Epigenetics, the storage of genetic information outside of the DNA relies on methylation. E.g. a smoking grandfather can cause problems for his grandchildren, even though this information is not stored inside the DNA but in the methylation patterns which are also inherited. It will be interesting how much epigenetics will have an influence on the prevention and cure of cancer.
"As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.[2] However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa."
While I’m of the opinion that trans-generational epigenetic inheritance is not typically important in human biology, the most convincing argument I’ve heard is that the egg cells that will become a grandchild are present and post-meiotic in the fetus of the mother, so exposures to the grandmother could have effects 2 generations down without requiring some relatively exotic pattern of inheritance.
Methylation is just one part of epigenetics. There are other types of chemical modifications such as histone acylation that play a role. Also physical interactions such as transcription factor binding, chromatin accessibility, etc. Increasingly the spatial organization of the genome into topologically associated domains (TADs) is thought to impact transcription.
This paper shows that deleting one 'TET' gene (https://en.wikipedia.org/wiki/TET_enzymes) leads to an increase in certain types of cancer. The protein encoded by that gene removes methyl (-CH3) groups from DNA, in a process called demethylation.
The 'opposite' process of methylation, in this case, is performed by the enzyme DNMT1 - and if you delete both TET and DNMT1 genes, there are less of these non-helical DNA structures and less cancer.
So the conclusion is that an imbalance between metylation and demethylation of the DNA can lead to cancer.
It's a summary of a particular paper, but it is not really written for a general audience. From a quick read I'd summarize it as follows:
We know that if a group of specific enzymes (TET) are disabled for some reason, you have increased cancer rates. We also know that in some cancers you observe unusual structures in the DNA called G-quadruplexes and R-loops, which are different from the usual double-helix. We also know that these unusual DNA structures destabilize the genome, leading to more mutation which in turn leads to more cancer.
What this paper showed that disabling these specific TET enzymes lead to an increase in these unusual DNA structures and to cancer. So it establishes the causal relationship between the lack of these enzymes and the unusual DNA structures.
What I find interesting is that the function of the TET enzymes we know, demethylation of DNA doesn't have anything direct to do with the formation of G-quadruplexes or R-loops.
Makes me wonder if this was discovered in mice engineered for inducible gene expression. TET/doxy mice are commonly used in experiments where you want to selectively turn on or off a particular gene.
https://en.wikipedia.org/wiki/Cancer_epigenetics
"As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations.[2] However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa."