Several recent papers have been published on the details of
cancer genetics which make the understanding a continuous process of
complexity. Let me first provide a brief précis of how we have progressed to
this point:
1. The clone. It has been asserted that almost all cancers
begin with a single aberrant cell, the clonal source. From this one cell we
have generate everything else. One single cell then replicates in an
uncontrolled manner.
2. The Vogelstein Paradigm: The Vogelstein Paradigm (VP)
states that the clone is created in some predictable sequence of gene changes
and that these changes can be detected and perhaps blocked.
3. The genetic profile: This concept uses the wealth, also
excess, of gene mutation data available from microarray analysis to determine “profiles”
for various cancers attempting to gain prognostic information as well as “individual”
profiling for treatment. In many ways the micro array tool provides “too much
data”, akin to the comment in Amadeus when the Emperor was asked about Mozart’s
music, and he remarked “too many notes”. Namely the wealth of data is essential
but the ability of the human processor is not quite up to it yet.
4. The pathway model: In this case we use pathways as a
means to understand what is going wrong in a cell by cell basis. Then we try to
block aberrant pathways to have the tumor no longer function as it has to that
point. We have argued that this approach has a strong core, namely a model
which can be verified and improved, but at the same time it lacks two major
factors; (i) is does not deal with intercellular communications well enough,
(ii) it does not deal with the issues of what causes the loss of gene activity
and homeostasis well enough.
Now there have been several papers in NEJM discussing
results on several cancers, kidney and AML, acute myeloid leukemia. Combined
they tell and interesting tale. I have already commented on the kidney paper by
Gerlinger et al but will add to it in this analysis.
As Gerlinger et al state:
Multiregion genetic
analysis of four consecutive tumors provided evidence of intratumor
heterogeneity in every tumor, with spatially separated heterogeneous somatic
mutations and chromosomal imbalances leading to phenotypic intratumor diversity
(activating mutation in MTOR) and uniformity (loss-of-function mutation
in SETD2 and PTEN). Of all somatic
mutations found on multiregion sequencing, 63 to 69% were heterogeneous and
thus not detectable in every sequenced region. Heterogeneous patterns of
allelic imbalance were found in all tumors, and ploidy heterogeneity was found
in two tumors. Therefore, we found that a single tumor-biopsy specimen reveals
a minority of genetic aberrations (including mutations, allelic imbalance, and
ploidy) that are present in an entire tumor.
Thus with this study we see significant genetic variability.
The sequencing of genetic changes and the expectation of clonal consistency
seems to be at variance.
In contrast, to justify the clonal progression, as Walter etal state regarding AML:
A unique aspect of the
biology of leukemia is that hematopoietic cells freely mix and recirculate
between the peripheral blood and the bone marrow. Clones that persist and grow
over time must retain the capacity for self-renewal. Mutations in new clones
must confer a growth advantage for them to successfully compete with ancestral
clones. The result is that these secondary-AML samples are not monoclonal but
are instead a mosaic of several genomes with unique sets of mutations; this
mosaic is shaped by the acquisition of serial mutations and clonal
diversification. Similarly, recent analysis of de novo AML samples with the use
of whole-genome sequencing showed that relapse after chemotherapy is associated
with clonal evolution and acquisition of new mutations. Analysis of individual
cancer cells may reveal additional layers of genetic complexity. Recent studies
of B-cell acute lymphoblastic leukemia have shown that serial acquisition of
cytogenetic abnormalities in that disease most often occurs through a branching
hierarchy and only rarely follows a simple linear path…. Our study has several
clinical implications. First, the distinction between the myelodysplastic
syndromes and secondary AML currently relies on manual enumeration of bone
marrow myeloblasts, a standard that is subject to interobserver bias but
nonetheless drives major decisions about treatment for patients with small
differences in myeloblast counts. Ultimately, identifying the patterns of
pathogenic mutations and their clonality in bone marrow samples from patients
with myelodysplastic syndromes should lead to greater diagnostic certainty and
improved prognostic algorithms.
Neither studies presented intracellular pathways models
which could be verified as state machines leading to malignant processes nor
did they provide any basis for the genetic variations observed. These two
factors will be essential in a better understanding of these diseases. However
we see strong hematopoietic clonality and non-hematopoietic non-clonality.
The question one may ask is: does the cancer cells as they
progress in a metastatic manner do so in a random ever changing manner
unconnected from one another or is there some rational basis for the changes in
a manner in which the cancer has become an alter-organism in the human host? Is
cancer a “slime mold” atop the human?
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