Tumor phylogeny in bilateral ovarian cancer

Question

[ceruleanivy]

I'm using different software in order to cluster tumor mutations and also reconstruct the phylogenetic tree of every tumor and I was just wondering what happens in the case that you have two different primary sites like both ovaries. Are you supposed to construct one tree for every primary site with all the metastatic included ? Note that I have only sequenced one sample from every site (primary or metastatic, with metastatic sites varying between 2-7).

Answer 1

[Noushin N]

You mention a very interesting scenario.

Can I ask if you have confirmed the two ovarian tumors to be independent primaries? A common approach would be to screen for somatic mutations in tumor suppressors or oncogenes and see if the two sites share same aberrations or not.

The question can be more complex if metastatic seeding events between the two sites can occur, or if the regions are adjacent (not the case in your data).

As far as I know, dealing with a single primary event [and the metastases it gives rise to] is a much more common case, and therefore is likely assumed in many phylogeny reconstruction methods.

I can share with you a workaround in SCHISM [1] (method I developed) for this scenario: You can include a hypothetical (or dummy) mutation/cluster which you can imagine is the last common event before the ancestors of cells giving rise to your two independent primaries diverged. This mutation/cluster will be present in all cancer cells, regardless of where they come from [cancer cell fraction at 1.00 at all samples]. By doing so, you have provided the method with a true clonal event and thus no assumptions are violated.

[1] Niknafs N, Beleva-Guthrie V, Naiman DQ, Karchin R. SubClonal Hierarchy Inference from Somatic Mutations: automatic reconstruction of cancer evolutionary trees from multi-region next generation sequencing. PLoS Comput Biol. 2015;11(10):e1004416.

Answer 2

[Eric T.]

Have you tried it? And, do you know if the two primaries arose independently, or if one could be a met of the other?

I'd recommend building a single tree including all primaries and metastatic sites, and this should provide evidence as to whether the two primaries are related and which primary each met came from. If you can, including a matched normal sample and use it to root the tree.