A network model of a cooperative genetic landscape in brain tumors.
A network model of a cooperative genetic landscape in brain tumors.
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DOI：
10.1001/jama.2009.997
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发表时间：
2009-07-15
影响因子：
120.7
通讯作者：
Sikic, Branimir I.
中科院分区：
文献类型：
--
作者：
Bredel, Markus;Scholtens, Denise M.;Harsh, Griffith R.;Bredel, Claudia;Chandler, James P.;Renfrow, Jaclyn J.;Yadav, Ajay K.;Vogel, Hannes;Scheck, Adrienne C.;Tibshirani, Robert;Sikic, Branimir I.
胶质瘤，尤其是胶质瘤母细胞瘤，是最致命的人类肿瘤之一。胶质瘤是通过反复的染色体改变的积累而出现的，其中一些针对的是尚未发现的癌症基因。在胶质瘤形成过程中，这些改变的共选择的生物学基础是一个持续存在的问题。描述神经胶质瘤中合作遗传景观的网络模型并评估其临床相关性。来自美国多个学术中心和癌症基因组图谱试点项目（TCGA）的501名胶质瘤患者的多维基因组图谱和临床图谱（在2001年至2004年期间收集的初始发现集中有45个肿瘤，在2006年至2008年期间公开的验证集中有456个肿瘤）。同源基因的鉴定、基因剂量和基因表达的相关性以及多种功能的相互作用；这些基因和病人存活率之间的联系。胶质瘤选择非随机遗传景观-染色体改变的一致模式-涉及染色体1p， 7,8q, 9p, 10, 12q, 13q, 19q， 20和22q上的改变区域（“区域”）（错误发现率校正P< 0.05）。一个网络模型显示，这些区域含有具有协同作用、促肿瘤关系的基因。在胶质母细胞瘤中，这些基因中最相互作用的共改变与不利的患者生存有关。基于7个景观基因（POLD2、CYCS、MYC、AKR1C3、YME1L1、ANXA7和PDCD4）的多基因风险评分模型与TCGA 189例胶质母细胞瘤样本的总生存期相关（比较0-2、3 - 4和5-7剂量改变基因患者的3条生存曲线的全局log-rank P= 0.02）。0 ~ 2个（低危组）和5 ~ 7个（高危组）剂量改变基因组每100人年死亡人数分别为49.24和79.56人（风险比[HR]为1.63；95%可信区间[CI]为1.10-2.40；Cox回归模型P= 0.02）。这些与生存的关联通过3项独立胶质瘤研究的基因表达数据得到验证，包括76例（全局log-rank P= 0.003；高危与低风险每100人年死亡47.89人vs 15.13人；Cox模型HR为3.04；95% CI为1.49-6.20；P= 0.003）和70例（全局log-rank P= 0.008；高危与低风险每100人年死亡83.43人vs 16.14人；HR为3.86；95% CI为1.59-9.35；P= 0.003）高级别胶质瘤和191例胶质母细胞瘤(全局log-rank P= 0.003；每100人年83.23 vs 34.16的死亡率：高风险vs低风险；人力资源,2.27;95% ci, 1.44-3.58；P <措施)。胶质瘤中复发性染色体畸变引起的多个网络基因的改变通过多种合作机制解除了关键信号通路的调节。这些突变可能是由于胶质瘤形成过程中不同遗传景观的非随机选择，与患者预后相关。
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. To describe a network model of a cooperative genetic landscape in gliomas and to evaluate its clinical relevance. 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). Identification of genes with coincident genetic alterations, correlated gene dosage and gene expression, and multiple functional interactions; association between those genes and patient survival. 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). 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.
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影响因子：
9.7
作者：
Leighton, X;Srikantan, V;Srivastava, M
通讯作者：
Srivastava, M
影响因子：
56.9
作者：
Golub, TR;Slonim, DK;Lander, ES
通讯作者：
Lander, ES
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
2.7
作者：
FLEISS, JL;COHEN, J
通讯作者：
COHEN, J
影响因子：
4.8
作者：
Furge, LL;Chen, K;Cohen, S
通讯作者：
Cohen, S