A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis.
A global view of cancer-specific transcript variants by subtractive transcriptome-wide analysis.
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DOI：
10.1371/journal.pone.0004732
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Zhou R
中科院分区：
文献类型：
--
作者：
He C;Zhou F;Zuo Z;Cheng H;Zhou R
前体mRNA选择性剪接（AS）在产生复杂蛋白质组中起着重要作用，并影响发育和疾病。然而，AS在人类肿瘤发生中的调节和病因学尚不清楚。构建了人类肿瘤和正常组织表达序列标签（expressed sequence tags，ESTs）的基本局部比对搜索工具数据库。EST/EST比对中的插入或缺失用于鉴定可变剪接的转录物。EST与基因组序列的比对进一步用于确认AS。然后对每个组织中的选择性剪接转录物进行消减交叉筛选以获得组织特异性变体。我们系统地识别和表征了癌症/组织特异性和人类基因组中的可变剪接变体。我们从27种人类癌症中鉴定了9，989个基因的15，093个癌症特异性变体，从35种正常组织中鉴定了7，240个基因的14，376个正常组织特异性变体，这些变体涵盖了人类肿瘤和正常组织的主要类型。大约70%的转录本是新的。将这些数据整合到数据库HCSAS（http：//202.114.72.39/database/human.html，pass：68756253）中。此外，我们观察到癌基因和抑癌基因的癌症特异性AS与特定的癌症类型相关。癌症在选择可变剪接位点和利用可变剪接类型方面表现出偏好。人类癌症的这些特征，以及癌症相关基因的大量新剪接形式的发现，表明癌症特异性AS在人类肿瘤发生过程中的重要和全球性作用。我们建议使用癌症特异性选择性剪接作为人类癌症新的诊断，预后，预测和治疗工具的潜在来源。肿瘤特异性AS的整体观不仅有助于探索肿瘤转录组的复杂性，而且拓宽了临床研究的视野。
Alternative pre-mRNA splicing (AS) plays a central role in generating complex proteomes and influences development and disease. However, the regulation and etiology of AS in human tumorigenesis is not well understood. A Basic Local Alignment Search Tool database was constructed for the expressed sequence tags (ESTs) from all available databases of human cancer and normal tissues. An insertion or deletion in the alignment of EST/EST was used to identify alternatively spliced transcripts. Alignment of the ESTs with the genomic sequence was further used to confirm AS. Alternatively spliced transcripts in each tissue were then subtractively cross-screened to obtain tissue-specific variants. We systematically identified and characterized cancer/tissue-specific and alternatively spliced variants in the human genome based on a global view. We identified 15,093 cancer-specific variants of 9,989 genes from 27 types of human cancers and 14,376 normal tissue-specific variants of 7,240 genes from 35 normal tissues, which cover the main types of human tumors and normal tissues. Approximately 70% of these transcripts are novel. These data were integrated into a database HCSAS (http://202.114.72.39/database/human.html, pass:68756253). Moreover, we observed that the cancer-specific AS of both oncogenes and tumor suppressor genes are associated with specific cancer types. Cancer shows a preference in the selection of alternative splice-sites and utilization of alternative splicing types. These features of human cancer, together with the discovery of huge numbers of novel splice forms for cancer-associated genes, suggest an important and global role of cancer-specific AS during human tumorigenesis. We advise the use of cancer-specific alternative splicing as a potential source of new diagnostic, prognostic, predictive, and therapeutic tools for human cancer. The global view of cancer-specific AS is not only useful for exploring the complexity of the cancer transcriptome but also widens the eyeshot of clinical research.
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