Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion

Autor: Faith Cisneros, Austin Christofferson, Deanna Mitchell, Jawhar Rawwas, Don E Eslin, Randal K. Wada, Javier Oesterheld, Genevieve Bergendahl, Xinyu Wen, Jun S. Wei, Hue V. Reardon, Tyler Izatt, Jeffrey M. Trent, William Roberts, William P.D. Hendricks, Virginia L Harrod, Karl Dykema, Sara Nasser, Sara A. Byron, Elizabeth VanSickle, Bryce Turner, Jacqueline M. Kraveka, Peter E. Zage, Alison Roos, Apurva M. Hegde, Valerie I. Brown, Kathleen A. Neville, Albert Cornelius, Jonathan J Keats, Szabolcs Szelinger, Rebecca F. Halperin, Michael S. Isakoff, William S. Ferguson, Daniel Enriquez, Javed Khan, Abhinav Nagulapally, Jeffrey P. Bond, Hsien-Chao Chou, Giselle Saulnier Sholler
Rok vydání: 2021
Předmět:
Male
Cancer Research
medicine.medical_treatment
Drug Resistance
Disease
Transcriptome
Neoplasms
Antineoplastic Combined Chemotherapy Protocols
Longitudinal Studies
Child
Cancer
Pediatric
Tumor
Prognosis
Gene Expression Regulation
Neoplastic
Survival Rate
Oncology
Local
Child
Preschool
Female
medicine.drug
Adult
Cell signaling
Adolescent
Pediatric Cancer
Oncology and Carcinogenesis
Somatic hypermutation
Biology
Article
Young Adult
Immune system
Rare Diseases
Clinical Research
MHC class I
medicine
Genetics
Biomarkers
Tumor
Humans
Oncology & Carcinogenesis
Preschool
Immune Evasion
Chemotherapy
Neoplastic
Temozolomide
Human Genome
Infant
Neoplasm Recurrence
Good Health and Well Being
Gene Expression Regulation
Drug Resistance
Neoplasm
Mutation
biology.protein
Cancer research
Neoplasm
Neoplasm Recurrence
Local
Biomarkers
Follow-Up Studies
Zdroj: Cancer Res
Cancer research, vol 81, iss 23
ISSN: 1538-7445
Popis: 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.
Databáze: OpenAIRE
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