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DNA, RNA Sequencing Found to Be Useful at Evaluating Risk of Tumors in Children


Genomic sequencing was found to be an effective way to identify and evaluate the risk of pathogenic and likely pathogenic variants detected in pediatric patients with a range of cancer types.

DNA and RNA genomic sequencing was found to be a useful tool for identifying and characterizing genetic drivers of relapsed or refractory (R/R) cases of several pediatric cancers, according to a recent study published in Cancer Discovery.

The prospective nontherapeutic study analyzed the general usefulness of next-generation sequencing (NGS) using a 3-platform approach consisting of combined whole genome (WGS), exome, and RNA sequencing of tumor and paired normal tissues, an approach that had previously only been evaluated for specific tumor types or high-risk disease.

“This study demonstrates the power of a 3-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers,” wrote the investigators.

Evidence has proved NGS to be helpful to providers as they refine or change cancer diagnoses, provide prognostic information, identify therapeutic targets or markers of therapy resistance, detect variants showing pharmacogenetic significance, and reveal genetic predisposition.

However, most of these studies assess NGS in patients with difficult-to-treat or R/R cancers and have rarely addressed patients with new diagnoses or standard risk cancers. Additionally, more research needs to be dedicated to investigating new diagnostic and prognostic subgroups and the full list of genetic drivers for many rare pediatric cancers.

The 3-platform approach developed by the investigators was validated using a retrospective cohort of patients with high-risk pediatric cancer. Data were collected from the Genomes for Kids (G4K) study and included 309 pediatric patients with cancer who were selected without regard to tumor type or stage and were treated at St. Jude Children’s Research Hospital from August 2015 to March 2017.

Among the 309 patients, 82% (n = 253) had their tumors examined using all 3 platforms, 166 were male, and the average age at cancer diagnosis was 7.4 (range, 4 days to 25.7 years) years. At the time of study enrollment, 85% (n = 262) of patients had newly diagnosed cancers and 15% (n = 47) had R/R cancers.

By cancer type, 128 (41%) patients had hematological malignancies of 28 subtypes, 97 (31%) had brain humors of 27 subtypes, and 84 (27%) had tumors that were not associated with the central nervous system of 26 types. Rare tumor types were identified in 45 (15%) patients. Hodgkin and non-Hodgkin lymphoma were underrepresented, and leukemia and retinoblastoma were overrepresented.

Using the 3-platform approach of paired tumor and normal tissue revealed that 86% (n = 218/253) of patients had at least 1 diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer predisposing genetic variant (18%).

Additionally, utilization of WGS allowed for providers to detect activating gene fusions (36% of tumors), enhancer hijacks (8% of tumors), and mutational signatures that showed pathogenic variant effects, of which 55% were discovered to be relevant to tumor development when evaluating paired tumor-normal data.

Of the patients whose tumors were sequenced, 78 had or developed metastatic, R/R disease, and 41% of the tumors displayed potentially targetable lesions. Therapy regimens were changed for 12 patients based on tumor genomic data, 5 of whom responded to the newly directed therapy.

“Our screening through G4K uncovered germline [pathogenic or likely pathogenic] variants in 55 patients, of whom almost two-thirds would not have been detected based on routine clinical indications for genetic testing,” said the investigators.

They listed the inability to source fresh frozen tissue for all patients, the inability for comprehensive genomic profiling to become standard of care due to cost, and the long turnaround time to receive results as study limitations.

“As genomic sequencing technologies become less expensive and more widely available, their use will be an important adjunct to gene panels in the evaluation and management of children with newly diagnosed as well as relapsed or refractory cancers,” the investigators noted.


Newman S, Nakitandwe J, Kesserwan CA, et al. Genomes for kids: the scope of pathogenic mutations in pediatric cancer revealed by comprehensive DNA and RNA sequencing. Cancer Discov. Published online July 23, 2021. doi:10.1158/2159-8290.CD-20-1631

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