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Etiology of oncogenic fusions in 5,190 childhood cancers and its clinical and therapeutic implication.
Liu, Yanling; Klein, Jonathon; Bajpai, Richa; Dong, Li; Tran, Quang; Kolekar, Pandurang; Smith, Jenny L; Ries, Rhonda E; Huang, Benjamin J; Wang, Yi-Cheng; Alonzo, Todd A; Tian, Liqing; Mulder, Heather L; Shaw, Timothy I; Ma, Jing; Walsh, Michael P; Song, Guangchun; Westover, Tamara; Autry, Robert J; Gout, Alexander M; Wheeler, David A; Wan, Shibiao; Wu, Gang; Yang, Jun J; Evans, William E; Loh, Mignon; Easton, John; Zhang, Jinghui; Klco, Jeffery M; Meshinchi, Soheil; Brown, Patrick A; Pruett-Miller, Shondra M; Ma, Xiaotu.
Afiliación
  • Liu Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Klein J; Department of Cell and Molecular Biology and Center for Advanced Genome Editing, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Bajpai R; Department of Cell and Molecular Biology and Center for Advanced Genome Editing, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Dong L; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Tran Q; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Kolekar P; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Smith JL; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Ries RE; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
  • Huang BJ; Department of Pediatrics and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
  • Wang YC; Children's Oncology Group, Monrovia, CA, USA.
  • Alonzo TA; Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
  • Tian L; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Mulder HL; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Shaw TI; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA.
  • Ma J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Walsh MP; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Song G; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Westover T; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Autry RJ; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Gout AM; Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • Wheeler DA; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Wan S; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Wu G; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Yang JJ; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Evans WE; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Loh M; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Easton J; Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Zhang J; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute and the Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
  • Klco JM; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Meshinchi S; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • Brown PA; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. Jeffery.Klco@stjude.org.
  • Pruett-Miller SM; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. smeshinc@fredhutch.org.
  • Ma X; Bristol Myers Squibb, Princeton, NJ, USA. Patrick.Brown@bms.com.
Nat Commun ; 14(1): 1739, 2023 04 05.
Article en En | MEDLINE | ID: mdl-37019972
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Subunidad alfa 2 del Factor de Unión al Sitio Principal / Leucemia-Linfoma Linfoblástico de Células Precursoras Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Child / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Subunidad alfa 2 del Factor de Unión al Sitio Principal / Leucemia-Linfoma Linfoblástico de Células Precursoras Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Child / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido