Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias.
Multiple pathways in the FGF signaling network are frequently deregulated by gene amplification in oral dysplasias.
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DOI：
10.1002/ijc.24611
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Lam WL
中科院分区：
文献类型：
--
作者：
Tsui IF;Poh CF;Garnis C;Rosin MP;Zhang L;Lam WL
口腔癌前病变（OPLs）是口腔鳞状细胞癌（OSCC）的前体，其基因改变可能代表疾病发生和发展的关键变化。我们想知道DNA扩增是否发生在癌症发展的早期阶段，以及哪些致癌途径在OPL中被破坏。在这里，我们评估了50个高级别发育不良和低级别发育不良，后来发展为癌症的基因剂量畸变使用平铺路径DNA微阵列。早期发生的DNA扩增和纯合性缺失经常被检测到，40%（20/50）的这些早期病变表现出这样的功能。在5个独立的头颈癌数据集中评估了7个复发扩增子中88个基因的表达，发现40个候选基因相对于正常组织过表达。这些基因在经典的ERK/MAPK、FGF、p53、PTEN和PI 3 K/AKT信号通路中显著富集（P = 8.95 × 10 -3--3.18 × 10 -2）。这些确定的途径在一个信号网络中共享相互作用，并且在30.0%的这些浸润前病变中发现了该网络的扩增介导的失调。在14例没有进展的低度发育不良中没有发现这种改变，而43.5%（10/23）的OSCC在DNA扩增的途径中发现了改变的基因。多靶点FISH显示EGFR和CCND 1的扩增可以在口腔异型增生的单个细胞中共存，提示OPL的进展依赖于多个癌基因。总的来说，这些发现确定了一个关键的生物网络，该网络在高风险OPL中经常被破坏，不同个体中不同的特定基因被破坏。
Genetic alteration in oral premalignant lesions (OPLs), the precursors of oral squamous cell carcinomas (OSCCs), may represent key changes in disease initiation and development. We ask if DNA amplification occurs at this early stage of cancer development and which oncogenic pathways are disrupted in OPLs. Here we evaluated 50 high-grade dysplasias and low-grade dysplasias that later progressed to cancer for gene dosage aberrations using tiling-path DNA microarrays. Early occurrences of DNA amplification and homozygous deletion were frequently detected, with 40% (20/50) of these early lesions exhibiting such features. Expression for 88 genes in seven recurrent amplicons were evaluated in five independent head and neck cancer datasets, with 40 candidates found to be overexpressed relative to normal tissues. These genes were significantly enriched in the canonical ERK/MAPK, FGF, p53, PTEN, and PI3K/AKT signaling pathways (P = 8.95x10-3--3.18×10-2). These identified pathways share interactions in one signaling network, and amplification-mediated deregulation of this network was found in 30.0% of these preinvasive lesions. No such alterations were found in 14 low-grade dysplasias that did not progress, while 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multi-target FISH showed that amplification of EGFR and CCND1 can co-exist in single cells of an oral dysplasia, suggesting the dependence on multiple oncogenes for OPL progression. Taken together, these findings identify a critical biological network that is frequently disrupted in high-risk OPLs, with different specific genes disrupted in different individuals.
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Toyooka, Shinichi