Detection of recurrent alternative splicing switches in tumor samples reveals novel signatures of cancer.
Detection of recurrent alternative splicing switches in tumor samples reveals novel signatures of cancer.
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DOI：
10.1093/nar/gku1392
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发表时间：
2015-02-18
影响因子：
14.9
通讯作者：
Eyras E
中科院分区：
文献类型：
--
作者：
Sebestyén E;Zawisza M;Eyras E
在癌症中表达的选择性剪接异构体的测定是发展用于预后和治疗的肿瘤特异性分子靶点的基础，但它受到肿瘤的异质性和患者之间的变异性的阻碍。我们开发了一种新的计算方法，对生物和技术变异性具有鲁棒性，可识别多个样本中的显著转录异构体变化。我们将这种方法应用于癌症基因组图谱项目的4000多个样本，以获得预测9种不同癌症类型的新型剪接特征，并发现涉及肿瘤驱动因子CTNND 1的基底样乳腺肿瘤的特异性特征。此外，我们的方法确定了244个亚型开关，其中的变化发生在最丰富的转录本。这些开关中的一些发生在已知的肿瘤驱动因子中，包括PPARG、CCND3、RALGDS、MITF、PRDM1、ABI1和MYH11，对于这些肿瘤驱动因子，开关意味着蛋白质产物的变化。此外，一些开关不能用简单的剪接事件来描述。令人惊讶的是，除了肿瘤抑制因子FBLN2和致癌基因MYH11之外，同种型开关不依赖于体细胞突变。我们的方法揭示了肿瘤特异性表达的转录异构体的癌症新特征，为预后和治疗提供了新的潜在分子靶点。数据和软件可在http://dx.doi.org/10.6084/m9.figshare.1061917和https://bitbucket.org/regulatorygenomicsupf/iso-ktsp上获得。
The determination of the alternative splicing isoforms expressed in cancer is fundamental for the development of tumor-specific molecular targets for prognosis and therapy, but it is hindered by the heterogeneity of tumors and the variability across patients. We developed a new computational method, robust to biological and technical variability, which identifies significant transcript isoform changes across multiple samples. We applied this method to more than 4000 samples from the The Cancer Genome Atlas project to obtain novel splicing signatures that are predictive for nine different cancer types, and find a specific signature for basal-like breast tumors involving the tumor-driver CTNND1. Additionally, our method identifies 244 isoform switches, for which the change occurs in the most abundant transcript. Some of these switches occur in known tumor drivers, including PPARG, CCND3, RALGDS, MITF, PRDM1, ABI1 and MYH11, for which the switch implies a change in the protein product. Moreover, some of the switches cannot be described with simple splicing events. Surprisingly, isoform switches are independent of somatic mutations, except for the tumor-suppressor FBLN2 and the oncogene MYH11. Our method reveals novel signatures of cancer in terms of transcript isoforms specifically expressed in tumors, providing novel potential molecular targets for prognosis and therapy. Data and software are available at: http://dx.doi.org/10.6084/m9.figshare.1061917 and https://bitbucket.org/regulatorygenomicsupf/iso-ktsp.
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DOI：
10.1158/1541-7786.mcr-09-0528
发表时间：
2010-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Lapuk A;Marr H;Jakkula L;Pedro H;Bhattacharya S;Purdom E;Hu Z;Simpson K;Pachter L;Durinck S;Wang N;Parvin B;Fontenay G;Speed T;Garbe J;Stampfer M;Bayandorian H;Dorton S;Clark TA;Schweitzer A;Wyrobek A;Feiler H;Spellman P;Conboy J;Gray JW
通讯作者：
Gray JW
影响因子：
37.3
作者：
Hill VK;Hesson LB;Dansranjavin T;Dallol A;Bieche I;Vacher S;Tommasi S;Dobbins T;Gentle D;Euhus D;Lewis C;Dammann R;Ward RL;Minna J;Maher ER;Pfeifer GP;Latif F
通讯作者：
Latif F
影响因子：
8
作者：
Law, E. W. L.;Cheung, A. K. L.;Lung, M. L.
通讯作者：
Lung, M. L.
影响因子：
6.4
作者：
Cariati, Massimiliano;Naderi, Ali;Purushotham, Anand D.
通讯作者：
Purushotham, Anand D.
影响因子：
16
作者：
Bechara, Elias G.;Sebestyen, Endre;Valcarcel, Juan
通讯作者：
Valcarcel, Juan