In Mouse ID7, and a parallel increase in BUB1 transcription in Mouse ID12. Thus, the two mice had similar but different changes in transcription that could lead to genome instability. Although both p53 and pRB are considered to be essential “guardians of the genome”, they are frequently overexpressed in human tumors, and overexpression of p53 or pRB is 25033180 often associated with poor prognosis [24,25]. We note that Mouse ID7 had increased transcription of p53, whereas Mouse ID12 had increased transcription of pRBL1. To summarize, 
the tumors from both Mouse ID7 and Mouse ID12 showed changes that were consistent with the hallmarks of cancer. Some of the transcriptional changes were shared, but many were specific to the individual mice.In Docosahexaenoyl ethanolamide site looking at the overall transcriptional patterns in the tumor, we are looking at a snapshot of the transcriptional activity at a given time (normal tail, papilloma or carcinoma). Although it is believed that tumor development is driven by a small number of “order Imazamox driver” mutations, thousands of “passenger” mutations are found by the time a tumor is detected. In the microarray analysis, we looked at overall changes in cellular activity, whether these were caused by drivers or by passengers. We saw extensive differences between all 31 mice, both in overall transcriptional changes and in the cellular functions that were significantly changed in each mouse. Mouse ID7 and Mouse ID12 showed very different overall patterns of transcriptional change between carcinoma and normal skin (Figure 5). Yet, the detailed analysis of Mouse ID7 and Mouse ID12 provided a rational explanation for their shared cancer phenotype. When we analyzed the hallmarks of cancer [20,21] we found that these were enhanced in both mice, both via shared pathways and via pathways that were unique to each mouse. These findings are all the more surprising when one considers that the mice analyzed were extremely closely related to one another, and that the cancers were all caused by an identical treatment regime. In humans, of course, neither of these conditions pertains. Therefore, the degree of heterogeneity between human tumors is expected to be much greater. Our data emphasize the need for individualized cancer therapy. Individualized therapy requires appropriate tumor characterization, and the ability to choose tailored treatment that is appropriate to the molecular aberrations in the specific tumor. To summarize, we found that mice sharing very similar genetic background, living in the same environment and treated with the same carcinogens develop the same kind of cancer, squamous cell carcinoma, but via different molecular mechanisms. We show that in each mouse different genes can participate in the hallmarks that lead to the tumorigenic phenotype, such that each tumor has a unique pattern of gene expression.Supporting InformationTable S1 A: DAVID annotations that were increased between normal skin and carcinoma (C/N) according 16574785 to “heterogeneity analysis.” B: DAVID annotations that were decreased between normal skin and carcinoma (C/N) according to “heterogeneity analysis.” (DOCX) Table S2 Genes increased in at least 4-fold change between normal skin and carcinoma in Mouse ID7 and Mouse ID12. (DOCX) Table S3 Genes that were increased in at least 4-fold change and were involved in “Cytokine-cytokine receptor interaction” according to KEGG in mouse ID7 and mouse ID12. (DOCX) Table S4 Genes that were increased in at least 4-fold change and w.In Mouse ID7, and a parallel increase in BUB1 transcription in Mouse ID12. Thus, the two mice had similar but different changes in transcription that could lead to genome instability. Although both p53 and pRB are considered to be essential “guardians of the genome”, they are frequently overexpressed in human tumors, and overexpression of p53 or pRB is 25033180 often associated with poor prognosis [24,25]. We note that Mouse ID7 had increased transcription of p53, whereas Mouse ID12 had increased transcription of pRBL1. To summarize, the tumors from both Mouse ID7 and Mouse ID12 showed changes that were consistent with the hallmarks of cancer. Some of the transcriptional changes were shared, but many were specific to the individual mice.In looking at the overall transcriptional patterns in the tumor, we are looking at a snapshot of the transcriptional activity at a given time (normal tail, papilloma or carcinoma). Although it is believed that tumor development is driven by a small number of “driver” mutations, thousands of “passenger” mutations are found by the time a tumor is detected. In the microarray analysis, we looked at overall changes in cellular activity, whether these were caused by drivers or by passengers. We saw extensive differences between all 31 mice, both in overall transcriptional changes and in the cellular functions that were significantly changed in each mouse. Mouse ID7 and Mouse ID12 showed very different overall patterns of transcriptional change between carcinoma and normal skin (Figure 5). Yet, the detailed analysis of Mouse ID7 and Mouse ID12 provided a rational explanation for 
their shared cancer phenotype. When we analyzed the hallmarks of cancer [20,21] we found that these were enhanced in both mice, both via shared pathways and via pathways that were unique to each mouse. These findings are all the more surprising when one considers that the mice analyzed were extremely closely related to one another, and that the cancers were all caused by an identical treatment regime. In humans, of course, neither of these conditions pertains. Therefore, the degree of heterogeneity between human tumors is expected to be much greater. Our data emphasize the need for individualized cancer therapy. Individualized therapy requires appropriate tumor characterization, and the ability to choose tailored treatment that is appropriate to the molecular aberrations in the specific tumor. To summarize, we found that mice sharing very similar genetic background, living in the same environment and treated with the same carcinogens develop the same kind of cancer, squamous cell carcinoma, but via different molecular mechanisms. We show that in each mouse different genes can participate in the hallmarks that lead to the tumorigenic phenotype, such that each tumor has a unique pattern of gene expression.Supporting InformationTable S1 A: DAVID annotations that were increased between normal skin and carcinoma (C/N) according 16574785 to “heterogeneity analysis.” B: DAVID annotations that were decreased between normal skin and carcinoma (C/N) according to “heterogeneity analysis.” (DOCX) Table S2 Genes increased in at least 4-fold change between normal skin and carcinoma in Mouse ID7 and Mouse ID12. (DOCX) Table S3 Genes that were increased in at least 4-fold change and were involved in “Cytokine-cytokine receptor interaction” according to KEGG in mouse ID7 and mouse ID12. (DOCX) Table S4 Genes that were increased in at least 4-fold change and w.
