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The Role of the Epigenome in Human Cancers

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Vogel and Motulsky's Human Genetics

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Abstract

Deregulation of the epigenome is an important mechanism involved in the development and progression of human diseases such as cancer. As opposed to the irreversible nature of genetic events, which introduce changes in the primary DNA sequence, epigenetic modifications are reversible. The conventional analysis of neo-plasias, however, has preferentially focused on elucidating the genetic contribution to tumorigenesis, which has resulted in a biased and incomplete understanding of the mechanisms involved in tumor formation. Epigenetic alterations, such as aberrant DNA methylation and altered histone modifications, are not only sufficient to induce tumors, but can also modify tumor incidence and even determine the type of neoplasia that will arise in genetic models of cancer. There is clear evidence that the epigenetic landscape in humans undergoes modifications as the result of normal aging. Thus, it has been proposed that the higher incidence of certain disease in older individuals might be, in part, a consequence of an inherent change in the regulation of the epigenome. These observations raise important questions about the degree to which genetic and epigenetic mechanisms cooperate in human tumorigenesis, the identity of the specific cooperating genes, and how these genes interact functionally to determine the diverse biological paths to tumor initiation and progression. The answers to these questions will partially rely on sequencing relevant regions of the 3 billion nucleotide genome, and determining the methylation status of the 30 million CpG dinucleotide methylome at single nucleotide resolution in different types of neoplasias. Here, we also review the emergence and advancement of technologies to map ever larger proportions of the cancer methylome, and the unique discovery potential of integrating these technologies with cancer genomic data. We discuss the knowledge gained from these large-scale analyses in the context of gene discovery, therapeutic application, and building a more widely applicable mechanism-based model of human tumorigenesis.

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Authors and Affiliations

  1. Department of Surgery, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, 91101, USA

    Romulo Martin Brena

  2. Department of Neurological Surgery, University of California San Francisco, Diller Family Comprehensive Cancer Center, San Francisco, CA, 94143, USA

    Joseph F. Costello

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  1. Romulo Martin Brena
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  2. Joseph F. Costello
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  1. Institute of Human Genetics, Medical University of Graz, Harrachgasse 21/8, Graz, 8010, Austria

    Michael R. Speicher

  2. Departments of Medicine (Division of Medical Genetics) and Genome Sciences, University of Washington School of Medicine, 1705 N.E. Pacific St., 355065, Seattle, WA, 98195-5065, USA

    Arno G. Motulsky (Professor Emeritus) (Professor Emeritus)

  3. Department of Genetic Medicine and Development, University of Geneva Medical School and University Hospitals of Geneva, 1 rue Michel-Servet, Geneva, 1211, Switzerland

    Stylianos E. Antonarakis

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Brena, R.M., Costello, J.F. (2010). The Role of the Epigenome in Human Cancers. In: Speicher, M.R., Motulsky, A.G., Antonarakis, S.E. (eds) Vogel and Motulsky's Human Genetics. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-37654-5_17

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