Consistent and Differential Genetic Aberrations between Esophageal Dysplasia and Squamous Cell Carcinoma Detected By Array Comparative Genomic Hybridization
Consistent and Differential Genetic Aberrations between Esophageal Dysplasia and Squamous Cell Carcinoma Detected By Array Comparative Genomic Hybridization
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DOI：
10.1158/1078-0432.ccr-12-3753
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发表时间：
2013-11-01
影响因子：
11.5
通讯作者：
Wang, Ming-Rong
中科院分区：
文献类型：
--
作者：
Shi, Zhi-Zhou;Shang, Li;Wang, Ming-Rong
目的：我们的目的是确定在食管鳞状细胞癌（ESCC）和食管异型增生频繁的基因组畸变，并发现重要的拷贝数驱动基因和microRNA（miRNA）在ESCC.Experimental Design：我们进行了基于阵列的比较基因组杂交（阵列CGH）对59 ESCC切除样本和16异型增生活检样本。采用实时荧光定量PCR（RT-PCR）和免疫组化（IHC）分析11q13.3基因的表达。结果：微阵列CGH共检测到11个扩增和8个纯合性缺失。将阵列CGH数据与匹配的基因表达微阵列数据进行综合分析，发现90个过表达基因和24个低表达基因与DNA拷贝数变化一致，其中包括12个拷贝数驱动的miRNA。在食管发育不良，6个增益，4个损失，12个扩增，和4个纯合子缺失检测。7p11.2和11q13.2-11q13.3（CCND 1）的扩增和9p21.3（CDKN 2A）的纯合性缺失在异型增生和癌中是一致的基因组变化。ANO 1在11q13.3在mRNA和蛋白质水平上在肿瘤中过表达，并且较高的mRNA表达与拷贝数增加相关。特别是，与正常食管上皮相比，中度不典型增生中ANO 1表达升高。免疫组化显示ANO 1的过表达与淋巴结转移和临床分期呈正相关。结论：拷贝数异常可作为食管异型增生和食管鳞癌早期诊断的潜在生物标志物。此外，ANO 1可能是食管肿瘤发生的一个候选靶基因。
Purpose: Our aim was to identify frequent genomic aberrations in both esophageal squamous cell carcinoma (ESCC) and esophageal dysplasia and to discover important copy number-driving genes and microRNAs (miRNA) in ESCC.Experimental Design: We conducted array-based comparative genomic hybridization (array CGH) on 59 ESCCresection samples and 16 dysplasia biopsy samples. Expression of genes at 11q13.3 was analyzed by real-time PCR (RT-PCR) and immunohistochemistry (IHC). Integrated analysis was conducted to identify genes or miRNAs with copy number-expression correlations.Results: Array CGH identified 11 amplifications and eight homozygous deletions in ESCC. Integrated analysis of array CGH data with matched gene expression microarray data showed that 90 overexpressed genes and 24 underexpressed genes were consistent with DNA copy number changes, including 12 copy number-driving miRNAs. In esophageal dysplasia, six gains, four losses, 12 amplifications, and four homozygous deletions were detected. Amplifications of 7p11.2 and 11q13.2-11q13.3 (CCND1) and homozygous deletion at 9p21.3 (CDKN2A) were consistent genomic changes in both dysplasia and carcinoma. ANO1 at 11q13.3 was overexpressed at the mRNA and protein levels in tumors, and higher mRNA expression was correlated with the copy number increase. In particular, ANO1 expression was elevated in moderate dysplasia compared with normal esophageal epithelium. IHC revealed that ANO1 overexpression was positively correlated with lymph node metastasis and advanced clinical stage. Knockdown of ANO1 significantly inhibited the proliferation of KYSE30 and KYSE510 cells.Conclusion: Copy number aberrations in both esophageal dysplasia and ESCC may be useful as potential biomarkers for early detection. In addition, ANO1 may be a candidate target gene in esophageal tumorigenesis.