British Journal of Cancer (2006) 94, 179 – 183 & 2006 Cancer Research UK All rights reserved 0007 – 0920/06 $30.00 www.bjcancer.com Minireview Epigenetics provides a new generation of oncogenes and tumour-suppressor genes M Esteller*,1 1Cancer Epigenetics Laboratory, 3rd Floor, Molecular Pathology Programme, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the ‘classical’ oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these ‘new’ oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies. British Journal of Cancer (2006) 94, 179 – 183. doi:10.1038/sj.bjc.6602918 www.bjcancer.com Published online 10 January 2006 & 2006 Cancer Research UK Keywords: epigenetics; DNA methylation; histones; chromatin CANCER AS AN EPIGENETIC DISEASE Great effort has been directed in recent years towards under- standing the establishment and relevance of aberrant epigenetic patterns in human tumours. For DNA methylation, it is known that two apparently contrasting phenomena coexist in the cancer cell: a profound loss of global 5-methylcytosine genomic content with discrete areas of dense hypermethylation (Jones and Baylin, 2002; Feinberg and Tycko, 2004; Esteller, 2005a). Overall hypomethylation takes place predominantly in DNA repetitive and endoparasitic sequences and has been linked to the generation of chromosomal instability (Feinberg and Tycko, 2004; Esteller, 2005a). On the other hand, hypermethylation occurs in the CpG islands located in the promoters of certain tumour-suppressor genes, such as p16INK4a, BRCA1 or hMLH, leading to gene silencing (Jones and Baylin, 2002; Esteller, 2005a). Histones are another key player in epigenetics. Today they are recognised as having a primary role in the control of gene expression and chromatin structure and are partners closely involved with the DNA methylation machinery (Fraga and Esteller, 2005). Our knowledge of the behaviour of histones in cancer cells is slight compared with that of DNA methylation. We know that certain histone modifications participate in tumour-suppressor *Correspondence: Dr M Esteller; E-mail: mesteller@cnio.es URL: http://grupos.cnio.es/epigenetica/ Received 21 October 2005; revised 25 November 2005; accepted 28 November 2005; published online 10 January 2006 gene silencing, in conjunction with CpG island hypermethylation (Fahrner et al, 2002; Ballestar et al, 2003) or in its absence, such as the case of p21WAF1. Most importantly, we have recently demonstrated that human tumours undergo an overall loss of monoacetylation of lysine 16 and trimethylation of lysine 20 in the tail of histone H4. These two histone-modification losses can be considered as almost universal epigenetic markers of malignant transformation (Fraga et al, 2005), as has now been accepted for global DNA hypomethylation and CpG island hypermethylation. Certain histone acetylation and methylation marks may have prognostic value (Seligson et al, 2005). Finally, we should not forget that DNA methylation and histone modifications are not isolated events, but occur in higher-order chromatin structure. Nucleosomes, formed by DNA wrapping around an octamer of histones, are the champions of that league. Multi-subunit complexes, such as those constituted by the SWI/ SNF proteins, use the energy of ATP to mobilise nucleosomes and allow the access of the transcriptional machinery (Gibbons, 2005); or massive repressive complexes counteract SWI/SNF functions, as does the polycomb group gene family (Valk-Lingbeek et al, 2004). In the end, the impact on gene expression in cancer cells is massive and the normal epigenetic programming of the healthy cell becomes merely a faint memory. Never the less, several pieces of the jigsaw are still missing. Are there molecular alterations acting as ‘dark horses’ behind this distorted epigenetic pattern? Could the epigenetic genes turn out to be the next generation of oncogenes and tumour-suppressor