December 2016/January 2017

Neuroblastoma Genetics Study Seeks to Spell Out Structural Errors

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As scientists learn to decipher and read more of the recipe book of life — our genomes — they have found many insights and opportunities about diseases in the errors in that text. Among those insights are numerous indicators that adult cancers often happen because of point mutations, a fairly easy-to-spot category of genetic mistake, like a one-letter typo that changes “well” to “hell.”

“In some childhood cancers we see far fewer point mutations in coding regions than in adult cancers — sometimes orders of magnitude less,” said Sharon Diskin, PhD, a cancer researcher at Children’s Hospital of Philadelphia and assistant professor of Pediatrics at the Perelman School of Medicine at the University of Pennsylvania.

Because a simple spell-check of the genome has not turned up many of these simple explanations for childhood cancers, Dr. Diskin is taking a closer read of the genetics of the deadly childhood cancer neuroblastoma. She hopes to find better indicators of disease risk and targets for future treatments through her project that was recently awarded funding from the National Cancer Institute (NCI).

Dr. Diskin’s three-pronged approach looks at the genomes of children with the disease, from their healthy cells, tumors at diagnosis, and tumors after relapse. Her focus is on structural variations in the genetics of this disease, which include many different types of changes in chromosomes, such as rearrangements of letters in a word (changing “Santa” to “Satan”) or words in a sentence, or repeated instances of a word (the difference in meaning between “well” and “well, well, well”), and even small deletions of words or passages.

One hypothesis she is pursuing is that the disease risk for neuroblastoma and potentially other childhood cancers can be read from the genome in the non-cancerous cells of affected children. This potential germline component to cancer could come from inherited risk genes that families carry or novel mutations arising at the child’s conception. She is analyzing genome sequences from the TARGET program, a collaborative effort of the NCI, Children’s Oncology Group (COG), and a network of investigators to intensively investigate the genetic drivers of childhood cancers. She will later analyze additional sequencing data to assess heritability in partnership with the labs of John Maris, MD, a world-recognized neuroblastoma specialist at CHOP and professor of Pediatrics at the Perelman School of Medicine, and Andrew Olshan, PhD, professor of Cancer Epidemiology and chair of the department of Epidemiology at the University of North Carolina.

In preliminary work on this project, the team has identified rare germline deletions on chromosome 16 that are enriched in neuroblastoma. With the new grant, they aim to replicate and build on these findings and probe into an intriguing finding of germline deletions in neuroblastoma that were previously linked to diverse phenotypes, including neurological disorders.

“These are rare events but have much larger effect size than typically seen by GWAS [genome-wide association study] approaches, and we think we’ll be able to uncover some of the ‘missing heritability’ in neuroblastoma,” Dr. Diskin said.

In parallel, the team is also looking at tumor DNA to seek disease-related structural variants, again using sequencing data from the TARGET project. In preliminary stages of this work, Dr. Diskin and colleagues have identified recurrent disruptions of a gene on chromosome 11 that may be a tumor suppressor gene. They have also identified structural variants affecting the promoter region for the TERT gene, which plays an important role in protecting DNA from damage. Dr. Diskin plans to continue investigating how this promoter region might shape neuroblastoma risk, and to extend the work to find more clues in other noncoding regions of the genome. Any such variants that turn out to be critical could be useful indicators of disease risk in newly diagnosed tumors, or even new molecular targets for future therapies.

The study’s third component focuses on the most critical and deadly cases: relapsed neuroblastoma. Little published genetic sequencing research on relapsed neuroblastoma tumors is yet available, in part because biological samples from across the evolution of this rare disease are hard to come by. To identify the mutations associated with relapse, neuroblastoma researchers need to have a series of samples from individual patients taken from their non-cancerous cells, from their tumor at the time of diagnosis, and from their tumor after relapse. For her study of structural variants in these relapsed tumors, Dr. Diskin is partnering with the lab of Yael Mossé, MD, a CHOP pediatric oncologist and associate professor of Pediatrics at the Perelman School of Medicine, who is leading a precision-medicine clinical trial for relapsed neuroblastoma that involves sequencing the relapsed tumor samples. Dr. Diskin will also partner with St. Jude Children’s Research Hospital and with the COG to work with additional samples and sequences, comparing relapsed tumors to tumors at diagnosis. These combined efforts could yield new insights about how the relapsed genome differs from primary tumors and point to potential targets for therapy.

Even beyond finding structural variants with the three-pronged approach to studying germline, diagnostic tumor, and relapsed tumor DNA, Dr. Diskin will look deeper into the biological mechanisms connecting these variants to disease. Already, she has begun bench work with two of the variations identified in her preliminary work — carrying out the error-laden recipes, not just marking up the problems in the text. This work could give a flavor of what new therapies might need to do to counteract the mutations’ effects.

“Now that we have all this sequencing data, I think this unexplored area could lead us to new insights,” Dr. Diskin said.

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