The history of cancer epigenetics

This timeline traces the beginnings of cancer epigenetics to 1982, when Feinberg and Vogelstein identified CpG hypomethylation in cancer cells, and here I will summarize some interesting ideas that I found in this paper. After this initial observation, other discoveries showed more facts related to DNA hypomethylation: (1) It may lead to gene activation; (2) the existence of a 'methylator phenotype', that might be linked to mismatch repair; (3) a relationship between CpG hypomethylation and chromosomal instability; and (4) some toxins, drugs, diets and viruses can provoke methylation alterations that could be found in tumor cells. The mechanism responsible for global hypomethylation in cancer remains unknown, but it has been linked to disfunctional chromatin-remodelling SNF2 family helicases. Later, hypermethylation of tumor suppressor genes was also observed in cancer -conveniently in Rb. By that time, parallel studies showed a relationship between CpG island hypermethylation, imprinting and gene inactivation, that were helpful to formulate the concept of gene silencing in cancer. Other investigations presented a classification between frequent and infrequent methylation groups, called CIMP (the 'methylator phenotype'), which is still a controversial definition. But it is not clear yet if hypermethylation is the cause or the consequence of gene silencing, and some studies point that this could help to maintain the silenced state, although it may not be the causal agent. The resistance to the idea comes from the fact that there are known disorders of the methylation machinery but these do not predispose to cancer.

"[...] the counter- argument from human genetic studies is that the many tumour- suppressor genes in cancer are not modifiers of DNA methylation, even though they are involved in virtually every other potential growth or regulatory pathway. On the other hand, many tumour-suppressor genes are involved in some aspect of chromatin structure [...]."

Another epigenetic mechanism, loss of imprinting (LOI), which may lead to a functional loss of heterozygosity, has been also associated to some tumor forms. A third epigenetic mechanism, the histone modification, is also linked to cancer development, and was first demonstrated by microinjection of in vitro methylated chromatin that would package into a silenced state. An open question in this field that remains undiscovered is whether histone replacement might be perturbed in tumor cells. Finally, solutions to these questions will help in the acceptance of the role of epigenetic disturbances in cancer: (1) explaining the epigenetic inheritance; (2) tumor suppresor genes are linked to almost every signalling pathway but not to DNA methylation (thus, epigenetic changes might be secondary causal elements); and (3) most epigenetic studies come from rare familial disorders. This review, although a little outdated, is interesting because shows the advances in Epigenetics historically, and it is not limited to the studies in cancer.

Feinberg, AP., and B.Tycko. 2004. Nat Rev Cancer 4:143-153
epigenetics