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Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion
Cancer Research  (IF12.701),  Pub Date : 2021-12-01, DOI: 10.1158/0008-5472.can-21-1033
Sara A. Byron, William P.D. Hendricks, Abhinav B. Nagulapally, Jacqueline M. Kraveka, William S. Ferguson, Valerie I. Brown, Don E. Eslin, Deanna Mitchell, Albert Cornelius, William Roberts, Michael S. Isakoff, Javier E. Oesterheld, Randal K. Wada, Jawhar Rawwas, Kathleen Neville, Peter E. Zage, Virginia L. Harrod, Genevieve Bergendahl, Elizabeth VanSickle, Karl Dykema, Jeffrey Bond, Hsien-Chao Chou, Jun S. Wei, Xinyu Wen, Hue V. Reardon, Alison Roos, Sara Nasser, Tyler Izatt, Daniel Enriquez, Apurva M. Hegde, Faith Cisneros, Austin Christofferson, Bryce Turner, Szabolcs Szelinger, Jonathan J. Keats, Rebecca F. Halperin, Javed Khan, Giselle L. Saulnier Sholler, Jeffrey M. Trent

Children with treatment-refractory or relapsed (R/R) tumors face poor prognoses. As the genomic underpinnings driving R/R disease are not well defined, we describe here the genomic and transcriptomic landscapes of R/R solid tumors from 202 patients enrolled in Beat Childhood Cancer Consortium clinical trials. Tumor mutational burden (TMB) was elevated relative to untreated tumors at diagnosis, with one-third of tumors classified as having a pediatric high TMB. Prior chemotherapy exposure influenced the mutational landscape of these R/R tumors, with more than 40% of tumors demonstrating mutational signatures associated with platinum or temozolomide chemotherapy and two tumors showing treatment-associated hypermutation. Immunogenomic profiling found a heterogenous pattern of neoantigen and MHC class I expression and a general absence of immune infiltration. Transcriptional analysis and functional gene set enrichment analysis identified cross-pathology clusters associated with development, immune signaling, and cellular signaling pathways. While the landscapes of these R/R tumors reflected those of their corresponding untreated tumors at diagnosis, important exceptions were observed, suggestive of tumor evolution, treatment resistance mechanisms, and mutagenic etiologies of treatment. Significance: Tumor heterogeneity, chemotherapy exposure, and tumor evolution contribute to the molecular profiles and increased mutational burden that occur in treatment-refractory and relapsed childhood solid tumors.