학술논문
Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion
Document Type
article
Author
Byron, Sara A; Hendricks, William PD; Nagulapally, Abhinav B; Kraveka, Jacqueline M; Ferguson, William S; Brown, Valerie I; Eslin, Don E; Mitchell, Deanna; Cornelius, Albert; Roberts, William; Isakoff, Michael S; Oesterheld, Javier E; Wada, Randal K; Rawwas, Jawhar; Neville, Kathleen; Zage, Peter E; Harrod, Virginia L; Bergendahl, Genevieve; VanSickle, Elizabeth; Dykema, Karl; Bond, Jeffrey; Chou, Hsien-Chao; Wei, Jun S; Wen, Xinyu; Reardon, Hue V; Roos, Alison; Nasser, Sara; Izatt, Tyler; Enriquez, Daniel; Hegde, Apurva M; Cisneros, Faith; Christofferson, Austin; Turner, Bryce; Szelinger, Szabolcs; Keats, Jonathan J; Halperin, Rebecca F; Khan, Javed; Saulnier Sholler, Giselle L; Trent, Jeffrey M
Source
Cancer Research. 81(23)
Subject
Language
Abstract
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.