Abstract PL02-01: Cancer genetic and epigenetic interactions.

Abstract

Abstract Cancer develops not only as a result of genetic mutations and genomic rearrangements, but also as a consequence of numerous epigenetic alterations, including extensive changes in the distribution of DNA methylation throughout the genome. DNA methylation changes contribute directly to cancer by transcriptional silencing of tumor-suppressor genes through promoter CpG island hypermethylation. Cancer genome studies have uncovered somatic mutations in dozens of epigenetic regulators in almost all types of cancer, and integrative analyses have revealed associations between various somatic genetic alterations and broad epigenomic profiles. Some somatic mutations are very tightly associated with distinct epigenetic subtypes, such as CpG Island Methylator Phenotypes (CIMP). In some cases, the somatic mutation appears to contribute causally to the epigenomic profile, such as in the case of mutation of IDH1 in G-CIMP glioblastoma, while in other cases the epigenomic alterations appear to be a prerequisite for somatic mutation, such as colorectal CIMP-associated changes contributing to suppression of mutant BRAF-mediated senescence. Other cancer epigenomic profiles are attributable to stochastic events or cell-of-origin chromatin states. For example, genomic loci targeted by Polycomb Group Repressors in embryonic stem cells, and involved in cellular differentiation are predisposed to aberrant DNA methylation in cancer cells, suggesting that an epigenetic block to cellular differentiation may sometimes be an initiating event in carcinogenesis. The analysis of whole methylomes at single-basepair resolution reveals that cancer-associated changes occur differentially across defined regions of the genome associated with the nuclear lamina. It is apparent that epigenomic analysis is essential for a full understanding of the relationship between alterations in the cancer genome and the origin and clinical diversity of individual tumors. Citation Format: Peter W. Laird. Cancer genetic and epigenetic interactions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr PL02-01. doi:10.1158/1538-7445.AM2013-PL02-01