美国学者研究发现，神经胶质瘤中存在多个基因突变相互作用构成的网络，使细胞信号通道失去调节。在这些基因中，ANXA7基因单倍剂量不足将促进肿瘤生长，影响患者的生存。相关论文发表于《美国医学会杂志》（JAMA 2009，302（3）：261；276）。
第1项研究首先从美国癌症基因组图谱试验计划（TCGA）多重学术中心的501例神经胶质瘤患者的多维基因组图谱和临床表征中发现，多个染色体上隐藏着可协同促进肿瘤生长基因的区域改变。胶质母细胞瘤中这些相互作用基因与患者的生存率低有关。
研究进一步纳入189例神经胶质瘤患者，按照其基因样本中7个主要突变基因数目的不同进行分组，比较其死亡率。结果显示，携带0-2个基因突变（低风险）的病人与携带5-7个基因突变（高风险）的病人相比，年死亡率分别为49.24%和79.56%（P=0.02）。该结果在胶质瘤和胶质母细胞瘤患者中得到进一步证实。
同期发表的另一项研究评估了7个主要突变基因之一的膜联蛋白A7（ANXA7）基因对表皮生长因子受体（EGFR）表达和病人生存的影响。结果显示，ANXA7基因剂量的减少，导致EGFR表达增强，进一步促进肿瘤生长，并使患者生存率下降。当ANXA7单倍剂量不足（一个等位基因突变后，另一个基因不能正常表达——编者注）时，胶质母细胞瘤更容易生长。研究者认为ANXA7基因可能成为将来治疗胶质母细胞瘤的理想靶位。（生物谷Bioon.com）
生物谷推荐原始出处：
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.
