Gibcus Johan H, Menkema Lorian, Mastik Mirjam F, Hermsen Mario A, de Bock Geertruida H, van Velthuysen Marie-Louise F, Takes Robert P, Kok Klaas, Alvarez Marcos Cesar A, van der Laan Bernard F A M, van den Brekel Michiel W M, Langendijk Johannes A, Kluin Philip M, van der Wal Jacqueline E, Schuuring Ed
Department of Pathology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
Clin Cancer Res. 2007 Nov 1;13(21):6257-66. doi: 10.1158/1078-0432.CCR-07-1247.
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.
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.
Using array-based comparative genomic hybridization analysis, we detected a region of approximately 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.
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.
11q13区域的扩增在人类癌症中是常见事件。头颈部鳞状细胞癌的发生率最高（36%）。最近，我们报道了30例伴有11q13扩增的喉癌和咽癌中的扩增子大小由独特的基因组结构决定，导致一组基因而非单个基因的扩增。
为了研究哪些基因驱动11q13扩增子，我们确定了与扩增重叠的最小区域以及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，我们在29例癌症中的25例以上检测到一个约1.7 Mb的区域，其中包含13个扩增基因。定量逆转录PCR显示，包括细胞周期蛋白D1、皮层肌动蛋白和Fas相关死亡结构域（FADD）在内的8个潜在驱动基因的过表达与DNA扩增显著相关。FADD蛋白水平与DNA扩增密切相关，这表明FADD也是11q13扩增子中的候选驱动基因。对167例喉癌的分析表明，FADD表达增加（P = 0.007）和Ser(194)磷酸化的FADD（P = 0.011）与较差的疾病特异性生存率相关。最近有报道称FADD参与细胞周期调控，并且表达高水平Ser(194)磷酸化异构体FADD的癌细胞对紫杉醇诱导的细胞周期停滞更敏感。
由于11q13区域在头颈部鳞状细胞癌中频繁扩增且FADD随之过表达，我们推测FADD是选择可能从基于紫杉醇的放化疗中获益的患者的一个标志物。
