Cancer Initiation: The Rattlesnake Hypothesis model predicts the alternative distributions of DNA methylation changes during cancer progression

Thursday, February 26, 2015

The Rattlesnake Hypothesis model predicts the alternative distributions of DNA methylation changes during cancer progression

We previously noted that cancer progression consists of both hyper methylation of tumor suppressors and hypomethylation of oncogenes. But, these errors are NOT the result of the same process. In our "rattlesnake" model, the hypomethylation errors are the result of failure to fully duplicate methylation patterns upon cell division. This being simple enough, we would expect to find hypo-methylation errors randomly throughout the genome of the affected cell.
  As we have mentioned, aberrant suppression of tumor suppressors  as a much more complicated process. Consider the following hypothetical steps:
  1.  A regulatory micro RNA which is suppressed becomes expressed as a result of failure to methylate its promoter upon cell division
  2.  The newly expressed micro RNA finds its antisense partner in the cell and forms a RNA Induced Suppression Complex (RISC)
  3.  The RISC mediates new or "de neuvo" promoter methylation on the gene which was targeted by the microRNA
  4. If that targeted gene was a tumor suppressor, the cell cycle of subsequent cells from that clone accelerates, and as such, the "grade", or observed malignancy of the neoplasm increases.
If this second model holds true, we would expect that aberrent methylation occurs around promoters, in the genome, as opposed to methylation loss, which is random. So the question is, has  this type of distribution of methylation errors ever been observed?
  It appears that the answer is "yes":
 From the abstract of Irizarry [1], we get the following:

 There was a notable overlap (45-65%) of the locations of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling that of noncolon normal tissues.
Unfortunately, I could not find anything in the body of Irizarry that supported any kind of "slam dunk" at all. But, what I also did not see was a conceptual model that could lead to an epistemelogical slam dunk on cancer progression.
  Given the proposed model here, we could easily see that we would like to follow through in two directions:
  First, were there micro RNAs that were being expressed that were associated with hypermethylation at particular promoters.
  Secondly,  are the regions of DNA that Irizarry calls "island shores" associated with particular functional operations of DNA duplication.  If methylation  data is being lost, is it lost progressively in the same region after each round of cell division? That would reinforce the proposal that hypomethylation is being lost as the result of a checkpoint.
 The loss of cell cycle check points as a cause of cancer was among the first proposals ever presented as to the nature of cancer. As Paul Nurse is primarily responsible for the concept, he was awarded a Nobel prize in medicine for his work on fission yeast.  Subsequently, The attention has turned away from DNA sequence duplication failure in cancer progression to DNA methylation failure. Unfortunately, the issue of check points still exists, but little is known about how a check point failure affects duplication of existing methylation patterns.


[1] Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, Ji H, Potash JB, Sabunciyan S, Feinberg AP.  The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 2009 Feb;41(2):178-86. [Pub Med Central]

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