Heterogeneity or Homogeneity? Which is it?

This is a complex post not for the faint of heart. In my travels in the prostate cancer research realm I encounter many perspectives of the genetics of prostate cancer. There is a definite trend to view prostate cancer as a cancer that comprises several genetic variances. Thus it is "Heterogeneous". But a recent paper by Dr. Pete Nelson, University of Washington, adds an interesting twist to the discussion. He submits that when you compare metastatic patients there is usually very little in common genetically. But rather that when you compare metastatic tumors in each patient the tumors are actually quite similar in nature. I will lead you to my post in my forum:

Heterogeneity or Homogeneity? Which is it?

advancedpcatalk.freeforums.net/thread/269/heterogeneity-homogeneity-which

So which is it? It probably depends on whether we are discussing early stage prostate cancer or metastatic prostate cancer.

Edited to fix typos.

Mike published a commentary on a study from Roswell that arrived at completely the opposite conclusion. Not only was the genetic make-up different between men, it was very heterogeneous even within the same man. Mike questions whether genetic tests like Prolaris, Oncotype Dx, and Decipher are reliable in light of this heterogeneity. Taking tissue samples from different places can lead to very different results.

Just how accurate are current genetic/genomic tests in the diagnosis and prognosis of prostate cancer?

I added the following comment:

Allen said...
This confirms similar studies that found wide genetic heterogeneity within a single tumor (see this link), that found that tumors within a single prostate may arise independently (see this link), and that a lethal metastatic cell can arise from a small, relatively low-grade cancer focus in the prostate, and not from the index tumor (see this link).

This has implications for focal treatment as well. The guiding principle of focal ablation is that it doesn’t matter that prostate cancer is multifocal because all the smaller foci spawn off from a single index lesion. According to that theory, ablating the index tumor renders the cancer non-lethal in that patient. Clearly the theory is wrong, at least in some patients. This makes me increasingly wary of focal ablation.

These are the links for anyone interested:
/www.ncbi.nlm.nih.gov/pmc/articles/PMC3709757/
jnci.oxfordjournals.org/content/90/3/233
www.jci.org/articles/view/70354/pdf/render

On the opposite side, apart from the citation Tony gave, we have two studies that support the index lesion theory. These suggest that metastases in a single person arose from a progenitor cancer in his prostate. They actually do not say which tumor in his prostate they came from (index or not).

www.nature.com/nm/journal/v15/n5/abs/nm.1944.html
conference.ncri.org.uk/abstracts/2011/abstracts/B243.html

With 20,000 or more coding genes in the human genome, it is not all that surprising to see conflicting results from genetic analyses. It all depends on where within the genome one looks for similarity or dissimilarity, and the definition of similar or dissimilar used in any study. For example, how many SNPs (single nucleotide polymorphisms - or genetic "errors") have to be in a gene before we label it as different? If there is a single SNP in a part of the gene that is inconsequential (and much of every gene is inconsequential) is it different? If so, then everyone is vastly different. But if the SNPs hit a tipping point, or if they are in an important part of a gene, it can make a huge difference in what the gene codes for. There are few sharp lines, mostly slow blurring of distinctions.

I'm not saying that personalized medicine will never be realized in a meaningful way, I'm just saying it is a tremendously difficult problem.

Tony-
I read your blog.

I think you are too quick to dismiss "old" studies - and some were as recent as 2013 and 2014.

Metastatic PC is certainly a different disease from non-metastatic PC. There is no question about that, and we've known that for about a century. We've known for a long time that certain genes get turned off, particularly tumor suppressor genes (like p53) and ones involved in apoptosis, and other genes that code for growth factors get turned on. But the question is not about mets being different from pre-metastatic tumors.

The question that Nelson asked was whether there was genetic diversity in the metastases of different men (there was, and all previous studies affirm that) and whether there was genetic diversity in the metastases of a single man (there was not, and this is controversial). Nelson's work supports a clonal origin for all tumors. He looked at certain genes (e.g., E2F1, RB1, FA-complex genes, ATM, etc.) and AR activity and found them to be similar across metastases within the same man (but different between men). Some other studies, perhaps looking at different genes or setting a different bar for what qualified as a meaningful difference in a gene's DNA, had different findings.

This has implications. If mets have a clonal origin from some mother tumor, it supports the index lesion theory and focal therapy, it supports de-bulking by removing the primary source, and it supports personalized medicine (because all of a given man's tumors could be treated with the same therapy).

If different mets have independent origins in the same man (as some of the other studies show), then the above therapies will not work well.

It may be that all the studies are true. Some mets are spread clonally from the "mother ship," and some are not. There are also known epigenetic factors that change genes depending on the environment they find themselves in. The "mixed model" hypothesis is supported by (1) the fact that some (but not all) men do seem to be cured by focal therapy, and (2) early retrospective studies that show an association between debulking the primary and longer survival (but not complete remission). The implication for personalized medicine is that a single remedy will not eliminate the cancer burden for any given man, although it may reduce it and lengthen his survival.

Hi Jojo,
Ty for the interest. I think Allen makes some great points and I truly respect his points of view. I don't always agree with him but I always have to go back and review my thoughts and his commentary because that's what makes me better at what I do in the research side of things. I could not thank Allen enough for that.

But I don't think I make any snap judgement on the data as he suggests. In this case I think Pete Nelson, whom I have never met, is on the mark with his research. But that stated, the thought that prostate cancer is only homogeneous in metastatic disease is clearly questionable.

Moving forward, the science of this is fascinating to me. And I'll leave all doors open to suggest that Nelson is wrong. But I do not think that Allen's points proved anything to the contrary. Is it possible we are both right? Of course.

I'm a stickler to stick evidence based conclusion. I still think that once the genie is out of the bottle in prostate cancer it largely maintains it's course genetically. And why would it not?

We'll have to follow the course we are on. Even if I am right, and Nelson is right, at this time it does not change treatment course.

Post Edited (Tony Crispino) : 9/26/2016 11:30:06 PM (GMT-6)