Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
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DOI：
10.1126/science.1164368
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发表时间：
2008-09-26
期刊：
影响因子：
--
通讯作者：
Kinzler KW
中科院分区：
文献类型：
--
作者：
Jones S;Zhang X;Parsons DW;Lin JC;Leary RJ;Angenendt P;Mankoo P;Carter H;Kamiyama H;Jimeno A;Hong SM;Fu B;Lin MT;Calhoun ES;Kamiyama M;Walter K;Nikolskaya T;Nikolsky Y;Hartigan J;Smith DR;Hidalgo M;Leach SD;Klein AP;Jaffee EM;Goggins M;Maitra A;Iacobuzio-Donahue C;Eshleman JR;Kern SE;Hruban RH;Karchin R;Papadopoulos N;Parmigiani G;Vogelstein B;Velculescu VE;Kinzler KW
目前对胰腺癌患者的治疗选择很少，迫切需要对这种致命疾病的发病机制有新的见解。为此，我们对24例胰腺癌进行了全面的基因分析。我们首先测定了这些样本中23,219个转录本的序列，代表20,661个蛋白质编码基因。然后，我们使用包含约106个单核苷酸多态的探针的微阵列来搜索肿瘤DNA中的纯合缺失和扩增。我们发现，胰腺癌平均包含63个基因改变，其中大部分是点突变。这些改变定义了一组核心的12个细胞信号通路和过程，每个都在67%到100%的肿瘤中发生了基因改变。用下一代合成测序技术对这些肿瘤的转录本进行分析，为这些途径和过程的重要性提供了独立的证据。我们的数据表明，只有当深入分析基因组的编码区时，基因改变的核心途径和调控过程才会变得明显。突变导致的这些核心途径和过程的失调可以解释胰腺肿瘤发生的主要特征。
There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for ~106 single-nucleotide polymorphisms. We found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors’ transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.
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