Comprehensive analysis of the <i>MLH1</i> promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional <i>MLH1</i> epimutation

Morak, Monika; Ibisler, Ayseguel; Keller, Gisela; Jessen, Ellen; Laner, Andreas; Gonzales-Fassrainer, Daniela; Locher, Melanie; Massdorf, Trisari; Nissen, Anke M.; Benet‐Pagès, Anna; Holinski‐Feder, Elke

doi:10.1136/jmedgenet-2017-104744

Cited by 27 publications

(21 citation statements)

References 44 publications

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“…As for the rest, we lack conclusive information regarding the cause as well as the risk of potential transmission between parents and children. In this respect, apart from a higher incidence of constitutive methylation in the general population, current findings for BRCA1 methylation resemble previous findings for MLH1 methylation and the risk of colorectal cancer [ 13 , 14 ].…”

supporting

confidence: 86%

BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

Lønning

Knappskog

2018

Clin Epigenet

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supporting

confidence: 86%

BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

Lønning

Knappskog

2018

Clin Epigenet

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“…In order to rule out the presence of regulatory sequence variants that might determine a cis -acting effect on promoter methylation and gene silencing, we performed Sanger sequencing of the BRCA1 5′-UTR, which confirmed the absence of variants in the 500 bp upstream of the translation starting site. This phenomenon, usually underlying heritable constitutional epimutations rather than sporadic methylation events, is well characterized for mismatch repair genes [34], and has been recently described for BRCA1 by Evans et al, who reported a co-segregation of the c.-107A>T variant with BRCA1 promoter methylation and gene silencing in multiple affected individuals of two families from North West England [35].…”

Section: Discussionmentioning

confidence: 99%

Constitutive BRCA1 Promoter Hypermethylation Can Be a Predisposing Event in Isolated Early-Onset Breast Cancer

Azzollini

Pesenti

Pizzamiglio

et al. 2019

Cancers

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Early age at onset of breast cancer (eoBC) is suggestive of an increased genetic risk. Although genetic testing is offered to all eoBC-affected women, in isolated cases the detection rate of pathogenic variants is <10%. This study aimed at assessing the role of constitutive promoter methylation at BC-associated loci as an underlying predisposing event in women with eoBC and negative family history. Promoter methylation at 12 loci was assessed by the MassARRAY technology in blood from 154 BRCA1/2 negative patients with eoBC and negative family history, and 60 healthy controls. Hypermethylation was determined, within each promoter, by comparing the patient’s mean methylation value with thresholds based on one-sided 95% bootstrap confidence interval of the controls’ mean. Three patients had hypermethylated results, two at BRCA1 and one at RAD51C. Analyses on tumor tissue from the patient exceeding the highest threshold at BRCA1 revealed a mean methylation >60% and loss of heterozygosity at chromosome 17q. The patient hypermethylated at RAD51C showed low methylation in the tumor sample, ruling out a role for methylation-induced silencing in tumor development. In isolated eoBC patients, BRCA1 constitutive promoter methylation may be a predisposing event. Further studies are required to define the impact of methylation changes occurring at BC-predisposing genes and their role in tumorigenesis.

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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%

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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Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation

Cited by 27 publications

References 44 publications

BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

BRCA1 methylation in newborns: genetic disposition, maternal transfer, environmental influence, or by chance only?

Constitutive BRCA1 Promoter Hypermethylation Can Be a Predisposing Event in Isolated Early-Onset Breast Cancer

DNA Methylation in the Diagnosis of Monogenic Diseases

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