Comprehensive genome sequencing is now fast enough and informative enough to help treat pediatric cancer patients in real time, according to a clinical study from St. Jude Children’s Research Hospital. In the study, called Genomes for Kids (G4K), researchers sequenced tumor genomes and matched germline samples using three methods: whole genome sequencing, whole exome sequencing, and RNA sequencing. The tactic uncovered actionable mutations in nearly 80% of patients with a turnaround time of under 40 days.

Scott Newman, Ph.D., presented the G4K findings at the recent American Society of Human Genetics annual meeting in San Diego. One key outcome of the project, he says, is widening the concept of “actionable mutations” to include diagnostic and prognostic clues, in addition to directly druggable targets. “At a hospital like St. Jude, we get lots of kids with rare cancers who don’t have a definite diagnosis,” Dr. Newman tells GEN. Pathology testing provides a starting point, he says, “and layering the genetics on top of that can, in many cases, get the correct diagnosis. Once you’ve got the right diagnosis, you can get the kid in the right trial.”

Furthermore, sequencing data can detect harbingers of tumor aggressiveness, informing therapy decisions. “Getting the child in the right risk category is one of the actions that we can take,” continues Dr. Newman. More aggressive tumors require different therapies than slower-growing ones.

Sequencing the samples three ways may sound excessive, but it allows for high sensitivity as well as cross-validation among the three datasets, cutting down on false positives. While exome sequencing is great at detecting single nucleotide mutations, that leaves out a lot of possible drivers. Structural variants and copy number alterations play a major role in pediatric cancers, and whole genome sequencing is much better at finding these.

Currently, the price tag for all this sequencing comes to about $8,600 per patient. If upfront genome sequencing replaces an extensive odyssey of tests, though, the cost may be justified. “You get tests piling on top of each other with no guarantee of finding anything,” Dr. Newman points out. Because pediatric cancers often arise from different mutations than adult cancers, gene panel tests don’t work as well in kids. Some 11–16% of the mutations caught by the G4K study would have slipped past current panel tests, according to Dr. Newman.

“Particularly for tumors that affect young adults and children, targeted panels developed on the basis of recurrently mutated genes that occur in adults not been very fruitful,” says pediatric oncologist Alex Kentsis, M.D., Ph.D., of Memorial Sloan Kettering Cancer Center.

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