Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; College of Bioinformatics Science and Technology and Bio-Pharmaceutical Key Laboratory of Heilongjiang Province, Harbin Medical University, Harbin 150081, China.
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Cell Rep. 2017 Oct 17;21(3):798-812. doi: 10.1016/j.celrep.2017.09.071.
It is increasingly appreciated that alternative splicing plays a key role in generating functional specificity and diversity in cancer. However, the mechanisms by which cancer mutations perturb splicing remain unknown. Here, we developed a network-based strategy, DrAS-Net, to investigate more than 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events. We identified more than 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact. Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes and increased expression of cell proliferation markers. Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations. Further stratification of 10,000 patients based on their mutation-splicing relationships identifies subtypes with distinct clinical features, including survival rates. Our work reveals how single-nucleotide changes can alter the repertoires of splicing isoforms, providing insights into oncogenic mechanisms for precision medicine.
越来越多的人认识到，选择性剪接在产生癌症功能特异性和多样性方面起着关键作用。然而，癌症突变干扰剪接的机制尚不清楚。在这里，我们开发了一种基于网络的策略 DrAS-Net，来研究超过 250 万个癌症类型中的变体，并将体细胞突变与癌症特异性剪接事件联系起来。我们在 33 种癌症类型中鉴定出超过 40,000 个候选驱动变体及其 80,000 个潜在的剪接靶标失调，并推断了它们的功能影响。引人注目的是，具有剪接扰动的肿瘤表现出免疫系统相关基因表达降低和细胞增殖标志物表达增加。同一基因中携带不同突变的肿瘤通常表现出不同的剪接扰动。进一步基于突变-剪接关系对 10,000 名患者进行分层，确定了具有不同临床特征的亚型，包括生存率。我们的工作揭示了单核苷酸变化如何改变剪接异构体的谱，为精准医学的致癌机制提供了见解。
