Friday, March 23, 2012

Cancer: An Evolving Puzzle

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?