[Show abstract][Hide abstract] ABSTRACT: Whole-genome profiling of gene expression is a powerful tool for identifying cancer-associated genes. Genes differentially expressed between normal and tumorous tissues are usually considered to be cancer associated. We recently demonstrated that the analysis of interindividual variation in gene expression can be useful for identifying cancer associated genes. The goal of this study was to identify the best microarray data-derived predictor of known cancer associated genes.
We found that the traditional approach of identifying cancer genes--identifying differentially expressed genes--is not very efficient. The analysis of interindividual variation of gene expression in tumor samples identifies cancer-associated genes more effectively. The results were consistent across 4 major types of cancer: breast, colorectal, lung, and prostate. We used recently reported cancer-associated genes (2011-2012) for validation and found that novel cancer-associated genes can be best identified by elevated variance of the gene expression in tumor samples.
The observation that the high interindividual variation of gene expression in tumor tissues is the best predictor of cancer-associated genes is likely a result of tumor heterogeneity on gene level. Computer simulation demonstrates that in the case of heterogeneity, an assessment of variance in tumors provides a better identification of cancer genes than does the comparison of the expression in normal and tumor tissues. Our results thus challenge the current paradigm that comparing the mean expression between normal and tumorous tissues is the best approach to identifying cancer-associated genes; we found that the high interindividual variation in expression is a better approach, and that using variation would improve our chances of identifying cancer-associated genes.
[Show abstract][Hide abstract] ABSTRACT: Identification of genes that are differently expressed is a common approach used to analyze genetic mechanisms underlying cancer development. However, recent study results suggest that many such genes relate to a small number of biological functions. We hypothesized that analysis of these functions provides a better understanding of tumor biology than does actual identification of these genes.
We re-analyzed publicly available gene expression data for paired samples of prostate tumor and adjacent normal tissue from the same patients to identify genes differently expressed in individual tumors and then used them to identify the functions.
We found significant interindividual variation in the type and the number of functions. After adjusting for redundancy and nonspecificity of the functional terms, we identified seven functions. Several of them showed a strong association with clinical traits, e.g. age at diagnosis, preoperative prostate-specific antigen concentration, Gleason grade, and biochemical recurrence. Actin cytoskeleton was the function most frequently associated with clinical traits. Of note, the association between function and clinical traits was much stronger than that between the genes differently expressed and those traits.
Different prostate tumors differ in their functional profiles. Functions of differently expressed genes are strongly associated with clinical traits. This suggests that analysis of functions of differently expressed genes may provide a better description of tumor biology than does analysis of the respective genes.
[Show abstract][Hide abstract] ABSTRACT: Identifying genes associated with cancer development is typically accomplished by comparing mean expression values in normal and tumor tissues, which identifies differentially expressed (DE) genes. Interindividual variation (IV) in gene expression is indirectly included in DE gene identification because given the same absolute differences in means, genes with lower variance tend to have lower p-values. We explored the direct use of IV in gene expression to identify candidate genes associated with cancer development. We focused on prostate (PCa) and lung (LC) cancers and compared IV in the expression level of genes shown to be cancer related with that in all other genes in the human genome. Compared with all those other genes, cancer-related genes tended to have greater IV in normal tissues and a greater increase in IV during the transition from normal to tumorous tissue. Genes without significantly different mean expression values between tumor and normal tissues but with greater IV in tumor than in normal tissue (note: the DE-based approach completely ignores those genes) had stronger associations with clinically important features like Gleason score in PCa or tumor histology in LC than all other genes were. Our results suggest that analyzing IV in gene expression level is useful in identifying novel candidate genes associated with cancer development.
Journal of Bioinformatics and Computational Biology 04/2012; 10(2):1241013. DOI:10.1142/S0219720012410132 · 0.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Housekeeping (HK) genes are involved in basic cellular functions and tend to be constitutively expressed across various tissues and conditions. A number of studies have analyzed the value of HK genes as an internal standard for assessing gene expression, but the role of HK genes in cancer development has never been specifically addressed. In this study, we sought to evaluate the expression of HK genes during prostate tumorigenesis. We performed a meta-analysis of gene expression during the transition from normal prostate (NP) to localized prostate cancer (LPC) (i.e., NP > LPC) and from localized to metastatic prostate cancer (MPC) (i.e., LPC > MPC). We found that HK genes are more likely to be differentially expressed during prostate tumorigenesis than is the average gene in the human genome, suggesting that prostate tumorigenesis is driven by modulation of the expression of HK genes. Cell-cycle genes and proliferation markers were up-regulated in both NP > LPC and LPC > MPC transitions. We also found that the genes encoding ribosomal proteins were up-regulated in the NP > LPC and down-regulated in the LPC > MPC transition. The expression of heat shock proteins was up-regulated during the LPC > MPC transition, suggesting that in its advanced stages, prostate tumor is under cellular stress. The results of these analyses suggest that during prostate tumorigenesis, there is a period when the tumor is under cellular stress and, therefore, may be the most vulnerable and responsive to treatment.
International Journal of Cancer 12/2009; 125(11):2603-8. DOI:10.1002/ijc.24680 · 5.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The genetic mechanisms of prostate tumorigenesis remain poorly understood, but with the advent of gene expression array capabilities, we can now produce a large amount of data that can be used to explore the molecular and genetic mechanisms of prostate tumorigenesis.
We conducted a meta-analysis of gene expression data from 18 gene array datasets targeting transition from normal to localized prostate cancer and from localized to metastatic prostate cancer. We functionally annotated the top 500 differentially expressed genes and identified several candidate pathways associated with prostate tumorigeneses.
We found the top differentially expressed genes to be clustered in pathways involving integrin-based cell adhesion: integrin signaling, the actin cytoskeleton, cell death, and cell motility pathways. We also found integrins themselves to be downregulated in the transition from normal prostate tissue to primary localized prostate cancer. Based on the results of this study, we developed a collagen hypothesis of prostate tumorigenesis. According to this hypothesis, the initiating event in prostate tumorigenesis is the age-related decrease in the expression of collagen genes and other genes encoding integrin ligands. This concomitant depletion of integrin ligands leads to the accumulation of ligandless integrin and activation of integrin-associated cell death. To escape integrin-associated death, cells suppress the expression of integrins, which in turn alters the actin cytoskeleton, elevates cell motility and proliferation, and disorganizes prostate histology, contributing to the histologic progression of prostate cancer and its increased metastasizing potential.
The results of this study suggest that prostate tumor progression is associated with the suppression of integrin-based cell adhesion. Suppression of integrin expression driven by integrin-mediated cell death leads to increased cell proliferation and motility and increased tumor malignancy.
BMC Medical Genomics 09/2009; 2(1):48. DOI:10.1186/1755-8794-2-48 · 3.91 Impact Factor