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Constitutional epimutation as a mechanism for cancer causality and heritability?

Abstract

Constitutional epimutation, which is an aberration in gene expression due to an altered epigenotype that is widely distributed in normal tissues (albeit frequently mosaic), provides an alternative mechanism to genetic mutation for cancer predisposition. Observational studies in cancer-affected families have revealed intergenerational inheritance of constitutional epimutation, providing unique insights into the heritability of epigenetic traits in humans. In this Opinion article, the potential contribution of constitutional epimutation to the 'missing' causality and heritability of cancer is explored.

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Figure 1: The contribution of genetic and putative epigenetic factors and their interactions to cancer causality.
Figure 2: Characteristic examples of primary and secondary constitutional epimutations.
Figure 3: Potential onset and erasure of constitutional epimutations during epigenetic reprogramming events in the human life cycle.
Figure 4: Observed inheritance patterns of constitutional MLH1 epimutations.

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Correspondence to Megan P. Hitchins.

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Glossary

Cancer heritability

There are various measures of the heritability of cancer phenotypes. In general, it is measured as the relative risk ratio of disease in the relatives of affected patients versus the general population, or the concordance rates between monozygotic and dizygotic twins.

Constitutional epimutations

Aberrant changes in gene expression owing to altered epigenotypes that are widespread in normal somatic tissues due to their origins in the gamete or early embryo.

Constitutional epivariants

Epigenetic differences between members of the general population that may contribute to natural phenotypic variation among humans.

Epigenetic marks

Refers to the molecular modifications to the primary DNA sequence. These include, but are not limited to, covalent modifications to cytosine, histone occupancy and variants, and histone tail moieties. This Opinion article primarily refers to 5-methylcytosine, which occurs mostly at CpG dinucleotides in mammals. Although RNA molecules are not considered epigenetic marks, they interact with epigenetic processes to bring about epigenetic change.

Epigenotype

The mitotically stable pattern or type of DNA modification or modifications to the primary DNA sequence; for example, the presence or absence of CpG methylation and other accompanying modifications that regulate transcriptional activity. It may refer to the epigenetic state at a particular genetic locus or more generally across the genome.

Epimutation

An aberrant change in gene expression owing to an altered epigenotype.

Index cases

The first case of a disease in a group (for example, a family or population) to be brought to clinical attention: that is, the first case to be identified with a novel causative defect.

Intergenerational inheritance of epigenetic effects

The non-genetic transmission of a phenotypic trait from one generation to another due to a shared environmental, lifestyle or nutritional exposure. If the exposure occurs systemically in a pregnant female (F0), the fetus (F1) is also exposed, as are the gamete precursors (primordial germ cells) of the next generation of progeny (F2). To definitively distinguish transgenerational epigenetic inheritance from the intergenerational inheritance of epigenetic effects, the trait would need to be observed in the F3 generation.

Proband

The cancer-affected member of a family who first sought medical attention and via whom the family was ascertained for genetic or epigenetic study.

Somatic epitypes

Types of epigenotypes that are acquired in somatic cells during the lifetime of an individual in response to environmental influences.

Transgenerational epigenetic inheritance

The transmission of an epigenetic state (a particular epigenotype) from parent to offspring via the gametes, independently of genetics. Transgenerational epigenetic inheritance does not necessitate that the epigenotype is conveyed through the gamete with its somatic epigenetic modifications intact (for example, in a hypermethylated state). This definition has been extended to include alternative forms of epigenetic signals (other than methylation) that convey a memory of the former parental somatic state via the gamete to become fully reinstated in the progeny. The molecular basis for transgenerational epigenetic inheritance remains unknown, although the transfer of epigenetic modifying RNA species via the gametes provides one possible unifying mechanism across species.

Vertical inheritance

Transmission of a trait (genetic, epigenetic or phenotypic) from parent to offspring.

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Hitchins, M. Constitutional epimutation as a mechanism for cancer causality and heritability?. Nat Rev Cancer 15, 625–634 (2015). https://doi.org/10.1038/nrc4001

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