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

被引：11

作者：

Byron, Sara A. ^{[1
]}

Hendricks, William P. D. ^{[1
]}

Nagulapally, Abhinav B. ^{[2
]}

Kraveka, Jacqueline M. ^{[3
]}

Ferguson, William S. ^{[4
]}

Brown, Valerie, I ^{[5
]}

Eslin, Don E. ^{[6
]}

Mitchell, Deanna ^{[7
]}

Cornelius, Albert ^{[7
]}

Roberts, William ^{[8
,9
]}

Isakoff, Michael S. ^{[10
]}

Oesterheld, Javier E. ^{[2
]}

Wada, Randal K. ^{[11
]}

Rawwas, Jawhar ^{[12
]}

Neville, Kathleen ^{[13
]}

Zage, Peter E. ^{[8
,9
]}

Harrod, Virginia L. ^{[14
]}

Bergendahl, Genevieve ^{[2
]}

VanSickle, Elizabeth ^{[7
]}

Dykema, Karl ^{[2
]}

Bond, Jeffrey ^{[7
]}

Chou, Hsien-Chao ^{[15
]}

Wei, Jun S. ^{[15
]}

Wen, Xinyu ^{[15
,16
]}

Reardon, Hue, V ^{[17
]}

Roos, Alison ^{[1
]}

Nasser, Sara ^{[1
]}

Izatt, Tyler ^{[1
]}

Enriquez, Daniel ^{[1
]}

Hegde, Apurva M. ^{[1
]}

Cisneros, Faith ^{[1
]}

Christofferson, Austin ^{[1
]}

Turner, Bryce ^{[1
]}

Szelinger, Szabolcs ^{[1
,18
]}

Keats, Jonathan J. ^{[1
]}

Halperin, Rebecca F. ^{[1
]}

Khan, Javed ^{[15
]}

Sholler, Giselle L. Saulnier ^{[2
]}

Trent, Jeffrey M. ^{[1
]}

机构：

[1] Translat Genom Res Inst TGen, Phoenix, AZ USA

[2] Levine Childrens Hosp, Charlotte, NC USA

[3] Med Univ South Carolina, Charleston, SC 29425 USA

[4] St Louis Univ, Sch Med, St Louis, MO USA

[5] Penn State Milton S Hershey Med Ctr, Penn State Hlth Childrens Hosp, Hershey, PA USA

[6] St Josephs Childrens Hosp, Tampa, FL USA

[7] Helen DeVos Childrens Hosp, Grand Rapids, MI USA

[8] Rady Childrens Hosp, Peckham Ctr Canc & Blood Disorders, San Diego, CA USA

[9] Univ Calif San Diego, Dept Pediat, Div Hematol Oncol, La Jolla, CA 92093 USA

[10] Connecticut Childrens Med Ctr, Ctr Canc & Blood Disorders, Hartford, CT USA

[11] Kapiolani Med Ctr Women & Children, Honolulu, HI USA

[12] Childrens Hosp & Clin Minnesota, Minneapolis, MN USA

[13] Univ Arkansas Med Sci, Little Rock, AR 72205 USA

[14] Dell Childrens Med Ctr, Austin, TX USA

[15] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

[16] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA

[17] Frederick Natl Lab Canc Res, Biomed Informat & Data Sci, Adv Biomed Computat Sci, Frederick, MD USA

[18] Ashion Analyt, Phoenix, AZ USA

来源：

CANCER RESEARCH | 2021年 / 81卷 / 23期

关键词：

EVOLUTIONARY HISTORY; GENE-EXPRESSION; MUTATIONS; CANCER; SIGNATURES; THERAPY; CHILDREN; GAIN;

D O I：

10.1158/0008-5472.CAN-21-1033

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. © 2021 American Association for Cancer Research Inc.. All rights reserved.

引用

页码：5818 / 5832

页数：15

共 2 条

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