Integrated whole-exome and transcriptome analysis of 250 treatment-refractory or relapsed (R/R) childhood solid tumors.
Authors: Sara A. Byron, William P. D. Hendricks, Abhinav B. Nagulapally, Karl Dykema, Jeffrey Bond, Hsien-Chao Chou, Jun S. Wei, Xinyu Wen, Hue V. Reardon, Sara Nasser, Tyler Izatt, Daniel Enriquez, Apurva M. Hegde, Szabolcs Szelinger, Jonathan J. Keats, Rebecca F. Halperin, Javed Khan, Giselle Linda Saulnier Sholler, Jeffrey M. Trent
Journal: Journal of Clinical Oncology (2021)

10006 Background: The major genomic profiling studies that have helped define the molecular landscapes of pediatric cancers have typically focused on untreated pediatric cancers at diagnosis. Despite improvements in overall survival for childhood cancers, patients with treatment-refractory or relapsed (R/R) solid tumors face a poor prognosis. The genomic underpinnings of R/R disease are less well-characterized. Here, we describe the integrated genomic and transcriptomic analysis of 250 R/R solid tumors from 202 children profiled within precision medicine studies (NCT01355679, NCT01802567, NCT02162732) conducted by the Beat Childhood Cancer Consortium. Methods: Tumor-normal whole-exome and tumor mRNA sequencing was performed by Ashion Analytics (Phoenix, Arizona), a CAP-accredited, CLIA-certified laboratory, or within the research setting at TGen. Longitudinal tumor samples were sequenced for 20 patients. Variant calling included single nucleotide variants, indels, copy number alterations, and fusions. Integrated genomic and transcriptomic research analysis included microsatellite instability assessment, immunogenomic profiling, and functional gene set enrichment analysis. Results: Forty-six tumor types were represented, grouped into four general categories: sarcomas (36.1%; n = 73), neuroblastomas (29.2%; n = 59), CNS tumors (23.3%; n = 47), and other rare tumors (11.4%; n = 23). For patients with whole exome sequencing data, 78.3% (n = 144/184) of tumors bore a somatic alteration in at least one known cancer gene. Over one-third (39.1%; 72/184) of the cohort bore oncogenic fusions and/or oncogenic/likely-oncogenic hotspot mutations in a known cancer gene. Pathognomonic fusions were identified in 25% (46/184) of tumors, occurring most frequently in sarcomas. Pathogenic or likely pathogenic germline variants were identified in 8.7% (16/184) of patients. Microsatellite instability was detected in five different tumor types. Despite nearly all tumors (94%, 173/184) having at least one predicted strong binding neoantigen, over a quarter of tumors lacked transcript expression of these neoantigens or exhibited low MHC class I expression. Further, a subset of tumors showed elevated expression of the co-inhibitory immune checkpoint molecule PDL1. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology tumor clusters associated with immune signaling, development, and cellular signaling pathways. Longitudinal analysis revealed temporal heterogeneity pointing to the importance of re-biopsy at relapse for targeted treatment planning. Conclusions: Together, these data suggest R/R childhood solid tumors exhibit shared molecular features that are reflective of underlying biology, demonstrating the importance of comprehensive profiling to inform molecularly-guided treatment of R/R disease.