Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, Maryland, USA.
BMC Genomics. 2010 Oct 18;11:576. doi: 10.1186/1471-2164-11-576.
Genomic instability plays an important role in human cancers. We previously characterized genomic instability in esophageal squamous cell carcinomas (ESCC) in terms of loss of heterozygosity (LOH) and copy number (CN) changes in tumors using the Affymetrix GeneChip Human Mapping 500K array in 30 cases from a high-risk region of China. In the current study we focused on copy number neutral (CN = 2) LOH (CNNLOH) and its relation to gene expression in ESCC.
Overall we found that 70% of all LOH observed was CNNLOH. Ninety percent of ESCCs showed CNNLOH (median frequency in cases = 60%) and this was the most common type of LOH in two-thirds of cases. CNNLOH occurred on all 39 autosomal chromosome arms, with highest frequencies on 19p (100%), 5p (96%), 2p (95%), and 20q (95%). In contrast, LOH with CN loss represented 19% of all LOH, occurred in just half of ESCCs (median frequency in cases = 0%), and was most frequent on 3p (56%), 5q (47%), and 21q (41%). LOH with CN gain was 11% of all LOH, occurred in 93% of ESCCs (median frequency in cases = 13%), and was most common on 20p (82%), 8q (74%), and 3q (42%). To examine the effect of genomic instability on gene expression, we evaluated RNA profiles from 17 pairs of matched normal and tumor samples (a subset of the 30 ESCCs) using Affymetrix U133A 2.0 arrays. In CN neutral regions, expression of 168 genes (containing 1976 SNPs) differed significantly in tumors with LOH versus tumors without LOH, including 101 genes that were up-regulated and 67 that were down-regulated.
Our results indicate that CNNLOH has a profound impact on gene expression in ESCC, which in turn may affect tumor development.
基因组不稳定性在人类癌症中起着重要作用。我们之前使用 Affymetrix GeneChip Human Mapping 500K 阵列在来自中国高危地区的 30 例食管鳞癌 (ESCC) 中对肿瘤的杂合性丢失 (LOH) 和拷贝数 (CN) 变化进行了基因组不稳定性的特征描述。在当前研究中，我们主要关注拷贝数中性 (CN = 2) 的 LOH (CNNLOH) 及其与 ESCC 基因表达的关系。
总体而言，我们发现观察到的所有 LOH 中有 70%是 CNNLOH。90%的 ESCC 表现出 CNNLOH（病例中的中位数频率为 60%），这是三分之二病例中最常见的 LOH 类型。CNNLOH 发生在所有 39 条常染色体臂上，19p（100%）、5p（96%）、2p（95%）和 20q（95%）上的频率最高。相比之下，具有 CN 缺失的 LOH 占所有 LOH 的 19%，仅在一半的 ESCC 中发生（病例中的中位数频率为 0%），并且在 3p（56%）、5q（47%）和 21q（41%）上最为常见。具有 CN 增益的 LOH 占所有 LOH 的 11%，发生在 93%的 ESCC 中（病例中的中位数频率为 13%），并且在 20p（82%）、8q（74%）和 3q（42%）上最为常见。为了研究基因组不稳定性对基因表达的影响，我们使用 Affymetrix U133A 2.0 阵列评估了来自 17 对匹配的正常和肿瘤样本（30 例 ESCC 的一个子集）的 RNA 谱。在 CN 中性区域中，与无 LOH 的肿瘤相比，在有 LOH 的肿瘤中，168 个基因（包含 1976 个 SNP）的表达有显著差异，其中 101 个基因上调，67 个基因下调。
我们的结果表明，CNNLOH 对 ESCC 中的基因表达有深远影响，进而可能影响肿瘤的发展。
