期刊
ANNALS OF ONCOLOGY
卷 33, 期 6, 页码 578-592出版社
ELSEVIER
DOI: 10.1016/j.annonc.2022.03.011
关键词
pediatric cancer; alternative splicing; exon inclusion/exclusion; splicing factors; alterations; therapy
类别
资金
- Nationwide Children's Hospital Technology Development Fund
- Ohio Development Services Agency and Third Frontier Technology Validation
- Alex's Lemonade Stand Foundation
- Cancer Free Kids Pediatric Cancer Research Alliance
- Ohio State University Comprehensive Cancer Center [R03CA259865]
- National Institutes of Health [R03CA259865, P30CA016058, R21CA227926, R01CA262873]
Alternative splicing plays a critical role in the formation and growth of pediatric cancers. This review highlights the various splice variants and affected genes in different types of cancers. Understanding the mechanisms of disease-inducing splicing events can contribute to the development of novel therapeutics.
Background: Compared with adult cancers, pediatric cancers are uniquely characterized by a genomically stable landscape and lower tumor mutational burden. Alternative splicing, however, a global cellular process that produces different messenger RNA/protein isoforms from a single messenger RNA transcript, has been increasingly implicated in the development of pediatric cancers. Design: We review the current literature on the role of alternative splicing in adult cancer, cancer predisposition syndromes, and pediatric cancers. We also describe multiple splice variants identified in adult cancers and confirmed through comprehensive genomic profiling in our institutional cohort of rare, refractory, and relapsed pediatric and adolescent young adult cancer patients. Finally, we summarize the contributions of alternative splicing events to neoantigens and chemoresistance and prospects for splicing-based therapies. Results: Published dysregulated splicing events can be categorized as exon inclusion, exon exclusion, splicing factor upregulation, or splice site alterations. We observe these phenomena in cancer predisposition syndromes (Lynch syndrome, Li-Fraumeni syndrome, CHEK2) and pediatric leukemia (B-cell acute lymphoblastic leukemia), sarcomas (Ewing sarcoma, rhabdomyosarcoma, osteosarcoma), retinoblastoma, Wilms' tumor, and neuroblastoma. Within our institutional cohort, we demonstrate splice variants in key regulatory genes (CHEK2, TP53, PIK3R1, MDM2, KDM6A, NF1) that resulted in exon exclusion or splice site alterations, which were predicted to impact functional protein expression and promote tumorigenesis. Differentially spliced isoforms and splicing proteins also impact neoantigen creation and treatment resistance, such as imatinib or glucocorticoid regimens. Additionally, splice-altering strategies with the potential to change the therapeutic landscape of pediatric cancers include antisense oligonucleotides, adeno-associated virus gene transfers, and small molecule inhibitors. Conclusions: Alternative splicing plays a critical role in the formation and growth of pediatric cancers, and our institutional cohort confirms and highlights the broad spectrum of affected genes in a variety of cancers. Further studies that elucidate the mechanisms of disease-inducing splicing events will contribute toward the development of novel therapeutics.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据