Elsevier

Advances in Genetics

Volume 70, 2010, Pages 201-243
Advances in Genetics

8 - Inheritance of Epigenetic Aberrations (Constitutional Epimutations) in Cancer Susceptibility

https://doi.org/10.1016/B978-0-12-380866-0.60008-3Get rights and content

Abstract

The pathogenic role for heritable mutations in the DNA sequence of tumor suppressor and DNA repair genes has been well established in familial cancer syndromes. These germ line mutations confer a high risk of developing particular types of cancer, according to the gene affected, at a young age of onset when compared to sporadically arising cancers of a similar type. The widespread role for epigenetic dysregulation in the development and progression of sporadic cancers is also well recognized. However, it has only become apparent in recent years that epigenetic aberrations can also occur constitutionally to confer a similar cancer phenotype as a genetic mutation within the same gene. These epigenetic errors are termed “constitutional epimutations” and are characterized by promoter methylation and transcriptional silencing of a single allele of the gene in normal somatic tissues in the absence of a sequence mutation within the affected locus. This is best exemplified in Lynch syndrome, which is an autosomal dominant cancer susceptibility syndrome characterized by the early development of colorectal, uterine, and additional cancers exhibiting microsatellite instability due to impaired mismatch repair. Lynch syndrome is usually caused by heterozygous loss-of-function germ line mutations of the mismatch repair genes, namely MLH1, MSH2, MSH6, and PMS2. Tumors develop following an acquired somatic loss of the remaining functional allele. However, a subset of Lynch syndrome cases without genetic mutations instead has a constitutional epimutation of MLH1 or MSH2. These epimutations are associated with distinct patterns of inheritance depending on the nature of the mechanisms underlying them.

Introduction

An epimutation describes an epigenetic aberration that alters gene activity to confer a phenotype without any change within the DNA code of the affected gene. The first observation of a naturally occurring epimutation was in 1999 in the toadflax plant (Linaria vulgaris; Cubas et al., 1999), which caused a floral phenotype first described as the “mutant peloric” pattern of radial petal symmetry by the famous botanist Linnaeus in 1749 (Fig. 8.1). In the same year, the first clear example of the inheritance of an altered epigenetic state in mammals was described at the agouti locus in mice, giving rise to a phenotype of yellow coat color, obesity, diabetes, and increased cancer risk (Morgan et al., 1999). The first description of what subsequently became known as a “constitutional epimutation” in humans came 3 years later, with aberrant methylation of the MLH1 mismatch repair gene detected in peripheral blood, which predisposed to the development of cancer (Fig. 8.2; Gazzoli et al., 2002). By this time, the genetic basis for a number of familial forms of cancer had been well established. A number of autosomal dominant familial cancer syndromes caused by heterozygous germ line mutations have been described, of which Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) is the most common (Lynch, 1999). Mutations in autosomal dominant cancer syndromes give rise to a high risk of cancer development, usually at an early age of onset. While the predisposition to cancer is transmitted in an autosomal dominant pattern, in order for cancer to develop, loss of both copies of the relevant gene is typically required in the somatic cells, as originally proposed by Knudson in his “two-hit” hypothesis. In this model, the germ line mutation serves as the “first hit,” with an acquired loss of the remaining functional allele in somatic cells through deletion, point mutation, or epigenetic inactivation representing the “second hit” (Knudson, 1996). However, apparent pathogenic germ line mutations in the relevant disease-associated gene fail to account for every case presenting with the clinical features of the given cancer syndrome. While the hunt for additional genes or cryptic mutations within known genes to identify the causes for disease in these outstanding cases continues, recent attention has been given to investigating the role for epigenetic-based disruption of gene activity in disease causation. Although it has also been well recognized that epigenetic silencing of crucial tumor suppressor and DNA repair genes is a common feature in the development and/or progression of sporadic cancers, a small number of cases with an early-onset cancer syndrome have now been identified, which are attributable to epigenetic silencing of the relevant disease-associated gene in their constitutional DNA. It is interesting to note that cases with constitutional epigenetic silencing of one allele in their normal cells occur in the absence of an identifiable sequence mutation within the genetic code of the gene—the affected locus itself remains intact. The term that has been broadly adopted to describe this novel type of epigenetic-based mechanism is “epimutation.” The epimutations identified in early-onset cancer syndromes to date are characterized by promoter methylation and transcriptional silencing of a single allele of the gene in normal somatic tissues in the absence of a sequence alteration within the affected gene locus (Fig. 8.2; Hitchins et al., 2005). Epimutations can thus represent an alternative mechanism for disease causation, or “phenocopy,” of a genetically based disease. While genetic mutations and epimutations may produce the same end result—a given disease—there are key distinctions. The first is molecular. In cases with an epimutation, the gene will be modified by an altered pattern of epigenetic moieties, but will not contain a conventional mutation of the DNA sequence. However, some epimutations may arise as a secondary consequence of a linked genetic alteration in the vicinity of the affected gene. Secondly, epimutations may give rise to an altered pattern of inheritance compared to that associated with sequence mutations of the same gene. Epimutations have been shown to give rise to both classic Mendelian or non-Mendelian patterns of inheritance, according to their underlying mechanism (Chan et al., 2006, Hitchins et al., 2007). Where the epigenetic disturbance is dependent upon a preexisting cis-acting genetic change located near the affected gene, the pattern of inheritance is likely to be Mendelian. However, the epigenetic modifications themselves are labile, and so where no such fundamental cis-genetic basis exists, epimutations may arise spontaneously but then be reversed in the germ line and thus may not be vertically transmissible to the next generation, or may demonstrate non-Mendelian inheritance patterns. This chapter will follow the journey of discovery of epimutations and describe the types of epimutation that have been reported, with a focus on human disease phenotypes, particularly cancer. Furthermore, this chapter will address the underlying origins and mechanisms (or potential mechanisms) of onset of the various types of epimutation, and describe how these correlate with the observed patterns of inheritance.

