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Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.
Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer
Enrichment of Targetable Mutations in the Relapsed Neuroblastoma Genome - Fig 1
<p><b>Study cohort overview</b> A) Tabulation of Children’s Oncology Group (COG) risk classification and treatment time points of biopsy for 151 samples. (Intermed. = intermediate risk group) B) Number of samples taken at each treatment time point for nine patients with serial biopsies. (HR = high risk, IR = intermediate risk, LR = low risk at time of biopsy; further information in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006501#pgen.1006501.s003" target="_blank">S2 Table</a>) C) Tabulation of all variants identified (VUS: variants of unknown significance) D) Total number of variants identified per sample, stratified by COG risk group. Inset shows a similar calculation for suspected driver variants only. Heavy line represents the median of the data. “n” indicates the number of patients in each risk group. E) Total number of variants in each sample. Each bar represents an individual sample; color corresponds to risk group (red = high, blue = intermediate, green = low).</p
Genetic variants from a single patient at different treatment time points.
<p>Each biopsy was at a different anatomic site. Red denotes suspected driver variants; gray denotes variants of unknown significance. Letter preceding tumor location indicates primary (P) or metastatic (M) site. Number in parentheses indicates inferred allelic fraction for mutation calls, or inferred copy number for amplification or deletion calls. See <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1006501#pgen.1006501.s003" target="_blank">S2 Table</a> for additional details. Note that this patient was treated with crizotinib following the 5<sup>th</sup> relapse.</p