Cancer Initiation: The principles of epigenetics imply a lack of equivalence between mutagenicity and carcinogenesis

Saturday, April 25, 2015

The principles of epigenetics imply a lack of equivalence between mutagenicity and carcinogenesis

   Inherent in the current system of carcinogenic risk analysis is the  precondition that the mutagenicity of a compound is equivalent to its carcinogenic potential. This equivalence dates back to the work of Bruce Ames during the 1980's, and his refinement of the "Ames Test".  In brief, the Ames test is a "reversion test", in which a small mutation is placed in a model organism ( salmonella ), and the ability of a test compound to perform random mutations that reverse the effects of the inserted mutation is quantified.
   This quantified assessment of a compounds mutagenicity, or ability to interfere with the proper replication of DNA is a priory assumed to be equivalent to its carcinogenic risk.  This causal-equivalence presumably arises from early work in genetics, primarily in fruit flies ( drosophila ) .
In fruit fly work, the eggs or larvae are exposed to radiation or known mutagenic chemicals, and resulting mutations (genes) are named after the development phenotype of the affected organism.
  So far so good. But, as I have mentioned, this particular model has since broken down as a model of carcinogenesis. Time after time, in studies of actual tumors in patients, the gene sequence of the presumed causative gene is normal, but the gene has been suppressed at the transcription level. The details of the particular suppression are part of a field of study known as "epigenetics".
    A PubMed search on "cancer epigenetics" returns thousands of hits. This has become the modern direction of cancer research. On the other hand, the "Ames test" remains the standard of risk determination, even though it only quantifies an effect that is no longer uniquely associated with carcinogenic risk.
    As a "literature experiment", I first placed the term "mutagenicity carcinogenisis ames" in the PubMed search bar. The resulting list ( April 2015 ) returned  13 pages of 247 articles.
  I then added the term "epigenetics" to the search and the result was "no items found"

Figure 1. Two searches, showing no review of the findings of "epigenetics" on the validity of the Ames test.
 Let me further clarify that carcinogensisis as a result of "genomic" mutation is a completely different process thatn that of "methylomic" mutation.  Genomic fidelity is associated with proteins known as DNA polymerases. On the other hand, the methylome is associated with the fidelity of the "maintenance DNA methyl transferase"  (DNMT).
   The continuing lack of differentiation between these two processes in the research and science education community is one of the primary reasons for proposing that a new foundation of biology be developed around maintenance of the methylome.

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