Ata are not unexpected, since signal transduction includes oncogenic and tumor suppressive processes. In summary, in the analysis of the individual mice, it became clear that even annotations with a clear relevance to cancer were significant in only some of the mice. Moreover, even among the mice for which a given 
annotation was significant, some mice showed overall positive regulation of the annotation, whereas others showed negative regulation of the same annotation. This compounds further the finding of heterogeneity between individual mice with the same tumors.normal, to get the most prominent changes. Figure 4 shows heatmaps for all 31 mice, of all of the transcripts that showed at least a four-fold change in the “58-49-1 cost average analysis”. It can clearly be seen that each of the mice has a unique pattern of transcriptional changes between C/N. In the “heterogeneity analysis”, for each annotation, we looked at the ratios between the expression value of each transcript in carcinoma and normal in each mouse separately. This analysis emphasizes the differences between the mice (see below). We compared the annotations from the two analyses that were denoted as significant. There were pronounced, biologically relevant differences between the analyses (Table 1 and 2). At the gene level, there were several cancer-related genes that were identified in a majority of the mice according to the heterogeneity analysis, but were not identified by the “average analysis” (Table 1 and 2). For example AKT1, a major anti-apoptotic gene, was not identified in the average analysis. In the heterogeneity analysis, AKT1 was prominent: it was induced in 10 mice, out of the 14 mice in which the DAVID annotation “regulation of Acid Yellow 23 programmed cell death” was significant. On the other hand, TP53 was identified in the average analysis, but was only altered in 5 of 14 mice in which “regulation of programmed cell death” was significant (Table 1). Similarly, for the annotation “cell cycle”, 8 genes that were significantly increased between C/ N in more than half of the mice were not identified by the average analysis. Three genes that were significant in the average analysis were significantly induced in less than half of the mice (Table 2). These data demonstrate that small effects in a large number of samples can be ignored by the average analysis, whereas extreme changes in a minority of samples can have an undue effect on the average analysis. The mouse-by-mouse analysis gives a more informative 
picture of the significant changes, although it is of course much more tedious than the average analysis.Differences between “average analysis” and “heterogeneity analysis”In the “average analysis” we took into account all the biological replicates of the same time point (e.g. carcinoma) and averaged them to get one value. We then examined the changes in gene expression level between the averaged value of carcinoma andHeterogeneity in cancer hallmarks: Comparison of two miceIn order to examine the role of heterogeneity in tumor progression in the individual mice, we looked at the specific transcripts that were significantly up-regulated or down-regulated between carcinoma and normal skin. For this purpose, we inserted a list of the significant genes for each mouse into the KEGGHeterogeneous Gene Expression in SCC Developmentdatabase. Only 49 genes were up-regulated and 37 genes were down-regulated in carcinoma vs. normal in all 31 mice. In each KEGG pathway, ther.Ata are not unexpected, since signal transduction includes oncogenic and tumor suppressive processes. In summary, in the analysis of the individual mice, it became clear that even annotations with a clear relevance to cancer were significant in only some of the mice. Moreover, even among the mice for which a given annotation was significant, some mice showed overall positive regulation of the annotation, whereas others showed negative regulation of the same annotation. This compounds further the finding of heterogeneity between individual mice with the same tumors.normal, to get the most prominent changes. Figure 4 shows heatmaps for all 31 mice, of all of the transcripts that showed at least a four-fold change in the “average analysis”. It can clearly be seen that each of the mice has a unique pattern of transcriptional changes between C/N. In the “heterogeneity analysis”, for each annotation, we looked at the ratios between the expression value of each transcript in carcinoma and normal in each mouse separately. This analysis emphasizes the differences between the mice (see below). We compared the annotations from the two analyses that were denoted as significant. There were pronounced, biologically relevant differences between the analyses (Table 1 and 2). At the gene level, there were several cancer-related genes that were identified in a majority of the mice according to the heterogeneity analysis, but were not identified by the “average analysis” (Table 1 and 2). For example AKT1, a major anti-apoptotic gene, was not identified in the average analysis. In the heterogeneity analysis, AKT1 was prominent: it was induced in 10 mice, out of the 14 mice in which the DAVID annotation “regulation of programmed cell death” was significant. On the other hand, TP53 was identified in the average analysis, but was only altered in 5 of 14 mice in which “regulation of programmed cell death” was significant (Table 1). Similarly, for the annotation “cell cycle”, 8 genes that were significantly increased between C/ N in more than half of the mice were not identified by the average analysis. Three genes that were significant in the average analysis were significantly induced in less than half of the mice (Table 2). These data demonstrate that small effects in a large number of samples can be ignored by the average analysis, whereas extreme changes in a minority of samples can have an undue effect on the average analysis. The mouse-by-mouse analysis gives a more informative picture of the significant changes, although it is of course much more tedious than the average analysis.Differences between “average analysis” and “heterogeneity analysis”In the “average analysis” we took into account all the biological replicates of the same time point (e.g. carcinoma) and averaged them to get one value. We then examined the changes in gene expression level between the averaged value of carcinoma andHeterogeneity in cancer hallmarks: Comparison of two miceIn order to examine the role of heterogeneity in tumor progression in the individual mice, we looked at the specific transcripts that were significantly up-regulated or down-regulated between carcinoma and normal skin. For this purpose, we inserted a list of the significant genes for each mouse into the KEGGHeterogeneous Gene Expression in SCC Developmentdatabase. Only 49 genes were up-regulated and 37 genes were down-regulated in carcinoma vs. normal in all 31 mice. In each KEGG pathway, ther.
