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Epigenetic modulators, modifiers and mediators in cancer aetiology and progression
Andrew P.Feinberg1, Michael A.Koldobskiy1 and Anita Gndr2
Abstract | This year is the tenth anniversary of the publication in this journal of a model suggesting the existence of tumour progenitor genes. These genes are epigenetically disrupted at the earliest stages of malignancies, even before mutations, and thus cause altered differentiation throughout tumour evolution. The past decade of discovery in cancer epigenetics has revealed a number of similarities between cancer genes and stem cell reprogramming genes, widespread mutations in epigenetic regulators, and the part played by chromatin structure in cellular plasticity in both development and cancer. In the light of these discoveries, we suggest here a framework for cancer epigenetics involving three types of genes: epigenetic mediators, corresponding to the tumour progenitor genes suggested earlier; epigenetic modifiers of the mediators, which are frequently mutated in cancer; and epigenetic modulators upstream of themodifiers, which are responsive to changes in the cellular environment and often linked to the nuclear architecture. We suggest that this classification is helpful in framing new diagnostic and therapeutic approaches to cancer.
Ten years ago, it was suggested that, in addition to oncogenes and tumour suppressor genes, epigenetic alterations disrupt the expression of hypothesized tumour progenitor genes that mediate stemness at the earliest stage of carcinogenesis, even as a field effect in normal tissues1. Epigenetically altered tumour progenitor genes were proposed to increase the likelihood of cancer when genetic mutations occurred and these same genes were suggested to be involved throughout tumour progression, helping to explain properties such as invasion and metastasis1. In the 10 years since this model was proposed, several discoveries have supported the idea of tumour progenitor genes, including the identification of many of the responsible genes, the role of widespread epigenomic changes involving the nuclear architecture and chromatin compaction, and the parts played by ageing and the environment in these properties.
Nowhere else is the contribution of epigenetic changes to cancer seen more clearly than in paediatric malignancies. Systematic analyses of genetic and epigenetic alterations in a variety of paediatric cancers have surprisingly identified tumour types...