Widespread hypertranscription in aggressive human cancers.
Widespread hypertranscription in aggressive human cancers.
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DOI：
10.1126/sciadv.abn0238
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发表时间：
2022-11-25
期刊：
影响因子：
13.6
通讯作者：
中科院分区：
文献类型：
--
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癌症通常由特定转录程序的失调来定义;然而，对全局转录变化的重要性了解较少。超转录是RNA输出的全基因组增加。在原发性人类癌症中，超转录的流行率、潜在驱动因素和预后意义尚不明确。这部分是由于表达谱分析方法的局限性，其假设样品之间的RNA输出相等。在这里，我们开发了一种计算方法来直接测量7494种人类肿瘤中的超转录，涵盖31种癌症类型。超转录在癌症中普遍存在，特别是在侵袭性疾病中。它定义了生存率较差的患者亚组，即使是在已确定的亚型中。我们的数据表明，转录抑制的损失是高转录表型的基础。单细胞分析揭示了超转录克隆，其主导转录产物，无论其大小。最后，具有超转录突变的患者对免疫检查点治疗的反应有所改善。我们的研究结果为人类癌症的基因失调提供了基本的见解，并可能有助于识别从新疗法中受益的患者。总体RNA输出增加是侵袭性肿瘤的基本特征，定义了癌症中预后较差的亚组。
Cancers are often defined by the dysregulation of specific transcriptional programs; however, the importance of global transcriptional changes is less understood. Hypertranscription is the genome-wide increase in RNA output. Hypertranscription’s prevalence, underlying drivers, and prognostic significance are undefined in primary human cancer. This is due, in part, to limitations of expression profiling methods, which assume equal RNA output between samples. Here, we developed a computational method to directly measure hypertranscription in 7494 human tumors, spanning 31 cancer types. Hypertranscription is ubiquitous across cancer, especially in aggressive disease. It defines patient subgroups with worse survival, even within well-established subtypes. Our data suggest that loss of transcriptional suppression underpins the hypertranscriptional phenotype. Single-cell analysis reveals hypertranscriptional clones, which dominate transcript production regardless of their size. Last, patients with hypertranscribed mutations have improved response to immune checkpoint therapy. Our results provide fundamental insights into gene dysregulation across human cancers and may prove useful in identifying patients who would benefit from novel therapies. Global RNA output increase is a fundamental feature of aggressive tumors, defining the subgroups with worse prognosis across cancer.
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影响因子：
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Ding L