DNA Microarray Data Analysis

我们探索了与自发癌症发展和化学诱导的癌症发生相关的转录模式。比较了未经治疗的B6C3F1小鼠肺部自发肿瘤的基因表达模式与未经治疗的年龄匹配的对照动物的肺样本。在自发性肿瘤中，与癌症相关的几个典型通路(例如，RhoA和PTEN信号)以及与代谢(例如，嘌呤和锥体代谢)和免疫反应(例如，白介素8和CXCR4信号)相关的通路都发生了改变。小鼠肿瘤与人类非小肺癌基因表达数据集的荟萃分析高度一致。在另一项研究中，我们还发现，与自发性肝细胞癌相比，B6C3F1小鼠暴露于银杏叶提取物后，其转录模式发生了变化，与肿瘤发生、肝细胞癌的发展以及慢性异物和氧化应激有关。 比较自发肿瘤发生中改变的分子途径与化学诱导的肿瘤中的分子途径，使我们能够在正常受试者的背景下探索这两种不同类型癌症进展的分子基础。在这两项研究中，有必要控制混合定向错误发现率，因为我们测试了多个比较，并且在宣布基因上调或下调时存在定向错误的可能性。我们目前正在评估一种在毒素基因组学实验中使用顺序限制推理和混合方向错误发现率标准来最小化样本量的方法。

We have explored transcriptional patterns associated with spontaneous cancer development and chemically-induced carcinogenesis. Gene expression patterns from spontaneous tumors arising in untreated B6C3F1 mouse lungs were compared with samples from lung in untreated age-matched control animals. Several canonical pathways associated with cancer were altered in the spontaneous tumors (e.g., RhoA and PTEN signaling), as well as pathways associated with metabolism (e.g., purine and pyramidine metabolism) and immune response (e.g., interleukin 8 and CXCR4 signaling). Meta-analysis of mouse tumors with human non-small lung cancer gene expression data sets were highly concordant. In another study, we also showed that exposure of B6C3F1 mice to Ginkgo biloba leaf extract involved altered transcriptional patterns associated with oncogenesis, hepatoceulluar carcinoma development and chronic xenobiotic and oxidative stress compared to spontaneous hepatocellular carcinoma. Comparing molecular pathways altered in spontaneous tumorigenesis versus those in chemically-induced tumors permitted us to explore the molecular underpinnings of these two different types of cancer progression in the context of normal subjects. In both studies, it was necessary to control mixed directional false discovery rate due to the fact that we tested for multiple comparisons and there is a potential for directional errors when declaring genes to be up- or downregulated. We are currently evaluating an approach to minimize sample size in toxicogenomics experiments using order-restricted inference and mixed-directional false discovery rate criteria.