據(jù)9月4日的《科學(xué)》(Science)雜志報(bào)道說(shuō),,有2 項(xiàng)新的研究對(duì)助長(zhǎng)正常細(xì)胞轉(zhuǎn)變?yōu)? 種最致命癌癥的基因組的變異進(jìn)行了描述,它們是多形性膠質(zhì)母細(xì)胞瘤(這是最常見(jiàn)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(gè)腫瘤都有所不同,,但這2 項(xiàng)研究披露了一個(gè)核心組的細(xì)胞信號(hào)通路和調(diào)節(jié)過(guò)程出現(xiàn)了偏差,從而導(dǎo)致了疾病的發(fā)生,。
在第一項(xiàng)研究中,,D. Williams Parsons 及其同事對(duì)來(lái)自22 個(gè)人類膠質(zhì)母細(xì)胞瘤樣本的2 萬(wàn)多個(gè)編碼蛋白質(zhì)的基因序列進(jìn)行了分析,以期發(fā)現(xiàn)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(dá)譜以及被拷貝基因的數(shù)量。他們發(fā)現(xiàn)了多種的影響基因的變異,而這些變異從前并沒(méi)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(zhì)母細(xì)胞瘤”中發(fā)生變異,,這種繼發(fā)性膠質(zhì)母細(xì)胞瘤起源于低度惡性的腫瘤,同時(shí)也出現(xiàn)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(huì)有較長(zhǎng)的生存時(shí)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(biāo)記,,盡管這些結(jié)果還需要在一個(gè)更大的實(shí)驗(yàn)分析中得到證實(shí),。在第2項(xiàng)研究中,同一批的科學(xué)家對(duì)胰腺癌的基因組成進(jìn)行了調(diào)查,。胰腺癌是一種常常在發(fā)現(xiàn)的時(shí)候已經(jīng)處于晚期的癌癥,,而且對(duì)這種癌癥的治療方法十分匱乏。
Sian Jones 及其同事對(duì)24 例人類胰腺腫瘤的樣本應(yīng)用了相同的基因組策略,,他們報(bào)道說(shuō),,有一核心組的12 種細(xì)胞信號(hào)通路或調(diào)節(jié)過(guò)程在70-100%的這些腫瘤中都逐一出現(xiàn)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(jié)論:“治療研發(fā)的最大希望可能是發(fā)現(xiàn)以變異通路和過(guò)程的生理效應(yīng)作為標(biāo)靶的藥物,,而不是針對(duì)它們的個(gè)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.