Pediatric cancer study shows usefulness of gene expression analysis

October 25, 2019

Analyzing gene expression in tumor cells from children with cancer is more likely to reveal targets for therapy than analysis of DNA mutations, according to a new study led by researchers at the UC Santa Cruz Genomics Institute.

The study, published October 25 in JAMA Network Open, looked at 144 tumor samples from 128 pediatric cancer patients enrolled in four precision medicine clinical studies in the United States and Canada.

For an increasing number of cancer patients, doctors analyze the specific gene mutations in the patient's tumor to help select the best treatment. In children, however, this kind of genetic profiling of tumors is much less likely to reveal a target for therapy, according to first author Olena Vaske, who holds the Colligan Presidential Chair in Pediatric Genomics at UC Santa Cruz.

"In pediatric cancer, it often isn't a DNA mutation driving the cancer but an error in development caused by a change in how gene expression is regulated," Vaske explained.

Vaske's team at the UCSC Treehouse Childhood Cancer Initiative has focused their efforts on analysis of gene expression data derived from RNA sequencing. When a gene is turned on, or activated, its DNA sequence is transcribed into a messenger RNA molecule. Sequencing the RNA molecules in tumor cells reveals not only which genes are turned on in those cells, but also how active they are (a more active gene makes more RNA transcripts).

Using the Treehouse Initiative's framework for comparative RNA sequence analysis of pediatric tumors, each patient's data were compared to a compendium of over 11,000 tumor RNA sequencing samples from public genomic datasets. The analysis identified unusual gene expression patterns that could be used to identify druggable genes and pathways for each patient.

"We're looking for the outliers, the over-expressed genes that are unusual compared to other cells and that might be driving this patient's disease," Vaske said.

The researchers found that gene expression analysis was potentially useful for 68% of the 144 tumor samples. In contrast, DNA mutation information was potentially useful for only 46% of the samples. In 36% of the samples, druggable over-expressed genes and pathways were identified based on RNA analysis alone and were not apparent in the tumor DNA analysis.

This cohort study was conducted as a consortium of five institutions: UC Santa Cruz, British Columbia Children's Hospital, Lucile Packard Children's Hospital at Stanford, Children's Hospital of Orange County, and the Pacific Pediatric Neuro-Oncology Consortium. The clinical partners sent UCSC researchers the RNA sequencing data for children and young adults with relapsed, refractory, or rare cancer who were being treated on precision medicine protocols. Each clinical site had its own precision medicine protocol in place, and UCSC served as a third-party institution conducting secondary analysis of each site's tumor data.

"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," said Vaske, an assistant professor of molecular, cell, and developmental biology at UCSC. "We showed for the first time that this framework can be used consistently across separate precision medicine clinical trials."

Although the study was not designed to assess clinical impact, the researchers did see correlations between the findings from gene expression analysis and the clinical responses of some patients.

The study also demonstrates the value of consolidating data from publicly available genomic datasets. The UCSC team processed all of the RNA sequencing data, from both public datasets and clinical partners, in a uniform way before doing the comparative analyses. The compendium of consolidated data, which now includes more than 12,000 tumor samples, is available to cancer researchers on the Treehouse Initiative's website. The team has now also built a compendium of RNA sequencing data from normal tissues.

"For the comparative analyses, it's a numbers game, so the larger the compendium, the more robust the analysis will be. That's why we believe so strongly in open sharing of data," Vaske said.

The Treehouse Childhood Cancer Initiative, which Vaske cofounded, brings the power of genomics and big-data analytics to bear on the challenge of finding effective treatments for children with cancer. Working with clinical partners, the Treehouse team now routinely participates in clinical "tumor boards," where doctors and geneticists meet to share information and ideas on treatments for individual cancer patients.

"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," Vaske said.
The Treehouse Initiative's research has been funded by St. Baldrick's Foundation, the California Initiative to Advance Precision Medicine, Unravel Pediatric Cancer, Team G Childhood Cancer Foundation, Live for Others Foundation, and Alex's Lemonade Stand Foundation for Childhood Cancer Research.

University of California - Santa Cruz

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to