據9月4日的《科學》（Science）雜志報道說,，有2 項新的研究對助長正常細胞轉變?yōu)? 種最致命癌癥的基因組的變異進行了描述,，它們是多形性膠質母細胞瘤（這是最常見類型的腦癌）和胰腺癌。盡管每種癌癥類型的特異性基因組變異每個腫瘤都有所不同,，但這2 項研究披露了一個核心組的細胞信號通路和調節(jié)過程出現了偏差,，從而導致了疾病的發(fā)生。
在第一項研究中,，D. Williams Parsons 及其同事對來自22 個人類膠質母細胞瘤樣本的2 萬多個編碼蛋白質的基因序列進行了分析,，以期發(fā)現可能的變異,。另外,，他們還觀察那些有著腫瘤特異性變化的基因表達譜以及被拷貝基因的數量。他們發(fā)現了多種的影響基因的變異,，而這些變異從前并沒有與這些腫瘤掛上鉤,。有一種叫做IDH1 的基因容易在所謂的“繼發(fā)性膠質母細胞瘤”中發(fā)生變異，這種繼發(fā)性膠質母細胞瘤起源于低度惡性的腫瘤,，同時也出現于較年輕的病人中,。在這一小型的研究中，病人的腫瘤如果有IDH1 變異的話會有較長的生存時間,，這表明IDH1 基因是一種可用于篩選和治療的有用的臨床標記,，盡管這些結果還需要在一個更大的實驗分析中得到證實。在第2項研究中,，同一批的科學家對胰腺癌的基因組成進行了調查,。胰腺癌是一種常常在發(fā)現的時候已經處于晚期的癌癥，而且對這種癌癥的治療方法十分匱乏,。
Sian Jones 及其同事對24 例人類胰腺腫瘤的樣本應用了相同的基因組策略,，他們報道說，有一核心組的12 種細胞信號通路或調節(jié)過程在70-100%的這些腫瘤中都逐一出現了基因變異,，表明這些通路的中斷是胰腺腫瘤發(fā)展的重大特征的形成原因,。文章的作者得出結論：“治療研發(fā)的最大希望可能是發(fā)現以變異通路和過程的生理效應作為標靶的藥物，而不是針對它們的個別基因組分的藥物,。”（生物谷Bioon.com）
生物谷推薦原始出處：
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.
