Institut Curie, Translational Research Department, PSL Research University, Paris, France.
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.
Oncogene. 2021 Jan;40(1):85-96. doi: 10.1038/s41388-020-01507-5. Epub 2020 Oct 14.
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.
参与 mRNA 剪接中 3'-剪接位点识别的基因构成了一类新兴的致癌基因。SF3B1 是癌症中突变频率最高的剪接因子，SF3B1 突变体破坏了分支点识别，导致使用隐蔽的 3'-剪接位点，并随后产生异常的剪接连接。为了全面确定导致这种剪接模式的改变，我们在 pan-TCGA 中对 SF3B1 特异性异常受体的使用进行了筛选。虽然大多数异常 3'-剪接模式可以用 SF3B1 突变来解释，但我们也检测到了九个 SF3B1 野生型肿瘤（包括五个肺腺癌）。这些肿瘤的基因组谱分析确定了这些病例中的五个存在剪接因子 SUGP1 的体细胞突变与杂合性丢失。在细胞系中模拟 SUGP1 缺失和突变显示，这两种改变都诱导了突变型-SF3B1 样异常剪接。我们的研究提供了明确的证据，表明 SUGP1 基因突变的拷贝数增加在肺腺癌和其他癌症中模拟了 SF3B1 突变。
