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美發現7個關鍵基因決定腦癌患者存活時間長短

美國科學家日前發現，人體腦瘤中有7個關鍵基因，不但決定著患者所患腦癌的嚴重程度，還決定患者存活時間的長短。這一研究成果將有助於相關藥物的研製。

　　美國西北大學研究人員在15日出版的《美國醫學協會週刊》上發表文章說，鋻於腦癌是由數百個基因變異造成，研究人員對變異過程中誘發腦瘤的基因進行了研究。

　　他們從500多個腦癌患者頭部提取了腦瘤基因樣本。這些人大部分都患有惡性神經膠質瘤，其餘則患有神經膠母細胞瘤。研究人員隨後對這些基因及其相互作用進行了檢測，發現共有11個“核心基因”決定著患者所患腦癌的嚴重程度，在那11個“核心基因”中有7個基因還決定著患者存活時間的長短。

　　研究人員表示，這項研究成果將有助於確定腦瘤的誘發基因及其表達機制，從而了解哪些基因受損後將造成危害。

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資料來源!

http://jama.ama-assn.org/cgi/content/full/302/3/261?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=A+Network+Model+of+a+Cooperative+Genetic+Landscape+in+Brain+Tumors&searchid=1&FIRSTINDEX=0&resourcetype=HWCIT

PDF下載 :http://jama.ama-assn.org/cgi/reprint/302/3/261.pdf

A Network Model of a Cooperative Genetic Landscape in Brain Tumors

Markus Bredel, MD, PhD ; Denise M. Scholtens, PhD ; Griffith R. Harsh, MD ; Claudia Bredel, PhD ; James P. Chandler, MD ; Jaclyn J. Renfrow, MA ; Ajay K. Yadav, PhD ; Hannes Vogel, MD, PhD ; Adrienne C. Scheck, PhD ; Robert Tibshirani, PhD ; Branimir I. Sikic, MD

JAMA. 2009;302(3):261-275.

Context  Gliomas, particularly glioblastomas, are among the deadliest of human tumors. Gliomas emerge through the accumulation of recurrent chromosomal alterations, some of which target yet-to-be-discovered cancer genes. A persistent question concerns the biological basis for the coselection of these alterations during gliomagenesis.

Objectives  To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance.

Design, Setting, and Patients  Multidimensional genomic profiles and clinical profiles of 501 patients with gliomas (45 tumors in an initial discovery set collected between 2001 and 2004 and 456 tumors in validation sets made public between 2006 and 2008) from multiple academic centers in the United States and The Cancer Genome Atlas Pilot Project (TCGA).

Main Outcome Measures  Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival.

Results  Gliomas select for a nonrandom genetic landscape—a consistent pattern of chromosomal alterations—that involves altered regions ("territories") on chromosomes 1p, 7, 8q, 9p, 10, 12q, 13q, 19q, 20, and 22q (false-discovery rate–corrected P<.05). A network model shows that these territories harbor genes with putative synergistic, tumor-promoting relationships. The coalteration of the most interactive of these genes in glioblastoma is associated with unfavorable patient survival. A multigene risk scoring model based on 7 landscape genes (POLD2, CYCS, MYC, AKR1C3, YME1L1, ANXA7, and PDCD4) is associated with the duration of overall survival in 189 glioblastoma samples from TCGA (global log-rank P = .02 comparing 3 survival curves for patients with 0-2, 3-4, and 5-7 dosage-altered genes). Groups of patients with 0 to 2 (low-risk group) and 5 to 7 (high-risk group) dosage-altered genes experienced 49.24 and 79.56 deaths per 100 person-years (hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.10-2.40; Cox regression model P = .02), respectively. These associations with survival are validated using gene expression data in 3 independent glioma studies, comprising 76 (global log-rank P = .003; 47.89 vs 15.13 deaths per 100 person-years for high risk vs low risk; Cox model HR, 3.04; 95% CI, 1.49-6.20; P = .002) and 70 (global log-rank P = .008; 83.43 vs 16.14 deaths per 100 person-years for high risk vs low risk; HR, 3.86; 95% CI, 1.59-9.35; P = .003) high-grade gliomas and 191 glioblastomas (global log-rank P = .002; 83.23 vs 34.16 deaths per 100 person-years for high risk vs low risk; HR, 2.27; 95% CI, 1.44-3.58; P<.001).

Conclusions  The alteration of multiple networking genes by recurrent chromosomal aberrations in gliomas deregulates critical signaling pathways through multiple, cooperative mechanisms. These mutations, which are likely due to nonrandom selection of a distinct genetic landscape during gliomagenesis, are associated with patient prognosis.