A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes.
A pan-cancer transcriptome analysis of exitron splicing identifies novel cancer driver genes and neoepitopes.
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DOI：
10.1016/j.molcel.2021.03.028
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发表时间：
2021-05-20
期刊：
影响因子：
16
通讯作者：
Yang R
中科院分区：
文献类型：
--
作者：
Wang TY;Liu Q;Ren Y;Alam SK;Wang L;Zhu Z;Hoeppner LH;Dehm SM;Cao Q;Yang R
外显子剪接（EIS）在蛋白质编码外显子内产生一个隐藏的内含子（称为外显子），以增加蛋白质组的多样性。EIS的特点很差，但新出现的证据表明EIS在癌症中的作用。通过对来自9,599个肿瘤转录组的33种癌症的EIS进行系统研究，我们发现EIS影响了63%的人类编码基因，其中95%的事件是肿瘤特异性的。值得注意的是，我们观察到一个相互排斥的模式之间的EIS和体细胞突变的影响基因。在功能上，我们发现EIS改变了已知和新的癌症驱动基因，导致功能获得或丧失，从而促进肿瘤进展。重要的是，我们鉴定了与MHC I类或II类结合的EIS衍生的新表位。对来自肾透明细胞癌队列的临床数据的分析揭示了EIS衍生的新抗原负荷与检查点抑制剂应答之间的关联。我们的研究结果确立了在提名癌症驱动事件和新抗原时考虑EIS改变的重要性。癌症中的出射子剪接事件的综合分析提供了候选癌症驱动事件、潜在免疫原性新抗原和仅通过遗传改变分析遗漏的免疫治疗应答的预测特征的参考。
Exitron splicing (EIS) creates a cryptic intron (termed an exitron) within a protein-coding exon to increase proteome diversity. EIS is poorly characterized, but emerging evidence suggests a role for EIS in cancer. Through a systematic investigation of EIS across 33 cancers from 9,599 tumor transcriptomes, we discovered EIS affected 63% of human coding genes and 95% of those events were tumor-specific. Notably, we observed a mutually exclusive pattern between EIS and somatic mutations in their affected genes. Functionally, we discovered EIS altered known and novel cancer driver genes for causing gain- or loss-of-function, by which promotes tumor progression. Importantly, we identified EIS-derived neoepitopes that bind to MHC class I or II. Analysis of clinical data from a clear cell renal cell carcinoma cohort revealed an association between EIS-derived neoantigen load and checkpoint inhibitor response. Our findings establish the importance of considering EIS alterations when nominating cancer driver events and neoantigens. The comprehensive analysis of exitron splicing events in cancer provides a reference of candidate cancer driver events, potential immunogenic neoantigens, and predictive signatures for immunotherapy response that are missed by genetic alteration analysis alone.
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影响因子：
64.5
作者：
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通讯作者：
Lo RS