Inferring tumour evolution – clones, again

Series on Tumor Evolution
How do you know the leaders in your field? Because they get invited by
Nature Medicine and Nature Biotechnology to a fancy place owned by the Volkswagen Foundation and write a report about it. For example, this one in the latest issue of Nature Medicine titled Toward understanding and exploiting tumor heterogeneity.

What did they discuss? Lots of things. But I got stuck already in the very first topic:

What is a clone? The term ‘clone’ is used widely in the field, but discussion in this group revealed that, perhaps surprisingly, there is no consensus about what it indicates; in fact, this question sparked some of the most animated discussion at the meeting.

Perhaps surprisingly? Readers of this blog know better than that.

Let’s see what the leaders in the field came up with and learn from them:

In principle, under the assumption that tumors arise from a single cell, each tumor can be considered a clone. In this scheme, trunk mutations—also called founder mutations—that are present in every cell have a cancer cell fraction (CCF) of 1.

In cell biology ‘clone’ often means ‘derived from the same cell‘ (Wikipedia told me).

It is not surprising then that if you assume that tumors are a clone, they can be considered a clone. More interesting is whether ‘derived from the same cell’ is a useful definition in cancer.

All cells within a tumor with a CCF < 1 can be considered subclones, at least in terms of their relative population frequency within a given lesion.

Now this sentence is just mumbo-jumbo.

Mutations have cancer cell fractions (CCFs), cells do not have cancer cell fractions.

However, the group recognized that even this definition is misleading owing to an illusion of clonality within a single biopsy, where a particular mutation can appear clonal in one biopsy, with a CCF of 1, but subclonal or absent altogether in subsequent tumor sampling.

A mutation with CCF of 1 is clonal. Correct. So maybe they were talking about clonality of mutations all along and not about cells.

But then again, ‘clonal evolution’ is what cell populations do, not mutations, so it would still be good to answer the question what a clone is.

I hope this confusion between mutations and cells does not reflect the general level of understanding at that meeting.

If you want a more detailed discussion of what a clone is, read on here.


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