Functional Genomic Analysis Identified Epidermal Growth Factor Receptor Activation as the Most Common Genetic Event in Oral Squamous Cell Carcinoma
Functional Genomic Analysis Identified Epidermal Growth Factor Receptor Activation as the Most Common Genetic Event in Oral Squamous Cell Carcinoma
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DOI：
10.1158/0008-5472.can-08-3199
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Tsai, Fuu-Jen
中科院分区：
文献类型：
--
作者：
Sheu, Jim Jinn-Chyuan;Hua, Chun-Hung;Tsai, Fuu-Jen
应用250K单核苷酸多态性芯片研究口腔鳞状细胞癌(OSCC)的亚染色体改变。29例口腔癌患者中，9例(31%)7p11.2基因扩增频率最高。最小基因组图谱验证了7号染色体上有一个独特的扩增片段，其长度从54.6到55.3Mb，包含SEC61G和表皮生长因子受体(EGFR)。荧光原位杂交、转录组和免疫组织化学分析结果表明，在7p11.2扩增的肿瘤中，EGFR的表达水平上调，而SEC61G的表达水平没有上调，且与DNA拷贝数密切相关。在erbB家族成员中，EGFR(HER1)被发现是在人类和小鼠口腔肿瘤中扩增和高表达最频繁的基因(P<；0.01)。EGFR下游效应基因，包括KRAS、丝裂原活化蛋白激酶1和CCND1，也被发现扩增或突变，导致55%的口腔鳞癌患者EGFR信号被激活。不同EGFR表达水平的头颈部鳞癌细胞对有效的EGFR抑制剂AG1478的抗肿瘤作用表现出不同的敏感性。在小鼠口腔癌模型中，AG1478诱导的EGFR失活显著抑制了肿瘤的发展和进展。我们的数据表明，EGFR信号在口腔癌的发展中很重要，抗EGFR治疗将使在肿瘤中携带7p11.2扩增子的患者受益。[癌症资源2009；69(6)：2568-76]
A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P < 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors. [Cancer Res 2009;69(6):2568-76]