Epigenome Chaos: Stochastic and Deterministic DNA Methylation Events Drive Cancer Evolution

SIMPLE SUMMARY: Cancer is a group of diseases characterized by abnormal cell growth with a high potential to invade other tissues. Genetic abnormalities and epigenetic alterations found in tumors can be due to high levels of DNA damage and repair. These can be transmitted to daughter cells, which assuming other alterations as well, will generate heterogeneous and complex populations. Deciphering this complexity represents a central point for understanding the molecular mechanisms of cancer and its therapy. Here, we summarize the genomic and epigenomic events that occur in cancer and discuss novel approaches to analyze the epigenetic complexity of cancer cell populations. ABSTRACT: Cancer evolution is associated with genomic instability and epigenetic alterations, which contribute to the inter and intra tumor heterogeneity, making genetic markers not accurate to monitor tumor evolution. Epigenetic changes, aberrant DNA methylation and modifications of chromatin proteins, determine the “epigenome chaos”, which means that the changes of epigenetic traits are randomly generated, but strongly selected by deterministic events. Disordered changes of DNA methylation profiles are the hallmarks of all cancer types, but it is not clear if aberrant methylation is the cause or the consequence of cancer evolution. Critical points to address are the profound epigenetic intra- and inter-tumor heterogeneity and the nature of the heterogeneity of the methylation patterns in each single cell in the tumor population. To analyze the methylation heterogeneity of tumors, new technological and informatic tools have been developed. This review discusses the state of the art of DNA methylation analysis and new approaches to reduce or solve the complexity of methylated alleles in DNA or cell populations.