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The Role of Epimutations of the Mismatch Repair Genes in the Development of Lynch Syndrome Related Cancers

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Book cover DNA Alterations in Lynch Syndrome

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Abstract

Lynch syndrome, characterised by an autosomal dominant predisposition to the development of young-onset colorectal, endometrial and additional cancers exhibiting the microsatellite instability phenotype, is typically caused by heterozygous germline mutations within one of the DNA mismatch repair genes. The MLH1 and MSH2 genes are the most frequently mutated of the mismatch repair genes. Until the turn of this century, no pathogenic mutation could be identified in up to one third of cases with a strong clinical suspicion of Lynch syndrome, but screens for disease-causing mutations within alternative genes were largely fruitless. In the past decade, an alternative aetiological mechanism for the development Lynch syndrome-­related cancers emerged, which involved epigenetic-based dysregulation of the two key mismatch repair genes MLH1 and MSH2. Termed a constitutional epimutation, this type of defect manifests as methylation of a single allele of the CpG island promoter accompanied by transcriptional inactivation of the affected allele within normal somatic tissues, in the context of a normal gene sequence. MSH2 epimutations are caused by linked germline deletions of the neighbouring EPCAM gene, although MSH2 itself remains intact, and demonstrate classic dominant inheritance. However MLH1 epimutations can arise spontaneously in the carrier and are reversible between generations, resulting in unpredictable non-Mendelian patterns of inheritance, or display dominant inheritance with particular genetic alleles due to the presence of a linked genetic alteration within or nearby MLH1. Constitutional epimutations are thus associated with complex underlying mechanisms, and furthermore, give rise to atypical cases of Lynch syndrome both in terms of phenotypic heterogeneity and the risk of intergenerational transmission. This confounds molecular diagnosis, clinical management and genetic counselling of carriers and their families. As more information emerges from clinical and molecular research in this nascent field, tailored management strategies need to be devised so patients can realise the benefits of these discoveries.

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Authors and Affiliations

  1. Medical Epigenetics Laboratory, Lowy Cancer Research Centre, Prince of Wales Clinical School, University of New South Wales, Randwick, 2052, Sydney, NSW, Australia

    Megan P. Hitchins

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  1. Megan P. Hitchins
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Correspondence to Megan P. Hitchins .

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  1. , Laboratory for Molecular Biology, National Institute of Chemistry, Hajdrihova 19, Ljubljana, SI-1001, Slovenia

    Matjaž Vogelsang

Glossary of Terms

Epigenetics 

The stable changes in gene expression that occur independent of (but can be affected by) changes in the primary DNA sequence [1]. These changes are brought about by the attachment of various biochemical modifications to the DNA sequence, which include DNA methylation, and other chromatin modifications. This chapter will refer only to methylation.

Methylation 

A reversible biochemical modification to the cytosine nucleotide within the DNA sequence, which is universal to vertebrates. Methyl groups can be enzymatically added to or removed from cytosine bases in the genetic code, but occur primarily at cytosine-guanine (CpG) dinucleotides in mammals and are associated with transcriptional silencing of the DNA sequence.

Monoallelic methylation 

Methylation affecting a single allele/copy of a gene, as detected by linking CpG methylation to a single allele of a polymorphism or other genetic variant for which the subject is heterozygous.

Hemiallelic methylation 

Methylation of half of alleles, but not linked to a particular allele eg if the subject is uninformative for a polymorphism such that the two genetic alleles cannot be distinguished.

Epimutation 

An epigenetic aberration that results in a change in the transcriptional state of a gene. This can take the form of transcriptional silencing of a gene that is normally active, or conversely, reactivation of a gene that is normally silent [2].

Primary Epimutation 

An epimutation that has arisen in the absence of any alteration to the DNA sequence in the locality of the epigenetic aberration.

Secondary Epimutation/genetically-facilitated epimutation 

An epimutation that has arisen as a consequence of (or is accompanied by) a genetic alteration on the affected allele.

Germline epimutation 

Origination in, or transmission through, the germline of an epigenetically intact epimutation (with epigenetic modifications remaining attached to the affected DNA sequence) [3].

Constitutional epimutation 

An epigenetic aberration present within normal somatic cells that causes/predisposes to disease, but neither precludes nor dictates that its origin is in the germline, or that it is distributed evenly throughout somatic tissues [4, 5].

Allelic epigenetic mosaicism 

Variation in the epigenetic state (methylation status or levels) of a particular allele within a particular cell type or organism.

Haplotype 

A combination of alleles at multiple loci that are transmitted together on the same chromosome.

De novo 

Spontaneously arising; not inherited from a parent.

Allelic expression imbalance 

Relative loss or reduction in expression of one allele of a gene as compared to the other allele.

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Hitchins, M.P. (2013). The Role of Epimutations of the Mismatch Repair Genes in the Development of Lynch Syndrome Related Cancers. In: Vogelsang, M. (eds) DNA Alterations in Lynch Syndrome. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6597-9_6

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