic mosaicism. The eventual identification and characterization of additional cases will be critical to ascertain the cancer risks associated with constitutional MLH1 epigenetic mosaicism.

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Primary constitutional MLH1 epimutations: a focal epigenetic event

Cited by 27 publications

References 31 publications

DNA Methylation in the Diagnosis of Monogenic Diseases

DNA Methylation in the Diagnosis of Monogenic Diseases

Genome-wide DNA methylation profiles of low- and high-grade adenoma reveals potential biomarkers for early detection of colorectal carcinoma

Highly sensitive MLH1 methylation analysis in blood identifies a cancer patient with low-level mosaic MLH1 epimutation

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