Genetic alterations ofSUGP1mimic mutant-SF3B1splice pattern in lung adenocarcinoma and other cancers

Genes involved in 3 '-splice site recognition during mRNA splicing constitute an emerging class of oncogenes.SF3B1is 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 bySF3B1mutations, we also detected nineSF3B1wild-type tumors (including five lung adenocarcinomas). Genomic profile analysis of these tumors identified somatic mutations combined with loss-of-heterozygosity in the splicing factorSUGP1in five of these cases. Modeling ofSUGP1loss and mutations in cell lines showed that both alterations induced mutant-SF3B1-like aberrant splicing. Our study provides definitive evidence that genetic alterations ofSUGP1genocopySF3B1mutations in lung adenocarcinoma and other cancers.