Epimutations and Cancer Susceptibility


Germline genetic testing often fails to detect a mutation in the coding region of the relevant predisposition gene despite a strong clinical suspicion of a hereditary cancer syndrome. In some cases, cancer predisposition is caused by a constitutional epimutation. Epimutations are epigenetic aberrations, typically defined by deoxyribonucleic acid (DNA) methylation, that predispose individuals to cancer through soma‐wide changes in the expression of the afflicted gene. They have been documented in patients with colorectal cancer, chronic lymphocytic leukaemias and some imprinting disorders. The molecular cause of most epimutations is unknown but it is hypothesised that they could be driven by hitherto unidentified genetic alterations in long‐range cis‐regulatory elements that manifest as DNA methylation or repressive histone modifications at a gene promoter. An understanding of the molecular origin of epimutations may help elucidate the basis of predisposition to cancer.

Key Concepts:

  • Constitutional epimutations predispose carriers to early‐onset cancer.

  • A constitutional epimutation inactivates expression from one allele of a gene throughout normal tissues.

  • Primary constitutional epimutations are not inherited in a Mendelian fashion. They are absent in the germline but are present in tissues derived from all three germ layers.

  • Secondary constitutional epimutations cosegregate with an in cis genetic change.

  • In cis DNA elements such as enhancers and insulators regulate gene expression and are potential sites of genetic alterations that give rise to epimutations.

  • Identifying the cause of epimutations will help explain the origin of some cases of familial cancer without a germline DNA mutation.

Keywords: antisense transcription; cancer predisposition; constitutional; DNA methylation; epigenetics; epimutation; histone modification; nucleosome

Figure 1.

Types of constitutional epimutation. Constitutional epimutations are classified as primary, secondary or nonclassical. (a) Primary constitutional epimutations are not associated with any known genetic changes and display a non‐Mendelian pattern of inheritance. (b) Secondary constitutional epimutations are inherited in a Mendelian fashion due to their physical linkage to an in cis genetic alteration such as transcriptional readthrough and promoter single‐nucleotide variation (SNV). (c) Nonclassical constitutional epimutations have low or no DNA methylation with no identified DNA sequence change. Green, normal allele; blue, epimutation allele; boxes, exons; black line, intron or intergenic region; arrow, direction of transcription; lollipops, CpG islands (white, unmethylated and black, methylated); dashed line, deletion; and *, SNV.

Figure 2.

The establishment of constitutional epimutations. A constitutional epimutation refers to an epigenetic aberration that is present on one parental allele throughout normal tissues, and which represses or activates expression from the affected allele. (a) Primary epimutations are erased in the germline but their soma‐wide distribution indicates that they are established at an early stage of development before differentiation of the three germ layers (endoderm, ectoderm and mesoderm). (b) Secondary mutations are facilitated by an in cis genetic alteration (*) that is also present in the germline. DNA methylation at CpG island promoters (black lollipops) is the most extensively described epimutation. Epimutations at the MLH1 locus preferentially arise on the maternal allele and constitute the first ‘hit’ in Knudson's two‐hit hypothesis that predisposes carriers to cancer.

Figure 3.

The effect of promoter SNV on MLH1 expression in Lynch syndrome. MLH1 and EPM2AP1 share a bidirectional CpG island promoter (green bar) on human chromosome 3. The position of common SNPs (c.‐269C>G and c.‐93G>A) and SNVs whose effect on MLH1 expression has been tested in human tissues (c.‐27C>A and c.85G>T) or luciferase promoter reporter assays in HCT116 and HEK293 cells (all others) are shown below the CpG island. *, DNA methylation cosegregates with the designated allele; blue, expression lost from the methylated allele in the germline of carriers; black, no effect on gene expression; grey, common SNP with reduced expression in one cell line; red, SNV with reduced expression in two cell lines. The c.‐27C>A and c.85G>T SNVs form a haplotype in families with Lynch syndrome (Hitchins et al., ; Ward et al., ).

Figure 4.

Cis‐regulatory regions in cancer predisposition genes. UCSC genome browser screenshots of the cancer predisposition genes: (a) MLH1, (b) APC and (c) BRCA2 showing the location of putative regulatory regions. DNase HS sites (DNase), transcription factor binding sites (TF), regions with enhancer signatures (H3K4me1 and H3K27Ac) (arrows) and CTCF binding sites (*) are shown for three cell lines derived from the ectoderm (HeLa), endoderm (A549) and the mesoderm (K562) (Encode Project Consortium et al., ). Curved lines below the MLH1 tracks represent potential interactions between the MLH1 promoter and distal regulatory elements.

Figure 5.

Novel potential mechanisms of epimutations. (a) An enhancer fails to engage with the promoter of a cancer predisposition gene because of a genetic mutation that prevents the binding of transcriptional activators. An unoccupied promoter results in DNA methylation and the recruitment of repressive histone modifications such as H3K27me3 to the promoter on the epimutation allele. (b) A genetic mutation in an insulator prevents binding of an insulator protein such as CTCF. The insulator is unable to defend the promoter of a cancer predisposition gene from the encroachment of repressive histone modifications or DNA methylation on the epimutation allele. (c) Antisense transcription induces the formation of DNA methylation and/or repressive histone modifications at an overlapping gene promoter. For clarity, other active (e.g., H3K4me2, H3K4me3, H3Ac and H4Ac) and repressive histone modifications (e.g. H3K9me3 and H4K20me3) that exist at gene promoters are not shown. In each model, genetic recombination between the promoter and the enhancer could explain the non‐Mendelian pattern of inheritance of primary and nonclassical constitutional epimutations.



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Sloane, Mathew Aidan, Hesson, Luke Benjamin, and Ward, Robyn Lynne(Mar 2014) Epimutations and Cancer Susceptibility. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024615]