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Application of comparative functional genomics to identify best-fit mouse models to study human cancer

Nature Genetics volume 36, pages 1306–1311 (2004)Cite this article

Abstract

Genetically modified mice have been extensively used for analyzing the molecular events that occur during tumor development. In many, if not all, cases, however, it is uncertain to what extent the mouse models reproduce features observed in the corresponding human conditions1,2,3. This is due largely to lack of precise methods for direct and comprehensive comparison at the molecular level of the mouse and human tumors. Here we use global gene expression patterns of 68 hepatocellular carcinomas (HCCs) from seven different mouse models and 91 human HCCs from predefined subclasses4 to obtain direct comparison of the molecular features of mouse and human HCCs. Gene expression patterns in HCCs from Myc, E2f1 and Myc E2f1 transgenic mice were most similar to those of the better survival group of human HCCs, whereas the expression patterns in HCCs from Myc Tgfa transgenic mice and in diethylnitrosamine-induced mouse HCCs were most similar to those of the poorer survival group of human HCCs. Gene expression patterns in HCCs from Acox1−/− mice and in ciprofibrate-induced HCCs were least similar to those observed in human HCCs. We conclude that our approach can effectively identify appropriate mouse models to study human cancers.

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Figure 1: Cluster analysis of mouse HCCs.
Figure 2: Cluster analysis of integrated human and mouse HCC.
Figure 3: Comparison of measurable phenotypes between two subclasses in human and mouse HCC.

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Acknowledgements

We thank R. Simon for discussions and advice on statistical analysis, J.W. Grisham for critical reading of the manuscript, E. Asaki for managing gene expression database and V.M. Factor and E.A. Conner for help with the mouse colonies.

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Authors and Affiliations

  1. Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892-4262, Maryland, USA

    Ju-Seog Lee, In-Sun Chu, Arsen Mikaelyan, Diego F Calvisi, Jeonghoon Heo & Snorri S Thorgeirsson

  2. Department of Pathology, Northwestern University, the Feinberg School of Medicine, Chicago, 60611-3008, Illinois, USA

    Janardan K Reddy

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Correspondence to Snorri S Thorgeirsson.

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Supplementary information

Supplementary Fig. 1

Correlation heat map. (PDF 101 kb)

Supplementary Fig. 2

Hierarchical clustering analysis of survival genes. (PDF 517 kb)

Supplementary Fig. 3

Comparison of predicted outcome. (PDF 38 kb)

Supplementary Fig. 4

Direct comparisons of top 500 orthologous genes. (PDF 43 kb)

Supplementary Fig. 5

Comparison of real-time RT-PCR and microarray experiments. (PDF 25 kb)

Supplementary Table 1

Complete list of 329 orthologous genes. (PDF 31 kb)

Supplementary Table 2

Comparison of mouse HCC and human DLBCL. (PDF 12 kb)

Supplementary Table 3

Comparison of mouse HCC and human ovarian cancer. (PDF 11 kb)

Supplementary Note (PDF 8 kb)

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Lee, JS., Chu, IS., Mikaelyan, A. et al. Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nat Genet 36, 1306–1311 (2004). https://doi.org/10.1038/ng1481

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