Hepatocellular Carcinoma Differential Network (SNP profiling of tumor and non-tumor tissue)

Background: In hepatocellular carcinoma (HCC) genes predictive of survival have been found in both adjacent normal (AN) and tumor (TU) tissues. The relationships between these two sets of predictive genes and the general process of tumorigenesis and disease progression remains unclear Methodology/Principal Findings: Here we have investigated HCC tumorigenesis by comparing gene expression (GSE25097), DNA copy number variation and survival using ~250 AN and TU samples representing, respectively, the pre-cancer state, and the result of tumorigenesis. Genes that participate in tumorigenesis were defined using a gene-gene correlation meta-analysis procedure that compared AN versus TU tissues. Genes predictive of survival in AN (AN-survival genes) were found to be enriched in the differential gene-gene correlation gene set indicating that they directly participate in the process of tumorigenesis. Additionally the AN-survival genes were mostly not predictive after tumorigenesis in TU tissue and this transition was associated with and could largely be explained by the effect of somatic DNA copy number variation (sCNV) in cis and in trans. The data was consistent with the variance of AN-survival genes being rate-limiting steps in tumorigenesis and this was confirmed using a treatment that promotes HCC tumorigenesis that selectively altered AN-survival genes and genes differentially correlated between AN and TU. Conclusions/Significance: This suggests that the process of tumor evolution involves rate-limiting steps related to the background from which the tumor evolved where these were frequently predictive of clinical outcome. Additionally treatments that alter the likelihood of tumorigenesis occurring may act by altering AN-survival genes, suggesting that the process can be manipulated. Further sCNV explains a substantial fraction of tumor specific expression and may therefore be a causal driver of tumor evolution in HCC and perhaps many solid tumor types 217 tumor samples from Hepatocellular carcinoma patients were profiled for DNA and expression variation and were compared to available clinical information 184 non-tumor samples from Hepatocellular carcinoma patients were profiled for DNA and expression variation and were compared to available clinical information

研究背景：在肝细胞癌（hepatocellular carcinoma, HCC）中，邻近正常组织（adjacent normal, AN）与肿瘤组织（tumor, TU）中均已鉴定出可预测患者生存的基因。然而，这两组预测基因与肿瘤发生及疾病进展的普遍过程之间的关联仍未明确。
研究方法与主要发现：本研究通过对比约250份分别代表癌前状态的AN样本与肿瘤发生结局的TU样本的基因表达谱（GSE25097）、DNA拷贝数变异与患者生存情况，解析肝细胞癌的肿瘤发生过程。本研究采用比较AN与TU组织的基因间相关性荟萃分析流程，定义参与肿瘤发生的基因。研究发现，AN组织中可预测生存的基因（AN-生存预测基因）在差异基因间相关性基因集里显著富集，表明这些基因直接参与肿瘤发生过程。此外，AN-生存预测基因在肿瘤发生后的TU组织中大多不再具备生存预测能力，这一表达模式转变与体细胞顺式和反式DNA拷贝数变异（somatic DNA copy number variation, sCNV）的效应密切相关，且该现象可在很大程度上由该效应解释。本研究数据支持AN-生存预测基因的表达变异是肿瘤发生过程中的限速步骤，这一结论通过一项可促进肝细胞癌发生的处理实验得到验证，该处理可选择性改变AN-生存预测基因以及AN与TU组织间存在差异相关性的基因。
结论与意义：本研究结果提示，肿瘤演化过程包含与肿瘤起源的背景组织相关的限速步骤，而这些步骤往往可预测临床结局。此外，可改变肿瘤发生概率的治疗手段可能通过调控AN-生存预测基因发挥作用，表明肿瘤发生过程可被干预。进一步研究表明，sCNV可解释肿瘤特异性表达的大部分变异，因此其可能是肝细胞癌乃至多种实体瘤中肿瘤演化的因果驱动因素。本研究对217份肝细胞癌患者的肿瘤样本进行了DNA与表达变异谱分析，并将其与可用的临床信息进行关联对比；同时对184份肝细胞癌患者的非肿瘤样本开展了相同的检测与关联分析。