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Treatment Targets Identified by RNA Sequencing in Pediatric Cancer Cases

NEW YORK – A team led by investigators at the University of California at Santa Cruz has demonstrated that RNA sequencing can uncover potentially targetable alterations in tumor samples from pediatric cancer patients that are missed by DNA-based profiling approaches.

"This was designed as a feasibility study to show that we can do this — get the data for prospective patients and process and analyze it fast enough to be useful," first and corresponding author Olena Vaske, a pediatric genomics, molecular, cell, and developmental biology researcher at UCSC, said in a statement. She and her colleagues published their proof-of-principle findings online today in the journal JAMA Network Open.

Using comparative RNA sequencing, the researchers searched for informative gene expression changes in 144 tumor samples from 128 children or young adults with rare, relapsed, or treatment resistant cancers, who were enrolled through clinical trials in the US and Canada. Through comparisons with publicly available RNA-seq data for thousands more pediatric or young adult tumors, they uncovered targetable alterations in more than two-thirds of the tumors assessed by RNA-seq.

On the other hand, in a subset of pediatric tumors with available DNA sequence data generated for the Children's Oncology Group NCI Pediatric MATCH basket trial, DNA sequences led to clinically actionable alterations in less than half of tumors, while expression analyses yielded actionable changes in more than 74 percent of those tumors.

"We showed for the first time that this framework can be used consistently across separate precision medicine clinical trials," Vaske said. "The next step will be to directly evaluate the clinical utility of this approach. This study has set the stage for us to do that."

Although precision medicine efforts have led to a rise in tumor DNA profiling, the team reasoned that gene expression shifts stemming from regulatory alterations may be even more informative in pediatric cancer cases, which typically contain fewer mutations than corresponding adult cancers.

"DNA sequencing is increasingly integrated in clinical trials to identify new molecular targets for children with incurable cancers," the authors explained. "However, molecular targets are found for only a small number of patients, and the yield is much lower than that of similar adult cancer trials."

As part of the UCSC's Treehouse Childhood Cancer Initiative, investigators at UCSC did RNA-seq on tumor samples from pediatric cancer patients between infancy and 26 years old who were participating in four precision medicine clinical trials.

Starting with 46 samples from patients enrolled at Children's Hospital of Orange County, 80 pediatric cancer samples collected at the Lucile Packard Children's Hospital at Stanford, two dozen samples provided by the Pacific Pediatric Neuro-Oncology Consortium, and 31 tumors from patients treated at the British Columbia Children's Hospital, the team focused in on 144 RNA sequenced samples that passed quality control criteria from 128 of the patients.

The researchers applied gene expression outlier analyses to these RNA-seq data, along with publicly available sequence data assembled for 11,340 tumors, comparing expression within and across related cancer types. In the process, they tracked down potential treatment targets in 99 of the tumors — just shy of 69 percent. In a subset of 74 tumors tested by DNA profiling, meanwhile, they narrowed in on promising treatment targets in 34 tumors (45.9 percent).

"Our work suggests that direct investigations of the clinical utility and effectiveness of tumor RNA-seq-derived gene expression information will be valuable, and the next phase of our project will focus on defining the incremental benefit of this approach," the authors wrote, suggesting "open sharing of cancer genomic data can benefit each pediatric and young adult patient with cancer so that every family's struggle contributes to the advancement of clinical care for the families that follow." 

Other teams have also started exploring the potential benefits of gene expression profiling in pediatric and adult cancers. For example, findings from the WINTHER trial, reported in Nature Medicine this spring, suggested that transcriptome features could unearth promising treatment targets and tumor biology insights in adult cancer patients, though that study did not reach its primary endpoint of progression-free survival when those features were used to match patients to treatment.