Tsui Ivy F L, Poh Catherine F, Garnis Cathie, Rosin Miriam P, Zhang Lewei, Lam Wan L
Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
Int J Cancer. 2009 Nov 1;125(9):2219-28. doi: 10.1002/ijc.24611.
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 7 recurrent amplicons were evaluated in 5 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 = 8.95 x 10(-3) to 3.18 x 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, whereas 43.5% (10/23) of OSCCs were found to have altered genes within the pathways with DNA amplification. Multitarget FISH showed that amplification of EGFR and CCND1 can coexist 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.
口腔癌前病变（OPL）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。我们研究DNA扩增是否发生在癌症发展的这一早期阶段，以及哪些致癌途径在OPL中被破坏。在这里，我们使用平铺路径DNA微阵列评估了50例后来进展为癌症的高级别发育异常和低级别发育异常的基因剂量畸变。经常检测到DNA扩增和纯合缺失的早期发生情况，这些早期病变中有40%（20/50）表现出此类特征。在5个独立的头颈癌数据集中评估了7个反复扩增区域中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PI3K/AKT信号通路中显著富集（p = 8.95×10⁻³至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例未进展的低级别发育异常中未发现此类改变，而在43.5%（10/23）的OSCC中发现途径内的基因因DNA扩增而改变。多靶点FISH显示，EGFR和CCND1的扩增可在口腔发育异常的单个细胞中共存，提示OPL进展依赖多种癌基因。综上所述，这些发现确定了一个在高危OPL中经常被破坏的关键生物网络，不同个体中不同的特定基因被破坏。
