Genome-epigenome interactions in cancer.

ABSTRACT

Genetic and epigenetic mechanisms contribute to the development of human tumors. However, the conventional analysis of neoplasias has preferentially focused on only one of these processes. This approach has led to a biased, primarily genetic view, of human tumorigenesis. Epigenetic alterations, such as aberrant DNA methylation, are sufficient to induce tumor formation, and can modify the incidence, and determine the type of tumor which will arise in genetic models of cancer. 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 and clinical paths to tumor initiation and progression. These gaps in our knowledge are, in part, due to the lack of methods for full-scale integrated genetic and epigenetic analyses. The ultimate goal to fill these gaps would include sequencing relevant regions of the 3-billion nucleotide genome, and determining the methylation status of the 28-million CpG dinucleotide methylome at single nucleotide resolution in different types of neoplasias. Here, we review the emergence and advancement of technologies to map ever larger proportions of the cancer methylome, and the unique discovery potential of integrating these 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.