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The role of epigenetics in Lynch syndrome

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Abstract

Recognition by Warthin of the familial clustering of colorectal and gynaecological cancers a century ago laid the foundation for the recognition of familial cancer. By tracking afflicted pedigrees, Lynch defined the clinical characteristics and argued for a heritable genetic component to this autosomal dominant cancer susceptibility condition, now termed Lynch syndrome. This was proven in the 1990s, with the discovery of deleterious germline mutations of the mismatch repair genes as its cause. Yet despite the genetic revolution at the turn of the twenty-first century, no pathogenic mutation was identifiable in approximately one-third of cases with suspected Lynch syndrome. In the past decade, the alternative mechanism of constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, was identified in a proportion of these outstanding cases. This epigenetic defect, characterized by methylation and transcriptional inactivation of a single genetic allele within normal tissues, predisposes to the development of Lynch-type cancers. MSH2 and some MLH1 epimutations have been linked to genetic alterations within their vicinity and demonstrate dominant inheritance, whilst other MLH1 epimutations are reversible between generations and demonstrate non-Mendelian inheritance. This review charts the discovery of mismatch repair epimutations, their aetiological role in Lynch syndrome and the mechanistic basis for their variable inheritance patterns.

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Acknowledgments

Dr Hitchins is funded by Career Development Fellowships from the Australian National Health and Medical Research Council and Cancer Institute NSW.

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

    Megan P. Hitchins

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Correspondence to Megan P. Hitchins.

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Appendix: Definition of terms

Appendix: Definition of terms

Epigenetics:

The stable changes in gene expression that occur independent of (but can be affected by) changes in the primary DNA sequence [5]. 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 e.g. 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 [59].

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 [7, 60].

Germline epimutation:

Origination in, or transmission through, the germline of an epigenetically intact epimutation (with epigenetic modifications remaining attached to the affected DNA sequence) [9].

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/genetically-facilitated epimutation:

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

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. The role of epigenetics in Lynch syndrome. Familial Cancer 12, 189–205 (2013). https://doi.org/10.1007/s10689-013-9613-3

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