Analysis Methods Integrated Tumor Transcriptome And Genetic Susceptibility

Lung cancer and breast cancer are the most common cause of cancer death for both men and women in the world. Recently, lots of studies, which include the pathogenesis and prevention, prognosis, therapy, drug, etc., had been performed to promote the survival. So far, abundant tumor-associated microarray datasets and articles had been accumulated in the public database on the web. With the integrated-analysis technology, we can take advantage of these datasets, extract the valuable data and information, and make some new findings for further investigation.In this article, we performed integrated-analysis, especially the effect size meta-analysis, to investigate the varied pathways between stages in lung adenocarcinoma (LAD), the expression of Axl in the adjacent normal tissues, and with some extend, to test the relationship between the risk of breast cancer and CYP1A1, which was selected from the LAD pathway analysis.Discovery of the progression-associated genes and pathways in LADs has important implications in understanding the molecular mechanism of tumor development. However, few studies had been performed to focus on the changes of pathways in lung adenocarcinoma development using microarray expression profile. We performed an integrated-analysis of 4 LAD microarray datasets, encompassing 353 patients, to reveal differentially expressed genes (DEGs) between normal lung tissues and LAD of different stages. Overall,1838 genes were found to be dys-regulated, and the adipogenesis, circadian rhythm, and Id pathways were significantly changed. Interestingly, most of the genes from the same gene family (such as Interleukin receptor, Matrix metallopeptidase, Histone cluster and Minichromosome maintenance complex component families) were found to be up-regulated (or down-regulated). Real-time PCR (qRT-PCR) and tissue microarray were applied to validate the integrated-analysis result. In the pathway analysis among stages, Oxidative stress, Glycolysis/ Gluconeogenesis and Integrin-mediated cell adhesion pathways, which were involved in cancer cell proliferation and metastasis, were showed to be significantly regulated in stages other than IA. Genes involved in adipogenesis and Id pathways might play important roles in development of LADs. The similar trend of expression of the gene family members suggested coordinate regulation in tumor progression. Throe pathways significantly regulated in stages other than stage IA suggested that genes and pathways conferring invasive character might be activated in the preinvasive stage IB, while the Oxidative stress and the Glycolysis/Gluconeogenesis pathways might have strong connections to cisplatin-based chemotherapy. The insignificantly regulated three pathways in stage IA might be used in early-stage detection of LAD.Pathways involved in metabolism were revealed to be associated with LAD progress in our study. The tumor cells have to derive material and oxygen from the environment, which is related to the metabolism. Tumor microenvironment has been illustrated to exert important role in tumor progression and treatment response. The experiment on cell lines in vitro could not reflect the real status in vivo. So we re-col lected the datasets and performed effect size meta-analysis of 21 microarray datasets on LAD samples to test the differential expression of Axl, Gas6 (the ligand) and MZF1 between normal tissues (or adjacent normal tissues) and tumors. We found that the expression of Axl was significantly overexpressed in adjacent normal tissues, but not in normal tissues, compared with tumors. In the meta-analysis, the comparison between tumors and normal tissues showed a high heterogeneity, while in the comparison tumors vs. adjacent normal tissues lower heterogeneity was observed, which suggested a reliable result. In the survival analysis, the higher expression level of Axl in adjacent normal tissues related to a better survival. Interestingly, no such relationship was found in paired tumors. These implied that the marker gene in adjacent normal tissues might be very valuable in the survival prediction. Axl might be a candidate marker gene in prognosis in the future.To extend the application of meta-analysis technology and the promising pathways, we performed a meta-analysis of 15 articles with conflict conclusions, to investigate the association between breast cancer and the polymorphisms of CYP1A1, an important member of Oxidative stress pathway. Our meta-analysis suggested that 2455 G/G genotype has a trend to reduce the risk of the breast cancer in east-Asian women or in pre-menopausal women on a worldwide population under recessive and additive model, while T3801C had no association to breast cancer. These interim conclusions help to find the specific population with high risk of breast cancer.