[Dean's World] Dave Schuler: The Earliest Stages of Cancer

[notify at powerblogs.com]

Posted by Dave Schuler:
The Earliest Stages of Cancer
http://www.deanesmay.com/posts/1186085523.shtml


   by George L Gabor Miklos, PhD and Phillip John Baird, MD PhD

   To understand how cancer begins, it is useful to examine readily
   accessible tissues for the earliest stages. One such place is the
   cervix where billions of PAP smears and other gynecological
   examinations have been conducted. Here the first microscopically
   recognizable changes reveal that some cells have four copies of their
   DNA instead of two (66-68). Why is this finding so important?

    Once four DNA copies are attained, all Hell breaks loose

   The two-copy to four-copy event is rare but can occur spontaneously in
   any normal cell population. Two normal cells may fuse, or a normal
   cell may replicate its DNA but then not divide. Such events can also
   be caused by viral infection (69).

   Once attained, a four-copy DNA state is 1000-fold more unstable than a
   two copy state (70-72). These cells with their doubled-up DNA begin to
   jettison the excess DNA or to silence their genes by mutation or
   chemical modifications. Systems fail, errors increase enormously and
   deletions, additions, rearrangements and mutations devastate the DNA.

   Thus every-day cell biological processes, once started, wreak havoc. A
   population of cells is generated with massively disrupted DNA contents
   leading to modifications in metabolism and further accumulation of
   changes including single letter mutations (65,73-76). The flexibility
   of this population far exceeds anything that can be achieved by
   mutations alone in a two-copy DNA system. It is this flexibility which
   drives the spread of cancer and subsequent drug resistance.

    The Mutationists

   The theory of the mutational basis of cancer in humans is predicated
   on the progressive accumulation of mutations in âcancerâ genes in
   two-copy DNA systems. This interpretation received a boost when three
   specific genes were experimentally introduced into a cell line and
   those human cells formed tumors when transplanted into mice (77,78).
   Mutations then became the drivers of cancer and the massively altered
   DNA contents of the metastatic cells in patients, (which are crucial
   to drug resistance), were quietly ignored.

   The results from this artificial three gene system, however, turned to
   dust. Reexamination of the original cells not only revealed them to
   have massively altered DNA contents, but other investigators could not
   repeat these findings using exactly the same three genes
   (79,80,81,82,83).

   These inconvenient truths, however, were ignored and investigators
   began a frenzied search for mutated âcancerâ genes in every tumor
   source. Having found mutations, however, few investigators attempted
   to determine their clinical significance. It is axiomatic that if a
   mutation in a gene causes cancer, then reintroducing a good copy of
   that gene into a cancerous cell should restore the cell to normalcy.
   When this simple test was conducted, however, the cells did not revert
   to normalcy(80). The basic premise of causality failed the most
   elementary test.

   Worse follows. Recent population-based data on two famous breast
   âcancerâ genes calls into question the clinical significance of the
   extensively studied mutations in these genes, for which many women are
   tested (84).

    The BRCA1 and BRCA2 breast cancer genes

   Most women are aware of these two genes and dread that they may carry
   mutations within them. After decades of detailed examination of
   mutations in these genes, however, definitive clinical data now reveal
   that breast cancer specific rates of death among women who are
   carriers of BRCA1 or BRCA2 mutations, are no different to those of
   women without these mutations (84). Clinical data have thus rendered
   irrelevant a decade or more of mutation-based research data.

   Despite all the clinical and experimental data to the contrary,
   leading cancer figures regard the mutational basis of cancer as some
   sort of Final Truth which is not to be questioned; only the details
   need to be filled out. Cancer researchers ferociously defend any genes
   on which they work as being absolutely crucial to some aspect of
   cancer, no matter how tenuous, distant or vaguely relevant the
   clinical connection may be. This is hardly surprising; finding
   âcancerâ genes is now a prerequisite for fundraising and for Big
   Science enterprises.

   (Next up, and the finale: Cancergate, The Hope, and Failure vs. Crime.
   To be published Monday August 6.--Dean)