Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

Genomic studies of pediatric cancer have primarily focused on specifi c tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNAseq), to examine tumor and germline genomes from 309 prospectively identifi ed children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor -normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-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. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions , and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identifi cation and characterization of genetic drivers across the full spectrum of pediatric cancers.

Automated summary

This study utilized a three-platform sequencing approach, including WGS, WES, and RNAseq, to examine tumor and germline genomes from 309 children with pediatric cancers. The study revealed the presence of diverse genetic variants in most patients, with WGS helping to detect activating gene fusions, enhancer hijacks, small intragenic deletions, and mutational signatures. The evaluation of paired tumor-normal data showed the relevance of pathogenic germline variants to tumor development in a significant portion of cases.