美國學(xué)者研究發(fā)現(xiàn),，神經(jīng)膠質(zhì)瘤中存在多個(gè)基因突變相互作用構(gòu)成的網(wǎng)絡(luò),，使細(xì)胞信號(hào)通道失去調(diào)節(jié),。在這些基因中,，ANXA7基因單倍劑量不足將促進(jìn)腫瘤生長,，影響患者的生存,。相關(guān)論文發(fā)表于《美國醫(yī)學(xué)會(huì)雜志》（JAMA 2009，302（3）：261,；276）,。
第1項(xiàng)研究首先從美國癌癥基因組圖譜試驗(yàn)計(jì)劃（TCGA）多重學(xué)術(shù)中心的501例神經(jīng)膠質(zhì)瘤患者的多維基因組圖譜和臨床表征中發(fā)現(xiàn)，多個(gè)染色體上隱藏著可協(xié)同促進(jìn)腫瘤生長基因的區(qū)域改變,。膠質(zhì)母細(xì)胞瘤中這些相互作用基因與患者的生存率低有關(guān),。
研究進(jìn)一步納入189例神經(jīng)膠質(zhì)瘤患者，按照其基因樣本中7個(gè)主要突變基因數(shù)目的不同進(jìn)行分組,，比較其死亡率,。結(jié)果顯示，攜帶0-2個(gè)基因突變（低風(fēng)險(xiǎn)）的病人與攜帶5-7個(gè)基因突變（高風(fēng)險(xiǎn)）的病人相比,，年死亡率分別為49.24%和79.56%（P=0.02）,。該結(jié)果在膠質(zhì)瘤和膠質(zhì)母細(xì)胞瘤患者中得到進(jìn)一步證實(shí)。
同期發(fā)表的另一項(xiàng)研究評(píng)估了7個(gè)主要突變基因之一的膜聯(lián)蛋白A7（ANXA7）基因?qū)Ρ砥どL因子受體（EGFR）表達(dá)和病人生存的影響,。結(jié)果顯示,，ANXA7基因劑量的減少，導(dǎo)致EGFR表達(dá)增強(qiáng),，進(jìn)一步促進(jìn)腫瘤生長,，并使患者生存率下降。當(dāng)ANXA7單倍劑量不足（一個(gè)等位基因突變后,，另一個(gè)基因不能正常表達(dá)——編者注）時(shí),，膠質(zhì)母細(xì)胞瘤更容易生長。研究者認(rèn)為ANXA7基因可能成為將來治療膠質(zhì)母細(xì)胞瘤的理想靶位,。（生物谷Bioon.com）
生物谷推薦原始出處：
JAMA. 2009;302(3):261-275.
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
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.
