Joseph F. Costello and Romulo M. Brena
from: Epigenetics (Edited by: Jörg Tost). Caister Academic Press, U.K. (2008)
Genetic and epigenetic mechanisms contribute to the development of human tumors, yet the typical analysis of tumors is focused on only one or the other mechanism. This approach has led to a biased, primarily genetic view of human tumorigenesis. Epigenetic alterations such as aberrant DNA methylation are mitotically heritable, sufficient to induce tumor formation, and can modify the incidence and tumor type in genetic models of cancer. Complex epigenetic modification of histones, and genetic alterations of the genes encoding histone modifying genes also contribute to gene and chromosome dysfunction in tumorigenesis. These initial studies raise important questions about the degree to which genetic and epigenetic pathways cooperate in human tumorigenesis, the identity of the specific cooperating genes and how they interact functionally to determine the differing biological and clinical course of tumors. These gaps in our knowledge are, in part, due to the lack of methods for full-scale integrated genetic and epigenetic analyses. The ultimate comprehensive analysis will include sequencing relevant regions of the 3 billion nucleotide genome, determining the methylation status of the 28 million CpG dinucleotide methylome at single nucleotide resolution, and mapping relevant histone modifications genome-wide in different types of cancer. Here we discuss the fundamental differences between normal and cancer epigenomes, and the unique discovery potential of integrating cancer epigenomic and genomic data. We discuss the knowledge gained from single gene and large-scale epigenome analyses in the context of gene discovery, therapeutic application, and building a more widely applicable mechanism-based model of human tumorigenesis read more ...