Likely this will sound as a silly question, but I don't know whom to ask. Ok, here it goes.

McGranahan et al link found that tumors with high clonal antigen load are more likely to respond to the immune checkpoint blockage.

Bozic et al link (at the same time) proposed a probabilistic model to determine the number of clonal and subclonal mutations. They found that fast growing cancer types (where growth is cell division over cell death) are more likely to generate a higher number of subclonal mutations.

Knowing that melanoma and NSCLC are fast growing cancer types, these results seem to contradict each other. We know that they are fast and we know that both melanoma and NSCLC are cancer types where immunotherapy is most effective.

Plus, probabilistically how likely it is for a certain cancer lesions to have lots of shared mutations? A totally genetically homogeneous lesion with no branches with a very high number of mutations.

Or (much more likely) I'm missing something.

  • $\begingroup$ Your question is not fully clear. Are you interested in knowing what is the rate of mutation in different cancer types? If so, here is a good starting point nature.com/nature/journal/v502/n7471/full/nature12634.html $\endgroup$ – alec_djinn May 5 '17 at 12:41
  • $\begingroup$ @alec_djinn rather than the rate of mutations, how mutations are distributed in a single lesion. $\endgroup$ – user1384636 May 5 '17 at 12:59
  • $\begingroup$ That depend on the cancer type. Most of the mutations are randomly distributed but some tend to cluster. Check the paper I have linked before. The question is maybe too broad, have a look here nature.com/tcga $\endgroup$ – alec_djinn May 5 '17 at 13:04
  • $\begingroup$ @alec_djinn (1/2) I will read it, thanks. But that's the thing, the first paper states that higher number of clonal mutations (present in all cancer cells) rather than subclonal (present in a subgroup of cancer cells) is more favorable for the treatment. The second paper states that fast growing cancer types are more likely to develop subclonal mutations rather than clonal. $\endgroup$ – user1384636 May 5 '17 at 13:10
  • $\begingroup$ @alec_djinn (2/2) Melanoma (for example) is a fast growing cancer, which should develop more subclonal mutations (following the model of the second paper) and should have worse outcome for the treatment (following the results of the first paper). But it's the one showing the best outcome. $\endgroup$ – user1384636 May 5 '17 at 13:13

They don't really contradict each other; the clonality of neoantigens adds an extra layer over the overall mutational load ; but overall mutational load (and consequently overall neoantigen burden, because mutations in a fixed sequence context generate neoantigens at a certain rate) by themselves are also predictive.

Tumours with a high neoantigen burden tend to generally respond better anyway (See Snyder et al, NEJM , Rizvi et al, Science and Van Allen et al, Science) and also the fact that mismatch repair deficient cancers generally tend to respond.

So if you take high neoantigen tumours already (both lung and melanomas have extremely high mutation burdens), and then stratify them based on neoantigen clonality , you tend to further stratify patients by response associating with checkpoint blockade.

The whole point of McGranahan et al was to point out that it is possible to raise immune responses that target all the cells in a tumour, and that the ability to do this may dictate survival in general and checkpoint blockade response in particular, but only when antigen presentation and immune infiltration are intact. McGranahan et al note that clonal neoantigens do nothing in Lung squamous cancers because of depleted CD8 infiltration and MHC class I expression and there is other work (See http://www.pnas.org/content/113/48/E7759.abstract )

As for this bit

Plus, probabilistically how likely it is for a certain cancer lesions to have lots of shared mutations? A totally genetically homogeneous lesion with no branches with a very high number of mutations.

That is quite complicated to answer; but as a general rule it is worth remembering that, as the number of divisions and the number of mutations (and ergo prospective subclones) increases, for tumours to stay clonal it requires extremely strong selective sweeps so that at any given time a very small number of clones tends to predominate, and at least in untreated/pre-treatment tumours, there is the tendency for a lot of them to show effectively neutral patterns of evolution ( http://www.nature.com/ng/journal/v48/n3/abs/ng.3489.html )


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