TY  - JOUR
AU  - Liu, Yanling
AU  - Klein, Jonathon
AU  - Bajpai, Richa
AU  - Dong, Li
AU  - Tran, Quang
AU  - Kolekar, Pandurang
AU  - Smith, Jenny L
AU  - Ries, Rhonda E
AU  - Huang, Benjamin J
AU  - Wang, Yi-Cheng
AU  - Alonzo, Todd A
AU  - Tian, Liqing
AU  - Mulder, Heather L
AU  - Shaw, Timothy I
AU  - Ma, Jing
AU  - Walsh, Michael P
AU  - Song, Guangchun
AU  - Westover, Tamara
AU  - Autry, Robert J
AU  - Gout, Alexander M
AU  - Wheeler, David A
AU  - Wan, Shibiao
AU  - Wu, Gang
AU  - Yang, Jun J
AU  - Evans, William E
AU  - Loh, Mignon
AU  - Easton, John
AU  - Zhang, Jinghui
AU  - Klco, Jeffery M
AU  - Meshinchi, Soheil
AU  - Brown, Patrick A
AU  - Pruett-Miller, Shondra M
AU  - Ma, Xiaotu
TI  - Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.
JO  - Nature Communications
VL  - 14
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2023-00710
SP  - 1739
PY  - 2023
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37019972
DO  - DOI:10.1038/s41467-023-37438-4
UR  - https://inrepo02.dkfz.de/record/275263
ER  -