Amplicon mapping and expression profiling identify the fas-associated death domain gene as a new driver in the 11q13.3 amplicon in Laryngeal/Pharyngeal cancer
Amplicon mapping and expression profiling identify the fas-associated death domain gene as a new driver in the 11q13.3 amplicon in Laryngeal/Pharyngeal cancer
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DOI：
10.1158/1078-0432.ccr-07-1247
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发表时间：
2007-11-01
影响因子：
11.5
通讯作者：
Schuuring, Ed
中科院分区：
文献类型：
--
作者：
Gibcus, Johan H.;Menkema, Lorian;Schuuring, Ed
目的：11 q13区域扩增是人类肿瘤中的常见事件，在头颈部鳞状细胞癌中发生率最高（36%）。最近，我们报道了30例11 q13扩增的喉癌和咽癌的扩增子大小由独特的基因组结构决定，导致一组基因而不是单个基因的扩增。实验设计：为了研究哪些基因驱动11 q13扩增子，我们确定了与扩增重叠的最小区域和该扩增子内所有基因的表达水平。使用基于阵列的比较基因组杂交分析，我们检测到一个类似的1.7 Mb的区域，包含13个扩增的基因在超过25的29个癌。定量逆转录-PCR显示，8个潜在的驱动基因，包括，细胞周期蛋白D1，corneumen，Fas相关死亡结构域（FADD）的过度表达，与DNA扩增显着相关。FADD蛋白水平与DNA扩增相关性良好，暗示FADD也是11 q13扩增子中的候选驱动基因。对167例喉癌的分析表明，FADD（P = 0.007）和Ser（194）磷酸化FADD（P = 0.011）表达增加与疾病特异性生存率降低相关。最近报道FADD参与细胞周期调控，并且高水平表达FADD的Ser（194）磷酸化亚型的癌细胞被证明对紫杉醇诱导的细胞周期阻滞更敏感。由于头颈部鳞状细胞癌中11 q13区域的频繁扩增和伴随的FADD过表达，我们假设FADD是筛选可能从紫杉醇为主的放化疗中获益的患者的标志物。
Purpose: Amplification of the 11q13 region is a frequent event in human cancer, The highest incidence (36%) is found in head and neck squamous cell carcinomas. Recently, we reported that the amplicon size in 30 laryngeal and pharyngeal carcinomas with 11q13 amplification is determined by unique genomic structures, resulting in the amplification of a set of genes rather than a single gene.Experimental Design: To investigate which gene(s) drive the 11q13 amplicon, we determined the smallest region of overlap with amplification and the expression levels of all genes within this amplicon.Results: Using array-based comparative genomic hybridization analysis, we detected a region of similar to 1.7 Mb containing 13 amplified genes in more than 25 of the 29 carcinomas. Quantitative reverse transcription-PCR revealed that overexpression of 8 potential driver genes including, cyclin D1, cortactin, and Fas-associated death domain (FADD), correlated significantly with DNA amplification. FADD protein levels correlated well with DNA amplification, implicating that FADD is also a candidate driver gene in the 11q13 amplicon. Analysis of 167 laryngeal carcinomas showed that increased expression of FADD (P = 0.007) and Ser(194) phosphorylated FADD (P = 0.011) were associated with a worse disease-specific survival. FADD was recently reported to be involved in cell cycle regulation, and cancer cells expressing high levels of the Ser(194) phosphorylated isoform of FADD proved to be more sensitive to Taxol-induced cell cycle arrest.Conclusion: Because of the frequent amplification of the 11q13 region and concomitant overexpression of FADD in head and neck squamous cell carcinomas, we hypothesize that FADD is a marker to select patients that might benefit from Taxol-based chemoradiotherapy.