New findings from researchers at Memorial Sloan Kettering Cancer Center published by Shukla et al in Nature Communications reported the results of using a comprehensive sequencing approach on 114 pediatric, adolescent, and young adult patients with solid tumors. The researchers found that their approach identified at least one additional cancer-associated oncogenic variant in 54% of patients (n = 62 of 114) compared with the current standard genetic sequencing test MSK-IMPACT. Of this group, 33 patients had one or more findings that were of direct clinical or potentially actionable relevance.
Differences in Adult and Pediatric Genetic Mutations
DNA sequencing tests that look for mutations in cancer-associated genes have become a standard of care at leading centers. MSK-IMPACT can detect mutations in more than 500 cancer-related genes. From this information, physicians can then determine if an available drug might benefit a particular patient based on the tumor’s genetic profile.
This cancer gene-panel approach works well for adults with common malignancies, like breast, colorectal, lung, and prostate cancers. But for rare cancers in children and young adults, these panel tests have not been as useful for matching patients to appropriate therapies. That is because, as researchers are coming to realize, the types of mutations that drive tumors in young patients tend to be different from those in adult patients.
Andrew Kung, MD, PhD
“Adult cancers are usually caused by a lifelong accumulation of mutations from exposure to things like sunlight, cigarette smoke, and carcinogens in the diet,” explained physician-scientist Andrew Kung, MD, PhD, Chair of the Department of Pediatrics at Memorial Sloan Kettering, whose research focuses on the molecular causes of childhood cancers. “Those mutations are usually what are called point mutations—where a single letter of DNA is changed in a gene…. With pediatric cancers, the driving mutations tend to be structural changes affecting whole sections of chromosomes. These are often located outside of the boundaries of known cancer genes, where they go undetected by existing tests.”
Role of Whole-Genome Sequencing
To better visualize these structural variants, researchers need a way of reading not only the changes to the spellings of particular “words,” or cancer genes, but also the organization of those words in the context of paragraphs and chapters, as can be provided by whole-genome DNA and RNA sequencing. Dr. Kung and his colleagues believe it may make an important difference in the care of children with cancer.
“Everyone agrees that whole-genome sequencing will eventually become the go-to diagnostic test to profile tumors,” said Elli Papaemmanuil, PhD, a computational oncologist at Memorial Sloan Kettering. “But there have been several obstacles standing in the way.” The biggest one, she said, is being able to make sense of the vast amount of data that comes from sequencing the billions of DNA letters making up an entire genome—pinpointing and, relatedly, conveying the clinically relevant information to physicians in a time frame that could help with care decisions.
As the authors wrote in the report, “Implementation of whole-genome and -transcriptome sequencing is challenged by the need to deliver results within clinically relevant time frames, concerns about assay sensitivity, reporting and prioritization of findings.” In the published research, the researchers have refined the analysis of such data to be accomplished in 9 days, compared with standard approaches that require weeks or months. Comparison of whole-genome and -transcriptome sequencing to diagnostic panel assays demonstrates the potential of whole-genome and -transcriptome sequencing to capture all clinically reported mutations with comparable sensitivity in a single workflow.
Not Yet a Replacement for Other Tests
The researchers emphasize that the new platform is not currently a replacement for panel-based tests, such as MSK-IMPACT, which work well for capturing relevant mutations in adult patients with common tumors—and have made a difference in their outcomes.
“What we are trying to do is to bring a more comprehensive approach to pediatric patients and others with rare cancers, a minority of whom benefit from panel-based testing,” said Dr. Kung. “We want to make precision medicine more inclusive and a possibility for every ... patient.” The study authors say the benefits for pediatric patients are so compelling that this type of testing is now being made available to every pediatric patient at Memorial Sloan Kettering (through philanthropic funding).
Disclosure: Funding for this study was provided by the Olayan Fund for Precision Pediatric Cancer Medicine. Memorial Sloan Kettering Cancer Center has intellectual property rights and financial interests related to Isabl Inc, the company licensing the technology described in the report. For full disclosures of the study authors, visit nature.com.