Alternative splicing can produce transcripts that affect cancer development and thus shows potential for cancer diagnosis and treatment. However, intron retention (IR), a type of alternative splicing, has been studied less in cancer biology research. Here, we generated a pan-cancer IR landscape for more than 10,000 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). We characterized differentially retained introns between tumor and normal samples and identified retained introns associated with survival. We discovered 988 differentially retained introns in 14 cancers, some of which demonstrated diagnostic potential in multiple cancer types. We also inferred a large number of prognosis-related introns in 33 cancer types, and the associated genes included well-known cancer hallmarks such as angiogenesis, metastasis, and DNA mutations. Notably, we discovered a novel intron retention inside the 5′UTR ofSTN1that is associated with the survival of lung cancer patients. The retained intron reduces translation efficiency by producing upstream open reading frames (uORFs) and thereby inhibits colony formation and cell migration of lung cancer cells. Besides, the IR-based prognostic model achieved good stratification in certain cancers, as illustrated in acute myeloid leukemia. Taken together, we performed a comprehensive IR survey at a pan-cancer level, and the results implied that IR has the potential to be diagnostic and prognostic cancer biomarkers, as well as new drug targets.
选择性剪接能够产生影响癌症发展的转录本，因此在癌症诊断和治疗中展现出潜力。然而，内含子保留作为选择性剪接的一种形式，在癌症生物学研究中的关注相对较少。本研究基于癌症基因组图谱计划中涵盖33种癌症类型的超过10,000例样本，构建了泛癌内含子保留图谱。我们系统分析了肿瘤与正常样本间的差异保留内含子，并鉴定了与生存期相关的保留内含子。在14种癌症中发现了988个差异保留内含子，其中部分在多种癌症类型中显示出诊断潜力。同时，在33种癌症类型中推断了大量预后相关内含子，其关联基因涵盖了血管生成、转移和DNA突变等经典癌症特征。值得注意的是，我们在STN1基因5′非翻译区内发现了一个与肺癌患者生存相关的新型内含子保留事件。该保留内含子通过产生上游开放阅读框降低翻译效率，从而抑制肺癌细胞的集落形成和细胞迁移能力。此外，基于内含子保留的预后模型在特定癌症中展现出良好的风险分层效果，如急性髓系白血病所示。综上所述，我们在泛癌层面开展了全面的内含子保留研究，结果表明内含子保留具有成为癌症诊断与预后生物标志物以及新型药物靶点的潜力。
Pan-Cancer Profiling of Intron Retention and Its Clinical Significance in Diagnosis and Prognosis
肿瘤(癌症)患者之家