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2007 Scientific Report

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VARI | 2007 Microarray gene expression profiling and bioinformatics High-density SNP genotyping has been performed on some of the specimens registered in our RCC expression database. We are currently focusing on analysis and data mining. Clinically, we continue to subclassify the tumors by correlation with clinicopathological information. One example is the study of the unclassified group of tumors for which the histological diagnosis is “unknown”. We have also identified a specific set of genes that can distinguish chromophobe (malignant) from oncocytoma (benign), two types that share a high degree of similarity in their expression profiles. Our database has proven to be very useful in RCC research, since we can obtain differential expression of any gene in seconds; this has led to numerous collaborations. We are currently combining SNP and expression data to identify novel RCC-related genes. Mouse models of kidney cancer and molecular therapeutic studies We have generated several kidney-specific conditional knock-outs including APC, PTEN, and VHL. The first two knock-outs give rise to renal cysts and tumors, whereas VHL remains neoplasia-free; double knock-outs are also being studied. We have successfully generated nine xenograft RCC models via subcapsular injection that have characteristic clinical features and outcomes. Tumors and serum have been harvested for a baseline data set. We are currently performing in vitro and in vivo studies on several new drugs for kidney cancer. Molecular and cellular studies We use numerous well-characterized kidney cancer cell lines to study the functions of novel kidney cancer–related genes by overexpressing or down-regulating the genes. In addition, we perform cell cycle, proliferation, and migration assays to assess the cellular effects of these genes. These studies are usually coupled with in vivo studies. 57 External Collaborators We have extensive collaborations with researchers and clinicians in the United States and overseas. From left: Zhang, Qian, Massie, Noyes, Westphal, Farber, Kort, Chen, Petillo, Matsuda, Teh

Van Andel Research Institute | Scientific Report Recent Publications Al-sarraf, N., S. Mahmood, J.N. Reif, J. Hinrichsen, B.T. Teh, E. McGovern, P. De Meyts, K.J. O’Byrne, and S.G. Gray. In press. DOK4/IRS-5 expression is altered in clear cell renal cell carcinoma. International Journal of Cancer. Daly, A.F., J.-F. Vanbellinghen, S.K. Khoo, M.-L. Jaffrain-Rea, L.A. Naves, M.A. Guitelman, A. Murat, P. Emy, A.-P. Gimenez-Roqueplo, G. Tamburrano, G. Raverot, A. Barlier, W. De Herder, A. Penfornis, E. Ciccarelli, et al. In press. Aryl hydrocarbon receptor interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. Journal of Clinical Endocrinology and Metabolism. Evans, Andrew J., Ryan C. Russell, Olga Roche, T. Nadine Burry, Jason E. Fish, Vinca W.K. Chow, William Y. Kim, Arthy Saravanan, Mindy A. Maynard, Michelle L. Gervais, Roxana I. Sufan, Andrew M. Roberts, Leigh A. Wilson, Mark Betten, Cindy Vandewalle, et al. 2007. VHL promotes E2 box–dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and Snail. Molecular and Cellular Biology 27(1): 157–169. Furge, Kyle A., Jindong Chen, Julie Koeman, Pamela Swiatek, Karl Dykema, Kseniji Lucin, Richard Kahnoski, Ximing J. Yang, and Bin Tean Teh. 2007. Detection of DNA copy number changes and oncogenic signaling abnormalities from gene expression data reveals MYC activation in high-grade papillary renal cell carcinoma. Cancer Research 67(7): 3171–3176. 58 Furge, K.A., M.H. Tan, K. Dykema, E. Kort, W. Stadler, X. Yao, M. Zhou, and B.T. Teh. 2007. Identification of deregulated oncogenic pathways in renal cell carcinoma: an integrated oncogenomic approach based on gene expression profiling. Oncogene 26(9): 1346–1350. Gad, S., S.H. Lefèvre, S.K. Khoo, S. Giraud, A. Vieillefond, V. Vasiliu, S. Ferlicot, V. Molinié, Y. Denoux, N. Thiounn, Y. Chrétien, A. Méjean, M. Zerbib, G. Benoît, J.M. Hervé, G. Allègre, B. Bressac-de Paillerets, B.T. Teh, and S. Richard. 2007. Mutations in BHD and TP53 genes, but not in HNF1β gene, in a large series of sporadic chromophobe renal cell carcinoma. British Journal of Cancer 96(2): 336–340. Greenman, Christopher, Philip Stephens, Raffaella Smith, Gillian L. Dalgliesh, Christopher Hunter, Graham Bignell, Helen Davies, Jon Teague, Adam Butler, Claire Stevens, Sarah Edkins, Sarah O’Meara, Imre Vastrik, Esther E. Schmidt, Tim Avis, et al. 2007. Patterns of somatic mutation in human cancer genomes. Nature 446(7132): 153–158. Lin, Fan, Ping L. Zhang, Ximing J. Yang, Jianhui Shi, Tom Blasick, Won K. Han, Hanlin L. Wang, Steven S. Shen, Bin T. Teh, and Joseph V. Bonventre. 2007. Human kidney injury molecule-1 (hKIM-1): a useful immunohistochemical marker for diagnosing renal cell carcinoma and ovarian clear cell carcinoma. American Journal of Surgical Pathology 31(3): 371–381. Qian, Chao-Nan, James H. Resau, and Bin Tean Teh. 2007. Prospects for vasculature reorganization in sentinel lymph nodes. Cell Cycle 6(5): 514–517. Wang, Kim L., David M. Weinrach, Chunyan Luan, Misop Han, Fan Lin, Bin Teh, and Ximing J. Yang. 2007. Renal papillary adenoma—a putative precursor of papillary renal cell carcinoma. Human Pathology 38(2): 239–246. Yang, X.J., M. Takahashi, K.T. Schafernak, M.S. Tretiakova, J. Sugimura, N.J. Vogelzang, and B.T. Teh. 2007. Does “granular cell” renal cell carcinoma exist? Molecular and histopathological reclassification. Histopathology 50(5): 678–680. Adley, Brian P., Anita Gupta, Fan Lin, Chunyan Luan, Bin T. Teh, and Ximing J. Yang. 2006. Expression of kidney-specific cadherin in chromophobe renal cell carcinoma and renal oncocytoma. American Journal of Clinical Pathology 126(1): 79–85.

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