Gene expression is highly correlated on the chromosome level in urinary bladder cancer

Abstract

Objective: Chromosome correlation maps display correlations between gene expression patterns on the same chromosome. Our goal was to map the genes on chromosome regions and to identify correlations through their location on chromosome regions.

Materials and methods: Following microarray analysis we used Ingenuity Pathway Analysis (IPA) to construct gene networks of the co-deregulated genes in bladder cancer. Chromosome mapping, mathematical modeling and data simulations were performed using the WebGestalt and Matlab(®) softwares.

Results: The top deregulated molecules among 129 bladder cancer samples were implicated in the PI3K/AKT signaling, cell cycle, Myc-mediated apoptosis signaling and ERK5 signaling pathways. Their most prominent molecular and cellular functions were related to cell cycle, cell death, gene expression, molecular transport and cellular growth and proliferation. Chromosome correlation maps allowed us to detect significantly co-expressed genes along the chromosomes. We identified strong correlations among tumors of Tα-grade 1, as well as for those of Tα-grade 2, in chromosomes 1, 2, 3, 7, 12 and 19. Chromosomal domains of gene co-expression were revealed for the normal tissues, as well. The expression data were further simulated, exhibiting an excellent fit (0.7 < R(2) < 0.9). The simulations revealed that along the different samples, genes on same chromosomes are expressed in a similar manner.

Conclusions: Gene expression is highly correlated on the chromosome level. Chromosome correlation maps of gene expression signatures can provide further information on gene regulatory mechanisms. Gene expression data can be simulated using polynomial functions.

Keywords: bladder cancer; chromosome correlation maps; data simulations; mathematical modeling; molecular networks.

Figure 1A. Ingenuity analysis of the top pathways affected in differentially expressed genes among 10 bladder cancer and five normal tissue samples (Cohort A). Y-axis is an inverse indication of p-value or significance (A). Gene networks involved in “cell-to-cell signaling and interaction, cellular assembly and organization, cellular function and maintenance” (B), and “cell signaling, molecular transport and nucleic metabolism” (C), generated by IPA for differentially expressed genes between bladder cancer and normal tissue. The selected scoring method was Fisher’s exact test p-value. The threshold value was set at p = 0.05. Red symbols are assigned for upregulated and green for downregulated genes. Node shape corresponds to the functional role of molecules as shown in the legend. Direct or indirect interactions are shown by complete or dashed lines.

Figure 1B and C. See Figure 1A legend.

Figure 2A. Ingenuity analysis of the top pathways affected in differentially expressed genes among 129 bladder cancer and 17 normal tissue samples (Cohort B). Y-axis is an inverse indication of p-value or significance. (A). Gene networks involved in “cell cycle, gene expression and cell death” (B), and “cell morphology, cellular function and maintenance and cell death” (C), generated by IPA for differentially expressed genes between bladder cancer and normal tissue. The selected scoring method was Fisher’s exact teast p-value. The threshold value was set at p = 0.05. Red symbols are assigned for upregulated and green for downregulated genes. Node shape corresponds to the functional role of molecules as shown in the legend. Direct or indirect interactions are shown by complete or dashed lines.

Figure 2B and C. See Figure 2A legend.

Figure 3. Chromosome correlation maps of the DE genes between Tα-grade 1 tumors and control samples, on chromosomes 1, 2, 3, 7, 12 and 19. The X and Y axes represent the individual genes that were differentially expressed between control and Ta-grade 1 tumors.

Figure 4. Simulations of the DE genes with respect to their chromosome location, among Tα-grade 1 tumors and control samples. Each chromosome is presented separately. All genes could be simulated with a third-degree polynomial and R² > 0.99. Axes represent gene expression values of the log₂ ratio of the Ta-grade 1 tumors over control samples, where each axis represents one sample from the tumor subtype (Ta-grade 1 tumor group consisted of three samples).

Figure 5. Chromosome correlation maps for Tα-grade 2 tumors allow visualization of co-expressed genes along all chromosomes.

Figure 6. Simulations of the DE genes with respect to their chromosome location, among Tα-grade 2 tumors and control samples. Each chromosome is presented separately. All genes could be simulated with a third degree polynomial and R² > 0.99. Axes represent gene expression values of the log₂ ratio of the Ta-grade 2 tumors over control samples, where each axis represents one sample from the tumor subtype. Ta-grade 2 consisted of 12 samples in total. The figure includes representative fittings of the samples GSM2526_Ta gr2, GSM2536_Ta gr2 and GSM2507_Ta gr2 for each chromosome respectively.

Figure 7. Chromosome correlation maps for T1-grade 2 tumors allow visualization of co-expressed genes along all chromosomes. The X and Y axes represent the individual genes that were differentially expressed between control samples and T1-grade 2 tumors.