Section snippets

Definitions

    Epimutation

    an epigenetic aberration that causes transcriptional silencing of a gene that is normally active, or activation of a gene that is normally silent, in the absence of an alteration to the DNA sequence within the affected gene (Holliday, 1987, Van Overveld et al., 2003).

    Germ line epimutation

    an epimutation that is present (with its epigenetic modifications intact) within the gamete to affect a single parental allele (Suter et al., 2004).

    Constitutional epimutation

    an epimutation that is

Epimutation Conferring Floral Symmetry in Toadflax

The first discovery of a naturally occurring epimutation was in the toadflax plant (Fig. 8.1; Cubas et al., 1999). As originally described by Linnaeus, the flowers of the toadflax plant have five petals, but have quite distinctive patterns (Linnaeus, 1749). The wild-type flowers have variously shaped petals that show lateral symmetry but dorsoventral asymmetry. In contrast, the peloric flowers show radial symmetry of the petals, with five spike-shaped petals spaced at even intervals in a

Nomenclature and Origins of Epimutations in Humans

The assignment of appropriate nomenclature for epimutations has been vociferously debated in the literature. The context of this controversy has surrounded the potential origins of epimutations; whether they arise in the germ line or in the somatic cells of the developing embryo or adult. An “epimutation” was originally defined as an epigenetic aberration that causes transcriptional silencing of a gene that is normally active, or conversely, reactivation of a gene that is normally silent, in

Epimutation of the Mismatch Repair Genes in Cancer Susceptibility

Constitutional epimutations of the mismatch repair genes MLH1 and MSH2 in Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), represent classic but very distinct examples of this phenomenon. While MLH1 epimutations typically arise spontaneously and demonstrate non-Mendelian inheritance patterns, in contrast, MSH2 epimutations arise secondarily due to a nearby cis-acting genetic defect and thus demonstrate Mendelian inheritance. These two forms of epimutations represent the

Epimutations of Additional Cancer Genes in Cancer Susceptibility Syndromes

In recent years there have been further reports of epimutations in additional cancer-related genes that give rise to other early-onset cancer phenotypes. While these isolated reports may suggest that epimutations may be exceedingly rare, or only affect certain genes, this field of study is nascent and a broader etiological role for epimutations in cancer susceptibility may emerge with further research.

Constitutional Epimutations in Other Human Diseases

Additional observations of constitutional epigenetic change resulting in altered gene activity in humans, which might also be regarded as constitutional epimutations, have also been identified in other high-penetrance genes to cause diseases other than cancer. These cases provide important insight into the underlying mechanisms that can give rise to epimutation in disease etiology in general.

Inheritance of Altered Epigenetic States in Mouse Phenotypes

Intergenerational epigenetic inheritance has been observed in particular inbred strains of mice, most notably the Avy yellow-coated mouse and the Axin-fused (AxinFu) tail-kink mouse (Fig. 8.9). In both strains, the phenotypes were attributable to the differential epigenetic states at cis-acting intra-cisternal A particle (IAP) retroelements (Morgan et al., 1999, Rakyan et al., 2003). When the retroelement is unmethylated and transcriptionally active, it overrides the activity of the endogenous

Conclusions

Following the completion of the human genome sequence, attention in the new millenium has turned to the epigenome and the role of epigenetics in human disease causation. While the genetic causes of many diseases are now well established, it has become clear that mutations within the coding regions of the relevant disease-associated gene fail to account for all cases with a positive clinical diagnosis. Some of these cases are likely to be attributable to cryptic genetic changes, including

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