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In a recent post, Philip Gerlee highlighted the two biggest contributions of mathematical oncology to cancer research: (1) increasing focus on the progress of cancer as an evolutionary process, and (2) looking at the importance of tumor heterogeneity.

For the first point, the standard historical reference is: Nowell, P. C. (1976). The clonal evolution of tumor cell populations. Science, 194(4260): 23-28.

However, for the second point, although I am vaguely familiar with modern work, I don't know of a historical reference. When was tumour heterogeneity first recognized as important to cancer dynamics and treatment? Was this work related to mathematical or other modeling insights? If not, what is the first important mathematical (or computational) modeling work on tumour heterogeneity?

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I more confident about the experimental evidence being older. The histological evidences are even presented in pathology books. The whole field of systems biology is relatively new- most cancer mathematical models have been published in the last decade only. The oldest model that uses the concept of tumor heterogeneity is this- published in 1996. [ Based on google search ] – WYSIWYG Mar 5 '14 at 5:09
you might look for 'clonal selection' and cancer. I've heard the term bandied around. – shigeta Mar 5 '14 at 6:09

It's quite interesting that the first reference that come to mind is not a mathematical/theoretical one (which is, in all likelihood, going to be a lot older than the one I am going to mention) but a clinical one. That would be Gerlinger and Swanton and their paper in the New England Journal of Medicine.

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This paper is quite recent. The concept of tumor heterogeneity was in discussion since long time back. I can't recall references but I have heard people talking in seminars about genome sequencing different regions of cancerous tissue to look for heterogeneity. Histological evidences are even older. I guess pathology books also have it. – WYSIWYG Mar 5 '14 at 5:01
That paper is very well cited (over 1000 times!), but I agree with @WYSIWYG that 2012 seems too recent. Is there a richer history with Gerlinger and Swanton that you could expand on in your answer? Or did you intend this as a comment? – Artem Kaznatcheev Mar 5 '14 at 5:29

The idea of tumour heterogeneity has been around for a long time (look at the below review and the refs therein), but the underlying causes have been revised in the light of theoretical advances and the novel (Gerlinger et al.) genetic data.

Firstly genetic heterogeneity was largely believed to be the cause of genetic instability (an increased mutation rate), and hence being attributed to drift rather than multiple fitness peaks (i.e. selection).

Secondly there was no evidence to determine if the observed phenotypic heterogeneity (from histology slides) could be attributed to genetic changes, or if it was the cause of phenotypic plasticity.

Alexandrova, Tumour Heterogeneity, Exp. Pathol. Parasitol (2001).

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Welcome to the site! Do you know any other sources for Alexandrova's essay apart from a dropbox link? I know a lot of people are unwilling to click those. Also, could you make your answer a bit more self-contained by taking a reference or two out of Alexandrova's essay for when you say "has been around for a long time", for example? That way people can have an idea of the timeline without having to leave this answer. – Artem Kaznatcheev Mar 7 '14 at 3:00
Actually it's a google drive link. In any case I uploaded it because I couldn't find a pdf of the manuscript anywhere. Do you know of a place that is considered "safe" in terms of downloading? – Philip Gerlee Mar 7 '14 at 12:30

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