Cells encode their heritable information in two major ways: genetic information, defined by the ordered sequence of nucleotides, and epigenetic modifications, which provide cells with heritable states of gene expression.

For years, research on cancer has been concerned with investigating genetic lesions and their downstream consequences, centered on the analysis of the function of target genes. This was due to the assumption that most of the information encoded by cells is harbored in their genomic sequence. However, the recognition of the importance of epigenetic information has been of enormous consequence in reorienting our efforts and opening new doors in cancer research.

E.Ballestar,M. Esteller

Cancer Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fern√°ndez Almagro 3,28029 Madrid, Spain, e-mail: [email protected]

Progress in Molecular and Subcellular Biology P. Jeanteur (Ed.) Epigenetics and Chromatin © Springer-Verlag Berlin Heidelberg 2005

Epigenetic changes are those heritable modifications that do not involve a change in gene sequence. In particular, these changes are involved in protecting cells from endoparasitic sequences, maintaining the imprinting and X-chromosome expression patterns and the identity of cells within a tissue type. In cancer, epigenetic alterations participate in and determine the loss of the original identity of the cell and are known to play a key role in cancer development and progression.

One of the best-studied epigenetic alterations in cancer is that of the content and distribution of 5-methylcytosine in the genome. In normal cells, methylation of the 5' carbon of the pyrimidine ring of cytosine in DNA is the main epigenetic modification of the genome. In mammals, cytosine methylation occurs in the context of the CpG dinucleotide sequence. CpGs are relatively infrequent in the genome, with the exception of regions of variable length, between 0.5 and 2.0 kb, known as CpG islands. Most CpG islands are coincident with the promoter of protein-coding genes and are normally unmethylated, in contrast with the remaining CpGs, which are methylated.

Early analysis of the role of methylation using tissue-specific genes introduced into mammalian cells by transfection gave rise to a general consensus that DNA methylation directs the formation of nuclease-resistant chromatin, leading to repression of gene activity (Keshet et al. 1986; Cedar 1988; Bird 1992). These conclusions have been greatly refined in recent years and detailed mechanisms will be discussed below.

In cancer, three major events related to the balance of the 5-methylcytosine have been demonstrated to occur: (1) the global reduction of 5-methylcyto-sine content in the genome. This was the first change in DNA methylation to be observed; (2) hypermethylation of the CpG island of many tumor-suppressor genes associated with their transcriptional silencing; and (3) everything occurs with a general increase in the expression of DNA methyltransferases (DNMTs), the enzymes responsible for maintaining and establishing methyla-tion. Thus, cancer is not a problem of the lack or the overexpression of DNMTs; rather, it is the erroneous targeting of DNMTs to incorrect regions of the genome.

Initially, global hypomethylation was thought to be the only significant methylation change in cancer and it was believed that it might lead to the massive overexpression of oncogenes. This is not the case. All the CpG islands of oncogenes are unmethylated in normal cells and cannot be more 'hypo-methylated' in cancer cells. However, there is a global decrease in 5-methylcy-tosine content, which reflects a heterogeneous change in DNA methylation: hypomethylation occurs in isolated CpGs scattered throughout the genome and those CpG dinucleotides present in CpG islands experience hypermethy-lation.

Currently, it is accepted that hypomethylation of repetitive and parasitic DNA sequences correlates with a number of adverse outcomes in cancer. For example, decreased methylation of repetitive sequences in the satellite DNA of the pericentric region of chromosomes is associated with increased chromo somal rearrangements, a hallmark of cancer. For instance, the finding that DNMT3b mutations, which occur in ICF syndrome, cause centromeric instability is indicative of how global demethylation destabilizes overall chromatin organization. Furthermore, decreased methylation of proviral sequences can lead to reactivation and increased infectivity. In fact, one primary function of DNA methylation is the suppression of transcription and expansion of parasitic elements such as transposons (e.g., SINES and LINES) (Yoder et al. 1997). The vast majority of methylated CpGs in normal cells reside within repetitive elements; global demethylation contributes to the reactivation of these parasitic sequences by transcription and movement.

The idea of the methylation of CpG islands of tumor-suppressor genes as a mechanism of gene inactivation in cancer was proposed in 1994 (Herman et al. 1994) when methylation-dependent silencing of the Von Hippel-Lindau (VHL) gene was demonstrated to be a mechanism of gene inactivation in renal carcinoma. In the following years, parallel studies in the laboratories of Dr. Stephen Baylin and Dr. Peter A. Jones established that CpG island hyper-methylation is a common mechanism of gene inactivation in cancer. Recently, we have demonstrated that the profile of CpG island hypermethylation is specific to the tumor type (Esteller et al. 2001). The analysis of a few selected hypermethylated CpG islands can be so powerful that they classify tumors of unknown origin (Paz et al. 2003a). CpG island hypermethylation of tumor-suppressor genes, which leads to their inactivation, is now considered the major epigenetic alteration in cancer (Esteller 2002).

Our vision of the role of genetic lesions in the development and progression of cancer, accepted for many years, has evolved, and nowadays cancer is accepted as having a double origin in which both genetic and epigenetic defects are responsible for the onset and progression of the disease.

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