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

Abstract

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole genome (WGS), exome, and RNA sequencing, to examine tumor and germline genomes from 309 prospectively identified 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. STATEMENT OF SIGNIFICANCEPediatric cancers are driven by diverse genomic lesions and sequencing has proven useful in evaluating high risk and relapsed/refractory cases. We show that combined whole genome, exome, and RNA-sequencing of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.Research.

Tumor Mutation Burden, Expressed Neoantigens and the Immune Microenvironment in Diffuse Gliomas

“…Despite the fact that we only analyzed a small cohort of glioma patients, 19% of them carried a germline monoallelic P/LP variant in CPG. The prevalence in our cohort is higher than what is reported in the literature in both pediatric and adult cancer patients [ 22 , 23 ]. To understand the spectrum of CPGs, particularly the P/LP mutations of CPGs in IDH-mutant and IDH-wildtype gliomas, we collected and analyzed germline genomic information in all cases.…”

Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

“…DNA was obtained from purified T cells (n=18), skin or bone marrow fibroblasts (n=70), or remission samples (n=3). Twenty-eight samples were sequenced through our clinical pipeline (n=28) (23,25).…”

“…1B and Supplemental Fig S2A). To further investigate these molecular alterations, we established a transcriptomic extension cohort with 417 additional pediatric AMLs from previous studies (5,7,10,(20)(21)(22)(23)(24), including 36 cases of a therapy-related AML cohort (15) (Supplemental Table S17), as well as samples sequenced through our clinical service (23,25). We detected fusion transcripts and somatic mutations with the same in-house pipeline and collectively evaluated the mutational and expression patterns (Supplemental Fig.…”

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

“…For example, the combination of WGS and WTS enables the identification of sequence mutations, DNA copy number alterations, aneuploidy and structural variants (from WGS) together with identification of fusion chimeras, mutant allele expression, and gene expression profiling (from WTS). The use of one or both approaches is becoming increasingly widely used, and at St Jude Children's Research Hospital, three platform sequencing (WGS, WTS and exome sequencing) is clinical standard of care, informs clinical decision making in ALL [148], and retrieves more actionable clinical information than any single platform alone [189]. WGS is offered using a paired non-tumor sample to aid identification of somatic variants and provides the opportunity to return clinically relevant germline findings.…”