Michael A. Dyer, MD, of the department of developmental neurobiology at the St Jude Children’s Research Hospital in Memphis, Tennessee, and Howard Hughes Medical Institute in Chevy Chase, Maryland, and colleagues recently examined the retinoblastoma epigenome and found that the best match for development of retinoblastoma was at a key stage in the middle of retinal development, providing a window of time in which to focus future studies to identify the cellular origins of this devastating eye cancer.1

The publication of this study represents the first in a series of papers exploring the epigenome of different cancers from the second phase of the Pediatric Cancer Genome Project (PCGP), a partnership between St Jude Children’s Research Hospital and The Genome Institute at Washington University School of Medicine in St Louis, Missouri.

The first phase, which is now complete, examined DNA sequencing, characterizing the genomic landscape of a variety of childhood cancers — leukemias, brain tumors, and solid tumors. 

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Cancer Therapy Advisor asked Dr Dyer to place the results of this study in a broader perspective and to comment on what he believes will be the clinical implications of these findings.

Cancer Therapy Advisor (CTA): What is the focus of the second phase of the Pediatric Cancer Genome Project (PCGP)?

Dr Dyer: The second phase of the PCGP is focusing on the epigenomic component. It’s not mutations in the DNA, but modifications to either the DNA itself, or the histones that the DNA is wrapped around, that control how the genes are expressed.

This is a really important part of pediatric cancers. Retinoblastoma was one of the simplest, and easiest, to tackle because there is not a lot of genetic heterogeneity in the tumors.

CTA: How will this basic science research eventually change clinical care?

Dr Dyer: We’ve learned a lot about gene mutations in cancer over the past 7 to 8 years. The revolution in genome sequencing really has transformed oncology.

From a clinical perspective, oncologists are now working with genomic data, using tests that will sequence patient tumors that can in some cases be used to make recommendations for therapy. This is the personalized medicine, individualized care movement which has been transformative in oncology.

The challenge we face in pediatric cancer in general and in retinoblastoma in particular, is the absence of mutations that are targetable. This is why we are now digging deeper into the epigenetic organization of the genome to identify vulnerabilities that are targetable.

The real revolution in pediatric oncology from all the sequencing over the past 7 to 8 years was the discovery that many epigenetic regulators are mutated in pediatric cancer. Virtually every class of epigenetic regulator was found to be mutated. That was actually a real surprise. Going into it, no one would have expected that frequency, that high rate of mutation of epigenetic regulators.

What happened then was a shift to think about the epigenome in 2 areas. One is to understand the biology, so if an epigenetic regulator is mutated, why is that and how it is contributing to cancer?

The second shift was, can we use that information to think about drugs that target the epigenetic regulators or the processes they modulate, and can that be effective for treatments down the road? So that was really beneficial. For those cancers that don’t have an obvious targetable mutation, this may be avenue to get some traction for therapy.