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

“This study demonstrates the power of a three-platform approach that includes WGS to interrogate and interpret the full range of genomic variants for both newly diagnosed and relapsed/refractory pediatric cancers,” the researchers wrote.

Evidence has shown that NGS is useful for healthcare providers in refining or altering cancer diagnoses, providing prognostic information, identifying therapeutic targets or markers of therapy resistance, detecting variants exhibiting pharmacogenetic significance, and revealing genetic predisposition.

However, most of these studies assess NGS in patients with difficult-to-treat or R/R cancers and rarely involve patients with new diagnoses or standard-risk cancers. In addition, more research needs to be done to explore new diagnostic and prognostic subgroups and the full list of genetic factors for many rare pediatric cancers.

The 3-platform approach developed by the researchers 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 cancer patients selected without regard to tumor type or stage and treated at St. Jude Children’s Research Hospital from August 2015 to March 2017.

Of the 309 patients, 82% (n = 253) had their tumors examined using all 3 platforms, 166 were male, and the mean 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 hematologic malignancies of 28 subtypes, 97 (31%) had cerebrospinal fluid of 27 subtypes, and 84 (27%) had tumors 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, it was found that 86% (n = 218/253) of patients had at least 1 diagnostic (53%), prognostic (57%), therapeutically relevant (25%) and/ or or cancer predisposing genetic variant (18%).

In addition, through the use of WGS activating gene fusions (36% of tumors), enhancer hijacks (8% of tumors), providers were able to detect mutational signatures exhibiting pathogenic variant effects, 55% of which were found to be relevant for 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 showed potentially targeted lesions. Therapy regimens were modified for 12 patients based on tumor genomic data, 5 of whom responded to the newly targeted therapy.

“Our screening through G4K discovered germline [pathogenic or likely pathogenic] variants in 55 patients, nearly two-thirds of whom would have gone undetected based on routine clinical indications for genetic testing,” the researchers said.

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

“As genomic sequencing technologies become cheaper and more widely available, their use will be an important addition to gene panels in the evaluation and management of children with newly diagnosed and recurrent or refractory cancers,” the researchers noted.


Newman S, Nakitandwe J, Kesserwan CA, et al. Childhood genomes: the magnitude of pathogenic mutations in pediatric cancer revealed by extensive DNA and RNA sequencing. Discovering cancer. Published online July 23, 2021. doi: 10.1158/2159-8290.CD-20-1631

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