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Genetic alterations of SUGP1 mimic mutant-SF3B1 splice pattern in lung adenocarcinoma and other cancers.

Authors
  • Alsafadi, Samar1, 2
  • Dayot, Stephane2
  • Tarin, Malcy1
  • Houy, Alexandre2
  • Bellanger, Dorine2
  • Cornella, Michele2
  • Wassef, Michel3, 4
  • Waterfall, Joshua J1, 2
  • Lehnert, Erik5
  • Roman-Roman, Sergio1
  • Stern, Marc-Henri6
  • Popova, Tatiana2
  • 1 Institut Curie, Translational Research Department, PSL Research University, Paris, France. , (France)
  • 2 Institut Curie, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale Contre le Cancer, PSL Research University, Paris, France. , (France)
  • 3 Institut Curie, PSL Research University, Sorbonne University, Paris, France. , (France)
  • 4 U934 INSERM, UMR3215 CNRS, Paris, France. , (France)
  • 5 Seven Bridges Genomics, Konigesberg, MA, USA.
  • 6 Institut Curie, INSERM U830, DNA Repair and Uveal Melanoma (D.R.U.M.), Equipe labellisée par la Ligue Nationale Contre le Cancer, PSL Research University, Paris, France. [email protected] , (France)
Type
Published Article
Journal
Oncogene
Publisher
Nature Publishing Group UK
Publication Date
Oct 14, 2020
Identifiers
DOI: 10.1038/s41388-020-01507-5
PMID: 33057152
Source
Medline
Language
English
License
Unknown

Abstract

Genes involved in 3'-splice site recognition during mRNA splicing constitute an emerging class of oncogenes. SF3B1 is the most frequently mutated splicing factor in cancer, and SF3B1 mutants corrupt branchpoint recognition leading to usage of cryptic 3'-splice sites and subsequent aberrant junctions. For a comprehensive determination of alterations leading to this splicing pattern, we performed a pan-TCGA screening for SF3B1-specific aberrant acceptor usage. While the most of aberrant 3'-splice patterns were explained by SF3B1 mutations, we also detected nine SF3B1 wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factor SUGP1 in five of these cases. Modeling of SUGP1 loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations of SUGP1 genocopy SF3B1 mutations in lung adenocarcinoma and other cancers.

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