The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers.
The landscape of long noncoding RNA-involved and tumor-specific fusions across various cancers.
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各种癌症中涉及长链非编码RNA和肿瘤特异性融合的景观
DOI：
10.1093/nar/gkaa1119
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发表时间：
2020-12-16
影响因子：
14.9
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Guo M;Xiao ZD;Dai Z;Zhu L;Lei H;Diao LT;Xiong Y
大多数人类基因组编码长链非编码RNA （lncRNA）基因，这些基因是各种细胞过程的关键调节因子，其数量大大超过蛋白质编码基因。然而，lncrna参与的融合尚未被调查和表征。在这里，我们对不同癌症类型的lncRNA融合格局进行了系统研究，并鉴定了bb30万个高可信度的肿瘤特异性lncRNA融合（使用8284个肿瘤样本和6946个正常样本）。融合与DNA损伤和肿瘤干性呈正相关，在微卫星不稳定（MSI）高或病毒感染的肿瘤中特异性低。此外，融合体在不同的癌症分子亚型中分布不同，但在微卫星稳定（MSS）、高体细胞拷贝数改变（SCNA）和生存差的肿瘤中具有共同的富集。重要的是，我们发现了一种潜在的新机制，由增强子rna （eRNA）介导，它产生二次融合，形成与fda批准的药物靶向的许多融合中心紧密连接的融合网络。最后，我们通过实验验证了两种来自mRNA-lncRNA融合体的促肿瘤嵌合蛋白KDM4B-G039927和EPS15L1-lncOR7C2-1的功能。EPS15L1融合蛋白可能调节（Gasdermin E） GSDME，在焦亡和抗肿瘤免疫中起关键作用。我们的研究完成了癌症融合的景观，揭示了融合机制，丰富了lncRNA在肿瘤发生和癌症进展中的功能。
Abstract The majority of the human genome encodes long noncoding RNA (lncRNA) genes, critical regulators of various cellular processes, which largely outnumber protein-coding genes. However, lncRNA-involved fusions have not been surveyed and characterized yet. Here, we present a systematic study of the lncRNA fusion landscape across cancer types and identify >30 000 high-confidence tumor-specific lncRNA fusions (using 8284 tumor and 6946 normal samples). Fusions positively correlated with DNA damage and cancer stemness and were specifically low in microsatellite instable (MSI)-High or virus-infected tumors. Moreover, fusions distribute differently among cancer molecular subtypes, but with shared enrichment in tumors that are microsatellite stable (MSS), with high somatic copy number alterations (SCNA), and with poor survival. Importantly, we find a potentially new mechanism, mediated by enhancer RNAs (eRNA), which generates secondary fusions that form densely connected fusion networks with many fusion hubs targeted by FDA-approved drugs. Finally, we experimentally validate functions of two tumor-promoting chimeric proteins derived from mRNA-lncRNA fusions, KDM4B–G039927 and EPS15L1–lncOR7C2–1. The EPS15L1 fusion protein may regulate (Gasdermin E) GSDME, critical in pyroptosis and anti-tumor immunity. Our study completes the fusion landscape in cancers, sheds light on fusion mechanisms, and enriches lncRNA functions in tumorigenesis and cancer progression.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Cancer Genome Atlas Research Network. Electronic address: wheeler@bcm.edu;Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
16.6
作者：
Cortes-Ciriano I;Lee S;Park WY;Kim TM;Park PJ
通讯作者：
Park PJ
影响因子：
14.9
作者：
Hu X;Wang Q;Tang M;Barthel F;Amin S;Yoshihara K;Lang FM;Martinez-Ledesma E;Lee SH;Zheng S;Verhaak RGW
通讯作者：
Verhaak RGW