Cancer initiation and development have traditionally been viewed as a consequence of primarily genetic alterations and mutations. However, many recent studies have provided strong evidence that tumorigenesis is also connected to epigenetic alterations. "Epigenetic" refers to stably inherited changes in gene expression and chromatin organization that do not involve alterations in the genetic code of the DNA structure. Chromatin (an association of DNA to proteins, among which histones) has several functions: to package the DNA and strengthen it to allow mitosis; to prevent DNA damage and engage damaged DNA into repair; and to control gene expressionand DNA replication. These processes are highly modulated by the chromatin compaction state, since they are dependent on the DNA accessibility for the different factors involved. Several epigenetic mechanisms (DNA methylation, histone modifications and RNA-mediated gene silencing) are in a constant interplay to induce a repressive chromatin state (through compaction)-leading to gene silencing- or on the contrary, to relax the chromatin structure and allow transcription activation and gene expression. Cancer initiation and progression are the results of different genetic and epigenetic modifications that, together, lead to an altered expression of certain genes, including tumor suppressors or proto-oncogenes.

Zdenko Herceg wonders: “a very important debate is: what are the primary and secondary events in cancer development? We find both genetic and epigenetic changes in virtually all cancers, but it is not clear whether the changes in the epigenome (a record of the chemical changes on the DNA and histone proteins of an organism) are simply a consequence of the genetic changes. It is a major issue now to identify what are the critical events (the primary drivers) that lead to cancer and distinguish them from those that are merely non-functional “passenger” events"[1].

Dr Herceg’s work has made an important contribution to this debate by deciphering histone modifications in response to DNA damage and cellular stress (part 1). The results derived suggest a potential impact of epigenetic events in tumor development.  But apart from the mechanistic insights brought about by this fundamental work, understanding the whereabouts of the part played by epigenetic events in cancer initiation and development may have strong repercussions:

First of all, it is a great step for the discovery of new biomarkers. The dynamics of appearance and ubiquity of epigenetic modifications in all phases of tumor initiation and development make epigenetic marks highly attractive targets for predictive and preventive strategies. This is best illustrated through Zdenko’s work in Part 4: Influence of risk factors on DNA methylation and Part 5: early detection of epigenetic marks  

Secondly, targeting the genes and pathways that were deregulated through epigenetic mechanisms might impair tumor development and thus, represent an effective therapeutic strategy, as illustrated in Part 2: histone modifications and stem cell maintenance and Part 3: DNA methylation and cancer stem cells

[1] Review: Z Herceg and T Vaissière, Epigenetics, 2011