2009 Scientific Report

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Van Andel Research Institute | Scientific Report Research Interests Kidney cancer, or renal cell carcinoma (RCC), is the tenth most common cancer in the United States (51,000 new cases and more than 13,000 deaths a year). Its incidence has been increasing, a phenomenon that cannot be accounted for by the wider use of imaging procedures. We have established a comprehensive and integrated kidney research program, and our major research goals are 1) to identify the molecular signatures of different subtypes of kidney tumors, both hereditary and sporadic, and to understand how genes function and interact in giving rise to the tumors and their progression; 2) to identify and develop diagnostic and prognostic biomarkers for kidney cancer; 3) to identify and study novel and established molecular drug targets and their sensitivity and resistance; and 4) to develop animal models for drug testing and preclinical bioimaging. Our program to date has established a worldwide network of collaborators; a tissue bank containing fresh-frozen tumor pairs (over 1,500 cases) and serum; and a gene expression profiling database of 700 tumors, with long-term clinical follow-up information for half of them. Our program includes molecular subclassification using microarray gene expression profiling and bioinformatic analysis, generation of RCC mouse models, and more recently, molecular therapeutic studies. RCC genomics We have been using high-density single nucleotide polymorphism (SNP) arrays to genotype RCC samples, and by combing this data and the gene expression data (see below), we have identified candidate chromosomal regions and genes that are involved in different subsets of tumors. Gene expression profiling and bioinformatics To date, we have studied over 600 RCC specimens. We are currently focusing on analysis and data mining. Clinically, we continue to subclassify the tumors by correlation with clinicopathological information, including rarer forms of RCC such as translation-related papillary RCC, mixed epithelial and stromal tumors, and adult Wilms. We are also in the process of trying to understand the underlying molecular signatures of some of the so-called unclassified group of tumors for which the histological diagnosis is “unknown”. Our database has proven to be very useful in RCC research, since we can obtain differential expression data for any gene in seconds. Mouse models of kidney cancer and molecular therapeutic studies We have generated several kidney-specific conditional knock-outs including BHD, PTEN, and VHL. The first two knock-outs give rise to renal cysts and tumors including urothelial cancer of the renal pelvis, whereas the VHL knock-out remains neoplasiafree; 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. 48
VARI | 2009 Targeted therapeutic studies We have focused on several targets we identified using gene expression profiling studies. In vitro and in vivo studies are being performed to verify these targets and their role in therapeutics. These include cell-cycle, proliferation, and migration assays to assess the cellular effects of these genes. In vivo studies are performed to understand the involvement of blood vessels in drug response. External Collaborators We have extensive collaborations with researchers and clinicians in the United States and overseas. Recent Publications Furge, K., and B.T. Teh. In press. Genetics of sporadic renal cell carcinoma. In Renal Cell Carcinoma, B.I. Rini and S.C. Campbell, eds. Clinical Oncology series, BC Decker Inc. Van Haaften, G., G.L. Dalgliesh, H. Davies, G. Bigness, C. Greenman, S. Edkins, C. Hardy, S. O’Meara, L. Chen, J. Teague, et al. In press. Somatic mutations of the histone H3K27 demethylase, UTX, in human cancer. Nature Genetics. Howell, Viive M., Anthony Gill, Adele Clarkson, Anne E. Nelson, Robert Dunne, Leigh W. Delbridge, Bruce G. Robinson, Bin T. Teh, Oliver Gimm, and Deborah J. Marsh. 2009. Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma. Journal of Clinical Endocrinology & Metabolism 94(2): 434–441. Hui, Zhouguang, Maria Tretiakova, Zhongfa Zhang, Yan Li, Xiaozhen Wang, Julie Xiaohong Zhu, Yuanhong Gao, Weiyuan Mai, Kyle Furge, Chao-Nan Qian, et al. 2009. Radiosensitization by inhibiting STAT1 in renal cell carcinoma. International Journal of Radiation Oncology Biology Physics 73(1): 288–295. Macher-Goeppinger, Stephan, Sebastian Aulmann, Katrin E. Tagscherer, Nina Wagener, Axel Haferkamp, Roland Penzel, Antje Brauckhoff, Markus Hohenfellner, Jaromir Sykora, Henning Walczak, et al. 2009. Prognostic value of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and TRAIL receptors in renal cell cancer. Clinical Cancer Research 15(2): 650–659. Wang, Y., O. Roche, M.S. Yan, G. Finak, A.J. Evans, J.L. Metcalf, B.E. Hast, S.C. Hanna, B. Wondergem, K.A. Furge, et al. 2009. Regulation of endocytosis via the oxygen-sensing pathway. Nature Medicine 15(3): 319–324. Zhou, Ming, Eric Kort, Philip Hoekstra, Michael Westphal, Cristina Magi-Galluzzi, Linda Sercia, Brian Lane, Brian Rini, Ronald Bukowski, and Bin T. Teh. 2009. Adult cystic nephroma and mixed epithelial and stromal tumor of the kidney are the same disease entity: molecular and histological evidence. American Journal of Surgical Pathology 33(1): 72–80. Camparo, Philippe, Viorel Vasiliu, Vincent Molinié, Jerome Couturier, Karl J. Dykema, David Petillo, Kyle A. Furge, Eva M. Comperat, Marick Laé, Raymonde Bouvier, et al. 2008. Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. American Journal of Surgical Pathology 32(5): 656–670. 49
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