DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms

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Abstract

Since the discovery of epigenetic alterations in cancer 20 years ago by Feinberg and Vogelstein, a variety of such alterations have been found, including global hypomethylation, gene hypomethylation and hypermethylation, and loss of imprinting (LOI). LOI may precede the development of cancer and may thus serve as a common marker for risk, but also as a model for understanding the developmental mechanism for normal imprinting.

Introduction

Epigenetics is defined as stable alterations in the genome, heritable through cell division, that do not involve the DNA sequence itself. Epigenetic alterations are reversible, at least in the germline, and they often act over a distance. The distance can be relatively small, in the order of kilobases, as in telomere silencing in yeast, or the distance can be large, in the order of megabases, as in position effect variegation in Drosophila. For these reasons, epigenetic alterations are all thought to involve modifications of chromatin, and one of the most intriguing questions in this field is whether common types of modification account for the diverse examples of epigenetic effects. As will be discussed in this review, some of the lessons gained from the study of imprinting in cancer do have general implication, not only in the understanding of cancer biology but chromatin in general.

The first indication that epigenetics played a role in cancer was the discovery in 1983, by Feinberg and Vogelstein,1 of altered methylation of genes in colorectal tumors. These alterations were found at the time to occur in all cancers and adenomas,2 making them by far the most common type of genetic change in cancer, which is still true in light of current knowledge. While these first observations were of colorectal cancer, they have been generalized to virtually all types of neoplasia.3 Many genes in cancers lose methylation, many gain methylation, and at least in colon cancer, there is also a generalized loss of total methylation content in the genome.3., 4., 5. Both gains and losses are likely important. Gains of methylation include promoters of tumor suppressor genes, and it has been hypothesized that the methylation alteration itself is responsible for gene silencing.6 While that may be true, it is also possible that other chromatin alterations play a primary role in gene silencing. For example, it has recently been shown in Neurospora that methylation is dependent upon histone modification.7 Similarly, losses of methylation likely lead to chromosome instability. This has been shown directly by treatment with 5-aza-2′-deoxycytidine,8 and by direct observation of tumors.9 The epigenetic alteration that is the main focus of this chapter is loss of genomic imprinting, which is linked to alterations in methylation. Indeed epigenetic and genetic alterations are interrelated.10

One of the most important ideas we wish to communicate in this review is that the study of human disease is an extremely powerful tool to understand normal biology. This is an old idea in genetics, of course, first promulgated by Garrod in his studies of inborn errors of metabolism, and has been true from the studies of alkaptonuria, through the great insights in cholesterol metabolism.11 However, in the study of epigenetics this idea is particularly important, since outbred populations may reflect a more normal epigenetic milieu than an inbred laboratory strain. This idea was brought home acutely in a recent study that showed that the very first mutation every studied, by the Swedish botanist Carl von Linne (who of course is remembered as Linnaeus), a change in symmetry of the flower Linaria vulgaris. Vincent and Coen12 found that this mutation was caused by an epigenetic modification, namely methylation of the Lcyc gene, rather than by a conventional mutation, and this epigenetic alteration has been stably propagated for at least 200 years! In a striking discussion, the authors argue that this type of epigenetic alteration, while uncommon in laboratory strains, may be much more common in the natural world.12 This idea, that some of the most important insights come from studies of disease, is certainly true in the study of genomic imprinting.

Section snippets

Genomic imprinting

Genomic imprinting is a form of epigenetic inheritance that distinguishes maternal and paternal alleles. Imprinting, and epigenetic alterations in general, are commonly studied in the context of gene silencing, but the intrinsic definition refers to the heritable modification itself. This modification may have consequences beyond gene expression changes, such as pairing of homologous chromosomes, or organization of chromatin. It should be borne in mind that differential expression is not the

Loss of imprinting (LOI) in cancer

LOI is defined as a parental origin-specific epigenetic modification that is disrupted, and can include gain or loss of methylation or other chromosomal marks, or loss of the normal pattern of parental origin-specific gene expression.14 The term was chosen because it does not require that a normally silenced allele is activated, but also includes silencing of a normally expressed allele. This is an important point, because it should clarify some confusion in the literature and it makes

LOI is associated with a subclass of Wilms tumors

A surprising recent study of Ravenel et al.34 offers a model for understanding the role LOI may play in childhood tumors, and the study shows that the prior conception of Wilms tumor genetics was likely incomplete. Wilms tumor shows a bimodal age distribution, with tumors arising in very early infancy, or at several years of age. Knudson and Strong35 proposed that the earlier tumors arise in patients who have a germline mutation and a second arising postnatally, and that the later tumors

Epigenetic lesions occur early in colorectal cancer

The analysis of LOI has also provided novel insights in the understanding of adult malignancies. Thus, Cui et al.40 found that about one-third of colorectal cancers undergo LOI, and that LOI is also found in the matched normal colon of the same patients. In order to prove that LOI was not simply a developmental alteration unrelated to cancer per se, these authors analyzed the normal colon of patients without colorectal cancer, and found that the frequency of LOI was threefold greater in cancer

Clusters of imprinted genes are differentially dysregulated in human diseases

The identification of imprinted genes on chromosomes 11 and 15 led from studies of Beckwith–Wiedemann syndrome (BWS) and Prader–Willi syndrome, respectively. In particular, Feinberg and coworkers41 mapped BWS, a disorder of prenatal overgrowth, birth defects and predisposition to Wilms and other tumors, to 11p15, and Mannens et al.42 observed that the disorder showed parental origin-specific disease penetrance. Feinberg and coworkers then identified the first cluster of imprinted genes,

Mechanisms of LOI and the role of imprinting control regions

Imprinting control regions (ICRs) provide a key to our understanding of LOI, since their manifestation ensures that gametic marks will be interpreted in the soma to establish parent of origin-dependent expression domains. As discussed before, not only the methylated state, but also the unmethylated state constitutes an imprint, since it is the methylation difference that matters. This is exemplified by the H19 ICR, which represses the maternal IGF2 allele when unmethylated and the paternal H19

The methylome: a novel perspective of cancer epigenetics

An important future direction for these studies is the definition of the components of the methylome, i.e. the total methylation content of the cell. The methylome cannot be found on the GenBank website, because ordinary sequencing does not reveal it. Nevertheless, it represents the fruitful target of epigenetic modifications in normal development and disease. Strichman-Almashanu et al.75 have recently made a jump toward identifying the methylome in a strategy designed to isolate normally

Acknowledgements

This work was supported by NIH grant CA65145 (APF) and grants from Swedish Cancer Foundation, Pediatric Cancer Foundation and Lundsberg Foundation (RO). We thank Melinda Graber for preparing the manuscript.

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