Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma
Integrative analysis of array-comparative genomic hybridisation and matched gene expression profiling data reveals novel genes with prognostic significance in oesophageal adenocarcinoma
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DOI：
10.1136/gut.2010.234179
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发表时间：
2011-10-01
期刊：
影响因子：
24.5
通讯作者：
Fitzgerald, R. C.
中科院分区：
文献类型：
--
作者：
Goh, X. Y.;Rees, J. R. E.;Fitzgerald, R. C.
背景和目的 食管腺癌 (OAC) 的发病率一直在迅速增加，生存率低至不足 20%。了解这种癌症的基因组畸变和生物学可能会增强疾病干预措施。本研究旨在利用全基因组基因组和表达数据来增强对 OAC 发病机制的理解并识别具有差异结果的群体。方法对 56 个新鲜冷冻 OAC 切除样本进行长期临床随访数据的阵列比较基因组杂交 (aCGH) 分析。使用全基因组单核苷酸多态性阵列进一步分析存在畸变的样本，以证实 aCGH 的发现。匹配的基因表达微阵列数据用于识别具有高拷贝数表达相关性的基因。使用来自显微解剖样本的 DNA 的巢式多重 PCR 和荧光原位杂交测定来进行目标验证。使用同一队列和独立样本 (n=371) 的免疫组织化学进行后续验证。 Kaplan-Meier 生存分析基于无监督 K 均值聚类（K=5、50 次迭代）和免疫组织化学数据后的 aCGH 数据进行。 结果 aCGH 识别出 17 个常见的增益区域（>5% 样本）和 11 个常见的损失区域，包括 OAC 中的新区域（基因座 11p13 和 21q21.2）。 aCGH 数据与匹配的基因表达微阵列数据的整合突出显示了具有高拷贝数表达相关性的基因：两个缺失（p16/CDKN2A、MBNL1）和四个增益（EGFR、WT1、NEIL2、MTMR9）。免疫组织化学显示靶标蛋白过度表达并获得增益：EGFR (10%)、WT1 (20%)、NEIL2 (14%) 和 MTMR9 (25%)。这些目标分别（p
Background and aims The incidence of oesophageal adenocarcinoma (OAC) has been increasing rapidly with a dismal survival rate of less than 20%. Understanding the genomic aberrations and biology of this cancer may enhance disease interventions. This study aimed to use genome-wide genomic and expression data to enhance the understanding of OAC pathogenesis and identify groups with differential outcomes.Methods Array-comparative genomic hybridisation (aCGH) analysis was carried out on 56 fresh frozen OAC resection samples with long-term clinical follow-up data. Samples with aberrations were further analysed with whole-genome single-nucleotide polymorphism arrays to confirm aCGH findings. Matched gene expression microarray data were used to identify genes with high copy number-expression correlations. Nested-multiplex PCR on DNA from microdissected specimens and fluorescence in situ hybridisation assays were used for target validation. Immunohistochemistry on the same cohort and independent samples (n=371) was used for subsequent validation. Kaplan-Meier survival analyses were performed based on aCGH data after unsupervised K-means clustering (K=5, 50 iterations) and immunohistochemistry data.Results aCGH identified 17 common regions (>5% samples) of gains and 11 common regions of losses, including novel regions in OAC (loci 11p13 and 21q21.2). Integration of aCGH data with matched gene expression microarray data highlighted genes with high copy number-expression correlations: two deletions (p16/CDKN2A, MBNL1) and four gains (EGFR, WT1, NEIL2, MTMR9). Immunohistochemistry demonstrated protein over-expression of targets with gains: EGFR (10%), WT1 (20%), NEIL2 (14%) and MTMR9 (25%). These targets individually (p