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

Oncogene. 2021 Jan;40(1):85-96. doi: 10.1038/s41388-020-01507-5. Epub 2020 Oct 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung / genetics*
  • Cell Line, Tumor
  • Codon Usage
  • Computer Simulation
  • HEK293 Cells
  • Humans
  • Loss of Heterozygosity
  • Lung Neoplasms / genetics*
  • Mutation*
  • Phosphoproteins / genetics*
  • RNA Splice Sites
  • RNA Splicing Factors / genetics*
  • Sequence Analysis, RNA

Substances

  • Phosphoproteins
  • RNA Splice Sites
  • RNA Splicing Factors
  • SF3B1 protein, human
  • SUGP1 protein, human