Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.
Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.
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DOI：
10.1001/jama.2009.1022
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发表时间：
2009-07-15
影响因子：
120.7
通讯作者：
Bredel, Markus
中科院分区：
文献类型：
--
作者：
Yadav, Ajay K.;Renfrow, Jaclyn J.;Scholtens, Denise M.;Xie, Hehuang;Duran, George E.;Bredel, Claudia;Vogel, Hannes;Chandler, James P.;Chakravarti, Arnab;Robe, Pierre A.;Das, Sunit;Scheck, Adrienne C.;Kessler, John A.;Soares, Marcelo B.;Sikic, Branimir I.;Harsh, Griffith R.;Bredel, Markus
胶质母细胞瘤-一致致命的脑肿瘤-通常既有10号染色体的单体，又有7号染色体上的表皮生长因子受体(EGFR)基因位点的获得，这种联系的机制尚不清楚。探讨在胶质母细胞瘤中EGFR在7p12和单体10上的共选择是否通过丢失10q21.1-q21.2上的膜联蛋白A7(ANXA7)基因来促进致瘤表皮生长因子(EGF)信号转导，以及ANXA7是否通过调节胶质母细胞瘤中的EGFR而发挥肿瘤抑制基因的作用。多维分析基因、编码序列、启动子甲基化、信使RNA(MRNA)转录本、ANXA7(和EGFR)的蛋白质数据，以及来自美国医学中心和癌症基因组图谱试点项目(2006-2008年公布；以及2001-2008年收集的未发表的肿瘤)的543例高级别胶质瘤的临床患者数据概况。使用LN229和U87胶质母细胞瘤细胞进行功能分析。ANXA7基因剂量、编码序列、启动子甲基化、mRNA转录本和蛋白表达之间的关系。ANXA7单倍体缺陷对EGFR信号转导和患者生存的影响。ANXA7缺失和EGFR表达增强在肿瘤发生中的联合作用与ANXA7野生型胶质母细胞瘤相比，ANXA7基因杂合性缺失与ANXA7mRNA转录表达显著降低(P=1×10−15；线性回归)和ANXA7蛋白表达降低91.5%(2.3%)相关(P=0.004；非配对t检验)。ANXA7功能的丧失稳定了胶质母细胞瘤细胞中的EGFR蛋白(EGFR蛋白丰度增加了72%-744%)，并增强了EGFR转化信号。ANXA7单倍体缺陷使胶质母细胞瘤细胞的致瘤潜能加倍，ANXA7基因敲除和EGFR过表达联合应用可协同促进肿瘤的发生。在肿瘤基因组图谱中，≈中75%的胶质母细胞瘤中ANXA7杂合性丢失，加上ANXA7突变的罕见频率(≈6%的肿瘤)，表明它是一个单倍体不足的基因。在191个胶质母细胞瘤中，ANXA7mRNA转录本的表达与患者的生存相关(对数等级P=0.008；风险比[HR]，0.667；95%可信区间[CI]，0.493-0.902；高与低ANXA7mRNA表达的46.9vs 74.8死亡/100人年)，以及180个高级别胶质瘤的单独组(对数等级P=0.00003；HR，0.476；95%CI，0.333-0.680；21.8vs50.0死亡/100人年与低ANXA7mRNA表达)。在189Gb胶质母细胞瘤中，ANXA7基因缺失与患者的生存不良有关(对数等级P=.042；HR，0.686；95%CI，0.476-0.989；野生型ANXA7与ANXA7缺失的死亡率分别为54.0vs80.1/100人年)。由于10号染色体单体导致的肿瘤抑制基因ANXA7的单倍性不足，为胶质母细胞瘤中EGFR信号的增强提供了一种临床上相关的机制，而不是EGFR基因的扩增。
Glioblastomas—uniformly fatal brain tumors—often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood. To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1–q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas. Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006–2008; and unpublished, tumors collected 2001–2008). Functional analyses using LN229 and U87 glioblastoma cells. Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis. Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P=1×10−15; linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P=.004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%–744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in≈75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (≈6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P=.008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493–0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P=.00003; HR, 0.476; 95% CI, 0.333–0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P=.042; HR, 0.686; 95% CI, 0.476–0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion). Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene.
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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：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
影响因子：
5.3
作者：
Dimri, GP;Itahana, K;Campisi, J
通讯作者：
Campisi, J
DOI：
10.1073/pnas.90.18.8392
发表时间：
1993-09-15
影响因子：
11.1
作者：
PEAR, WS;NOLAN, GP;BALTIMORE, D
通讯作者：
BALTIMORE, D
影响因子：
4.8
作者：
Furge, LL;Chen, K;Cohen, S
通讯作者：
Cohen, S