Recurrent R-spondin fusions in colon cancer.
Recurrent R-spondin fusions in colon cancer.
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DOI：
10.1038/nature11282
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发表时间：
2012-08-30
期刊：
影响因子：
64.8
通讯作者：
de Sauvage, Frederic J.
中科院分区：
文献类型：
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作者：
Seshagiri, Somasekar;Stawiski, Eric W.;Durinck, Steffen;Modrusan, Zora;Storm, Elaine E.;Conboy, Caitlin B.;Chaudhuri, Subhra;Guan, Yinghui;Janakiraman, Vasantharajan;Jaiswal, Bijay S.;Guillory, Joseph;Ha, Connie;Dijkgraaf, Gerrit J. P.;Stinson, Jeremy;Gnad, Florian;Huntley, Melanie A.;Degenhardt, Jeremiah D.;Haverty, Peter M.;Bourgon, Richard;Wang, Weiru;Koeppen, Hartmut;Gentleman, Robert;Starr, Timothy K.;Zhang, Zemin;Largaespada, David A.;Wu, Thomas D.;de Sauvage, Frederic J.
识别和理解癌症基因组的变化对于靶向治疗剂的发展至关重要。在这里，我们通过施加下一代测序来表征其外部，转录组和拷贝数的改变，系统地分析了70多对原代人类结肠肿瘤。我们已经确定了36,303种改变蛋白质的体细胞变化，其中包括Wnt途径基因TCF7L2中的几个新复发突变，染色质反射基因，例如TET2和TET3和TET3以及包括ERBBB在内的受体酪氨酸激酶。我们对显着突变的癌症基因的分析确定了23个候选者，包括细胞周期检查点激酶ATM。拷贝数和RNA-seq数据分析确定了在结肠肿瘤子集中IGF2的扩增和相应的过表达。此外，使用RNA-Seq数据，我们确定了多个融合转录本，包括涉及R-Spondin家族成员Rspo2和Rspo3的复发基因融合，它们共发生在10％的结肠肿瘤中。 RSPO融合与APC突变相互排斥，表明它们可能在Wnt信号传导和肿瘤发生的激活中起作用。与此相一致，我们表明RSPO融合蛋白能够增强Wnt信号传导。本研究中发现的R-Spondin基因融合和其他几种基因突变为结肠癌的治疗干预提供了新的潜在机会。
Identifying and understanding changes in cancer genomes is essential for the development of targeted therapeutics. Here we analyse systematically more than 70 pairs of primary human colon tumours by applying next-generation sequencing to characterize their exomes, transcriptomes and copy-number alterations. We have identified 36,303 protein-altering somatic changes that include several new recurrent mutations in the Wnt pathway gene TCF7L2, chromatin-remodelling genes such as TET2 and TET3 and receptor tyrosine kinases including ERBB3. Our analysis for significantly mutated cancer genes identified 23 candidates, including the cell cycle checkpoint kinase ATM. Copy-number and RNA-seq data analysis identified amplifications and corresponding overexpression of IGF2 in a subset of colon tumours. Furthermore, using RNA-seq data we identified multiple fusion transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 that together occur in 10% of colon tumours. The RSPO fusions were mutually exclusive with APC mutations, indicating that they probably have a role in the activation of Wnt signalling and tumorigenesis. Consistent with this we show that the RSPO fusion proteins were capable of potentiating Wnt signalling. The R-spondin gene fusions and several other gene mutations identified in this study provide new potential opportunities for therapeutic intervention in colon cancer.
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影响因子：
14.9
作者：
Ramensky, V;Bork, P;Sunyaev, S
通讯作者：
Sunyaev, S
影响因子：
30.8
作者：
通讯作者：
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影响因子：
5.8
作者：
Morgan, Martin;Anders, Simon;Gentleman, Robert
通讯作者：
Gentleman, Robert
影响因子：
14.9
作者：
Forbes, Simon A.;Tang, Gurpreet;Futreal, P. Andrew
通讯作者：
Futreal, P. Andrew
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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