TY - JOUR
T1 - Genomic and Transcriptomic Analysis of Relapsed and Refractory Childhood Solid Tumors Reveals a Diverse Molecular Landscape and Mechanisms of Immune Evasion
AU - Byron, Sara A.
AU - Hendricks, William P.D.
AU - Nagulapally, Abhinav B.
AU - Kraveka, Jacqueline M.
AU - Ferguson, William S.
AU - Brown, Valerie I.
AU - Eslin, Don E.
AU - Mitchell, Deanna
AU - Cornelius, Albert
AU - Roberts, William
AU - Isakoff, Michael S.
AU - Oesterheld, Javier E.
AU - Wada, Randal K.
AU - Rawwas, Jawhar
AU - Neville, Kathleen
AU - Zage, Peter E.
AU - Harrod, Virginia L.
AU - Bergendahl, Genevieve
AU - Vansickle, Elizabeth
AU - Dykema, Karl
AU - Bond, Jeffrey
AU - Chou, Hsien Chao
AU - Wei, Jun S.
AU - Wen, Xinyu
AU - Reardon, Hue V.
AU - Roos, Alison
AU - Nasser, Sara
AU - Izatt, Tyler
AU - Enriquez, Daniel
AU - Hegde, Apurva M.
AU - Cisneros, Faith
AU - Christofferson, Austin
AU - Turner, Bryce
AU - Szelinger, Szabolcs
AU - Keats, Jonathan J.
AU - Halperin, Rebecca F.
AU - Khan, Javed
AU - Sholler, Giselle L.Saulnier
AU - Trent, Jeffrey M.
N1 - Funding Information:
This work was supported by the Dell Inc. Powering the Possible Program, Beat NB Foundation, Meryl and Charles Witmer Foundation, TGen Foundation, Four Diamonds, Hyundai Hope on Wheels, Hartwell Foundation, Padres Pedal the Cause, and the Reid R. Sacco Adolescent and Young Adult Cancer Alliance. This research was supported in part by the NIH, the Intramural Research Program of the NIH, and the NCI Center for Cancer Research.
Funding Information:
W.P.D. Hendricks reports other support from Vidium Animal Health outside the submitted work. J.E. Oesterheld reports other support from Servier outside the submitted work. G.L. Saulnier Sholler reports grants from Dell Foundation during the conduct of the study. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research Inc.. All rights reserved.
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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 treatmentassociated 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 crosspathology 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. _2021 American Association for Cancer Research.
AB - 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 treatmentassociated 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 crosspathology 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. _2021 American Association for Cancer Research.
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UR - http://www.scopus.com/inward/citedby.url?scp=85120506563&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-21-1033
DO - 10.1158/0008-5472.CAN-21-1033
M3 - Article
C2 - 34610968
AN - SCOPUS:85120506563
SN - 0008-5472
VL - 81
SP - 5818
EP - 5832
JO - Cancer Research
JF - Cancer Research
IS - 23
ER -
