CTA: Is mutation of epigenetic regulators in childhood related to development?

Dr Dyer: We don’t understand why epigenetic regulators are so often mutated in pediatric cancer. It is possible that it is related to development. In this study, we learned that there are amazing and dramatic transitions in the epigenome in how the DNA is organized — far more extensive than actually I would have expected before this study — and that incredibly dynamic process is really tightly regulated.

But every now and then, there might be a vulnerability that if you get a mutation at a certain moment in development in this one particular gene in a particular epigenetic state, that can go on to lead to cancer.

It may be a combination of the dynamic epigenome during development, and then the accidental gene mutation at a particular moment during those developmental transitions. That story is really starting to emerge with the other pediatric solid tumors because they are developmental tumors, and the most dramatic epigenetic changes are happening during development.

CTA: Although retinoblastoma is the most common cancer in children, researchers still have not identified the specific cell type that causes it. Does this research point to any additional clues?

Dr Dyer: The cell of origin for retinoblastoma has been hotly debated for decades now and while this doesn’t point to the exact cell, it narrows down the window of time when we think the tumors are starting.

I would have thought going into this that it would have been the earliest progenitor cells that are proliferating at a rapid rate that would have been the most prone to form retinoblastoma, but that wasn’t the case. It was at a time during development when the progenitors are making an important transition, and it’s the period of the peak genesis of neurons from progenitors.

While we think we’ve narrowed down the window, we still don’t know the exact cell of origin. It may be a progenitor cell or a newly generated neuron during that period of development. But this epigenetic study now tells us where to look, in terms of the developmental time.

We now actually have a really exciting study using induced pluripotent stem cells made from patients who have germline retinoblastoma mutations. We’re making retinas from those stem cells to pinpoint that developmental stage and actually watch the tumors form in the laboratory in a way that you couldn’t do before. It’s not published yet, but it’s coming soon.