Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication

Yanling Liu, Jonathon Klein, Richa Bajpai, Li Dong, Quang Tran, Pandurang Kolekar, Jenny L. Smith, Rhonda E. Ries, Benjamin J. Huang, Yi-Cheng Wang, Todd A. Alonzo, Liqing Tian, Heather L. Mulder, Timothy I. Shaw, Jing Ma, Michael P. Walsh, Guangchun Song, Tamara Westover, Robert J. Autry, Alexander M. Gout, David A. Wheeler, Shibiao Wan, Gang Wu, Jun J. Yang, William E. Evans, Mignon Loh, John Easton, Jinghui Zhang, Jeffery M. Klco (), Soheil Meshinchi (), Patrick A. Brown (), Shondra M. Pruett-Miller () and Xiaotu Ma ()
Additional contact information
Yanling Liu: St. Jude Children’s Research Hospital
Jonathon Klein: St. Jude Children’s Research Hospital
Richa Bajpai: St. Jude Children’s Research Hospital
Li Dong: St. Jude Children’s Research Hospital
Quang Tran: St. Jude Children’s Research Hospital
Pandurang Kolekar: St. Jude Children’s Research Hospital
Jenny L. Smith: Fred Hutchinson Cancer Research Center
Rhonda E. Ries: Fred Hutchinson Cancer Research Center
Benjamin J. Huang: University of California San Francisco
Yi-Cheng Wang: Children’s Oncology Group
Todd A. Alonzo: University of Southern California
Liqing Tian: St. Jude Children’s Research Hospital
Heather L. Mulder: St. Jude Children’s Research Hospital
Timothy I. Shaw: Moffitt Cancer Center
Jing Ma: St. Jude Children’s Research Hospital
Michael P. Walsh: St. Jude Children’s Research Hospital
Guangchun Song: St. Jude Children’s Research Hospital
Tamara Westover: St. Jude Children’s Research Hospital
Robert J. Autry: St. Jude Children’s Research Hospital
Alexander M. Gout: St. Jude Children’s Research Hospital
David A. Wheeler: St. Jude Children’s Research Hospital
Shibiao Wan: St. Jude Children’s Research Hospital
Gang Wu: St. Jude Children’s Research Hospital
Jun J. Yang: St. Jude Children’s Research Hospital
William E. Evans: St. Jude Children’s Research Hospital
Mignon Loh: University of Washington
John Easton: St. Jude Children’s Research Hospital
Jinghui Zhang: St. Jude Children’s Research Hospital
Jeffery M. Klco: St. Jude Children’s Research Hospital
Soheil Meshinchi: Fred Hutchinson Cancer Research Center
Patrick A. Brown: Bristol Myers Squibb
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Xiaotu Ma: St. Jude Children’s Research Hospital

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-37438-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37438-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-37438-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().