The recent Nature paper elucidating the changes in patient's genes with prostate cancer is interesting. We have recently made some comments but believe that a few more are of note.
The authors note:
Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, ‘copy-neutral’) rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2–ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTENinteracting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.
Thus, besides the now well known PTEN deletion or suppression and fusion of TMPRSS2 and ERG, we have CADM2 and MAGI2. The details on the seven patients lays out a complex and varied pattern of genetic changes. There remains the following questions:
1. Cancer Stem Cells, CSC, are often viewed as the cope element of a cancer. If so do we have such in PCa and if so then what cells are we measuring gene changes in?
2. Pathways are key structure to understand causal relationships in cancer. We know PTEN and TMPRSS1-ERG fusion pathway effects but the complexity of other expressed genes if not as well known. We would argue that it will be necessary to understand the details of the pathways and that to effectively do so we will need hundreds of such detailed samples.
3. What causes the changes. What is the chicken and what is the egg? This will be a critical factor. Is there a sequence here that is followed or is there just random evolution of changes, and due to what?
4. What are random effects or secondary effects versus causal effects.
5. There was some methylation involved and one may ask if this is due to inflammation effects.
6. How did these gene changes change by cell type. Foe example if the patients had Gleason 7 or higher, then we had a mix of Gleason 2, 3, 4, and 5 cell clusters and if we had selected cells from each of those clusters how did the gene profile vary. Then is there a temporal progression as we go across the cells. This may elucidate the progression analysis.
This is an interesting first step but like so many reports it is exaggerated in the press.
All of the tumors sequenced so far have been from patients with high-risk tumors, so the team is not yet able to differentiate between aggressive and benign tumors. "It may well be that indolent tumors have much quieter genomes," Garraway said. "It raises the intriguing possibility that, if we were to apply this more widely, given the richness of the patterns we are seeing, there might be features we could sort out that would tell us [which tumors] are going to remain quiet and which are going to be bad actors."
These are useful results but for but seven patients and what appears to be based upon a collective of cells. It does raise the question that one may ask, namely, is prostate cancer, and most likely most cancers, really a collection of disparate genetic perturbations, or is there a core set of patterns and sequences that lead to understanding.
The main problem with many of these recent results is the proliferation of press articles which ofttimes state much more than the results, albeit useful and insightful results, bring to clarify our understanding.
The issues are all too often; what, when, and why. This in many ways adds to the what, the first of many questions. The when is a sequenced and networks set of answers which are in my opinion truly informative, and the why then leads to the ability to control, namely stop and reverse.
As one of the authors is quoted as saying:
"With additional studies and as we sequence more prostate cancer genomes, we may be able to distinguish benign from more aggressive prostate cancers and prevent unnecessary surgeries and treatments,"
However, it can be argued that what has been determined is the what of seven patients, useful, but a first step, of many. We have argued that what is required is a model for the controlling networks, one which shows critical paths and in turn what causes the path to diverge. For example, why did we get the PTN changes, what caused it to occur. We have outlined these in a first draft of our recent work on prostate cancer. As we have argued one must have a systems approach to this problem. Prostate cancer however is a rich area to work, mainly because of this very problem, namely the diversity of presentations, yet the similarity of result.
Take Bloomberg for example, they state:
This is frankly wrong. There complete map of prostate cancer was not charted. It was the gene mapping of seven patient each show substantial variability and no significant consistency. They did not look at seven different kinds of prostate cancer, they looked at seven patients, and more than likely there may have been dozens of "kinds" of prostate cancer. As to the findings, well they are as off as the first two paragraphs.
One wonders what responsibility the researchers have for getting the story straight. How much do you have to know to see that albeit good work this is not what the Press spells it out to be.
Take Bloomberg for example, they state:
A complete genetic map of prostate cancer has been charted for the first time by scientists, an achievement that may expand understanding of the disease and lead to new treatments.
Scientists looked at seven kinds of prostate tumors, using a technology that allowed them to sequence the full genetic plan, and compared them to sequences from normal tissue samples, in a study published in the journal Nature. The work was led by researchers from the Broad Institute of Harvard and the Massachusetts Institute of Technology in Cambridge, Massachusetts and Dana-Farber Cancer Institute in Boston.
This is frankly wrong. There complete map of prostate cancer was not charted. It was the gene mapping of seven patient each show substantial variability and no significant consistency. They did not look at seven different kinds of prostate cancer, they looked at seven patients, and more than likely there may have been dozens of "kinds" of prostate cancer. As to the findings, well they are as off as the first two paragraphs.
One wonders what responsibility the researchers have for getting the story straight. How much do you have to know to see that albeit good work this is not what the Press spells it out to be.
Posts
