Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion
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 clinic...
Saved in:
Published in | Cancer research (Chicago, Ill.) Vol. 81; no. 23; pp. 5818 - 5832 |
---|---|
Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.12.2021
|
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | Authors’ Contributions S.A. Byron, W.P.D. Hendricks, and A.B. Nagulapally contributed equally as co-first authors of this article and G.L. Saulnier Sholler and J.M. Trent contributed as co-senior and co-corresponding authors of this article. S.A. Byron: Conceptualization, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft. W.P.D. Hendricks: Conceptualization, data curation, formal analysis, supervision, validation, investigation, visualization, methodology, writing–original draft, project administration, writing–review and editing. A.B. Nagulapally: Conceptualization, data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–original draft, writing–review and editing. J.M. Kraveka: Conceptualization, resources, writing–review and editing. W.S. Ferguson: Conceptualization, resources, writing–review and editing. V.I. Brown: Conceptualization, resources, writing–review and editing. D.E. Eslin: Conceptualization, resources, writing–review and editing. D. Mitchell: Conceptualization, resources, writing–review and editing. A. Cornelius: Conceptualization, resources, writing–review and editing. W. Roberts: Conceptualization, resources, writing–review and editing. M.S. Isakoff: Conceptualization, resources, writing–review and editing. J.E. Oesterheld: Conceptualization, resources, writing–review and editing. R.K. Wada: Conceptualization, resources, writing–review and editing. J. Rawwas: Conceptualization, resources, writing–review and editing. K. Neville: Conceptualization, resources, writing–review and editing. P.E. Zage: Conceptualization, resources, writing–review and editing. V.L. Harrod: Conceptualization, resources, writing–review and editing. G. Bergendahl: Conceptualization, resources, data curation, investigation, project administration, writing–review and editing. E. VanSickle: Data curation, writing–review and editing. K. Dykema: Data curation, software, formal analysis, validation, investigation, visualization, methodology, writing–review and editing. J. Bond: Data curation, software, formal analysis, validation, investigation, methodology, writing–review and editing. H.-C. Chou: Data curation, software, formal analysis, investigation, writing–review and editing. J.S. Wei: Data curation, software, formal analysis, investigation, writing–review and editing. X. Wen: Data curation, software, formal analysis, investigation, writing–review and editing. H.V. Reardon: Data curation, software, formal analysis, investigation, writing–review and editing. A. Roos: Data curation, formal analysis, investigation, writing–original draft. S. Nasser: Software, investigation, visualization, methodology, writing–review and editing. T. Izatt: Data curation, software, validation, writing–review and editing. D. Enriquez: Data curation, software, formal analysis, investigation, writing–review and editing. A.M. Hegde: Software, formal analysis, investigation, visualization, writing–review and editing. F. Cisneros: Software, formal analysis, writing–review and editing. A. Christofferson: Software, formal analysis, validation, investigation, writing–review and editing. B. Turner: Software, formal analysis, validation, investigation, writing–review and editing. S. Szelinger: Resources, software, formal analysis, supervision, validation, writing–review and editing. J.J. Keats: Conceptualization, resources, software, formal analysis, supervision, validation, investigation, visualization, methodology, writing–review and editing. R.F. Halperin: Conceptualization, resources, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, project administration, writing–review and editing. J. Khan: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, project administration, writing–review and editing. G.L. Saulnier Sholler: Conceptualization, resources, data curation, supervision, funding acquisition, investigation, project administration, writing–review and editing. J.M. Trent: Conceptualization, resources, data curation, software, supervision, funding acquisition, project administration, writing–review and editing. |
ISSN: | 0008-5472 1538-7445 |
DOI: | 10.1158/0008-5472.CAN-21-1033 |