据9月4日的《科学》（Science）杂志报道说，有2 项新的研究对助长正常细胞转变为2 种最致命癌症的基因组的变异进行了描述，它们是多形性胶质母细胞瘤（这是最常见类型的脑癌）和胰腺癌。尽管每种癌症类型的特异性基因组变异每个肿瘤都有所不同，但这2 项研究披露了一个核心组的细胞信号通路和调节过程出现了偏差，从而导致了疾病的发生。
在第一项研究中，D. Williams Parsons 及其同事对来自22 个人类胶质母细胞瘤样本的2 万多个编码蛋白质的基因序列进行了分析，以期发现可能的变异。另外，他们还观察那些有着肿瘤特异性变化的基因表达谱以及被拷贝基因的数量。他们发现了多种的影响基因的变异，而这些变异从前并没有与这些肿瘤挂上钩。有一种叫做IDH1 的基因容易在所谓的“继发性胶质母细胞瘤”中发生变异，这种继发性胶质母细胞瘤起源于低度恶性的肿瘤，同时也出现于较年轻的病人中。在这一小型的研究中，病人的肿瘤如果有IDH1 变异的话会有较长的生存时间，这表明IDH1 基因是一种可用于筛选和治疗的有用的临床标记，尽管这些结果还需要在一个更大的实验分析中得到证实。在第2项研究中，同一批的科学家对胰腺癌的基因组成进行了调查。胰腺癌是一种常常在发现的时候已经处于晚期的癌症，而且对这种癌症的治疗方法十分匮乏。
Sian Jones 及其同事对24 例人类胰腺肿瘤的样本应用了相同的基因组策略，他们报道说，有一核心组的12 种细胞信号通路或调节过程在70-100%的这些肿瘤中都逐一出现了基因变异，表明这些通路的中断是胰腺肿瘤发展的重大特征的形成原因。文章的作者得出结论：“治疗研发的最大希望可能是发现以变异通路和过程的生理效应作为标靶的药物，而不是针对它们的个别基因组分的药物。”（生物谷Bioon.com）
生物谷推荐原始出处：
Science，DOI: 10.1126/science.1164382，D. Williams Parsons，Kenneth W. Kinzler
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
D. Williams Parsons 1, Sian Jones 2, Xiaosong Zhang 2, Jimmy Cheng-Ho Lin 2, Rebecca J. Leary 2, Philipp Angenendt 2, Parminder Mankoo 3, Hannah Carter 3, I-Mei Siu 4, Gary L. Gallia 4, Alessandro Olivi 4, Roger McLendon 5, B. Ahmed Rasheed 5, Stephen Keir 5, Tatiana Nikolskaya 6, Yuri Nikolsky 7, Dana A. Busam 8, Hanna Tekleab 8, Luis A. Diaz Jr.2, James Hartigan 9, Doug R. Smith 9, Robert L. Strausberg 8, Suely Kazue Nagahashi Marie 10, Sueli Mieko Oba Shinjo 10, Hai Yan 5, Gregory J. Riggins 4, Darell D. Bigner 5, Rachel Karchin 3, Nick Papadopoulos 2, Giovanni Parmigiani 2, Bert Vogelstein 2*, Victor E. Velculescu 2*, Kenneth W. Kinzler 2*
Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs, and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.
Science，DOI: 10.1126/science.1164368，Sian Jones，Kenneth W. Kinzler
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Sian Jones 1, Xiaosong Zhang 1, D. Williams Parsons 2, Jimmy Cheng-Ho Lin 1, Rebecca J. Leary 1, Philipp Angenendt 1, Parminder Mankoo 3, Hannah Carter 3, Hirohiko Kamiyama 4, Antonio Jimeno 1, Seung-Mo Hong 4, Baojin Fu 4, Ming-Tseh Lin 4, Eric S. Calhoun 1, Mihoko Kamiyama 4, Kimberly Walter 4, Tatiana Nikolskaya 5, Yuri Nikolsky 6, James Hartigan 7, Douglas R. Smith 7, Manuel Hidalgo 1, Steven D. Leach 8, Alison P. Klein 9, Elizabeth M. Jaffee 9, Michael Goggins 9, Anirban Maitra 9, Christine Iacobuzio-Donahue 9, James R. Eshleman 9, Scott E. Kern 9, Ralph H. Hruban 9, Rachel Karchin 3, Nickolas Papadopoulos 1, Giovanni Parmigiani 10, Bert Vogelstein 1*, Victor E. Velculescu 1*, Kenneth W. Kinzler 1*
There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Towards 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 (SNPs). 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-synthesistechnologies provided independent evidence for the significance 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.
