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2005 Scientific Report

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Recent Publications

Recent Publications Robertson, Scott A., Jacqueline Schoumans, Brendan D. Looyenga, Jason A. Yuhas, Cassandra R. Zylstra, Julie M. Koeman, Pamela J. Swiatek, Bin T. Teh, and Bart O. Williams. 2005. Spectral karyotyping of sarcomas and fibroblasts derived from Ink4a/Arf-deficient mice reveals chromosomal instability in vitro. International Journal of Oncology 26(3): 629–634. Wu, Lin, Jun Gu, Huadong Cui, Qing-Yu Zhang, Melissa Behr, Cheng Fang, Yan Weng, Kerri Kluetzman, Pamela J. Swiatek, Weizhu Yang, Laurence Kaminsky, and Xinxin Ding. 2005. Transgenic mice with a hypomorphic NADPH-cytochrome P450 reductase gene: effects on development, reproduction, and microsomal cytochrome P450. Journal of Pharmacology and Experimental Therapeutics 312(1): 35–43. Graveel, Carrie, Yanli Su, Julie Koeman, Ling-Mei Wang, Lino Tessarollo, Michelle Fiscella, Carmen Birchmeier, Pamela Swiatek, Roderick Bronson, and George Vande Woude. 2004. Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele. Proceedings of the National Academy of Sciences U.S.A. 101(49): 17198–17203. From left to right: Swiatck, Koeman, Zahatnansky, Sisson 44

Laboratory of Cancer Genetics Bin T. Teh, M.D., Ph.D. Dr. Teh obtained his M.D. from the University of Queensland, Australia, in 1992, and his Ph.D. from the Karolinska Institute, Sweden, in 1997. Before joining the Van Andel Research Institute (VARI), he was an Associate Professor of medical genetics at the Karolinska Institute. Dr. Teh joined VARI as a Senior Scientific Investigator in January 2000. Dr. Teh’s research mainly focuses on kidney cancer, and he is currently on the Medical Advisory Board of the Kidney Cancer Association. He became VARI’s Deputy Director for Research Operations in the fall of 2003 and was promoted to Distinguished Scientific Investigator in 2005. Staff Miles Chao-Nan Qian, M.D., Ph.D. Pengfei Wang, M.D., Ph.D. Xin Yao, M.D., Ph.D. Jindong Chen, Ph.D. Kunihiko Futami, Ph.D. Laboratory Members Sok Kean Khoo, Ph.D. Douglas Luccio-Camelo, Ph.D. David Petillo, Ph.D. Eric Kort, M.S. Stephanie Potter, M.S. Jeff Bates, B.S. Timothy Yaw Bediako, B.S. Mark Betten, B.S. Aaron Massie, B.S. Research Interests Kidney cancer, or renal cell carcinoma (RCC), is the tenth most common cancer in the United States (34,000 new cases and more than 12,000 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 these genes function and interact in giving rise to the tumors and their progression; 2) to identify and develop novel biomarkers and key drug targets; and 3) to generate 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 700 cases) and serum, and a gene expression profiling database of 500 tumors with long-term clinical follow-up information for half of them. Our program includes positional cloning of hereditary RCC syndromes and functional studies of their related genes, microarray and bioinformatic analysis, and generation of RCC mouse models. Hereditary RCC syndromes – positional cloning and functional studies Following the identification of the HRPT2, BHD, and two familial RCC breakpoint genes (NORE1 and LSAMP) by us and others, we are now focusing on functional studies of these genes, including generating mouse models that harbor mutations of these genes (see below). We established the role of HRPT2 in parathyroid carcinoma by mutation analysis and immunohistochemical staining. We have shown that its protein, parafibromin, accumulates predominantly in the nucleus, and this nuclear localization is essential to maintaining its antiproliferative function. Microarray gene expression profiling and bioinformatics Based on microarray profiling of 400 kidney tumors using both our own spotted arrays and Affymetrix microarrays, we have identified the molecular signatures for 1) different subtypes of kidney tumors; 2) the prognosis for clear cell RCC and papillary RCC; and 3) the prediction of drug response (immunotherapy). Our studies have been validated by RT-PCR and immunohistochemical staining. We have also been working closely with VARI’s Kyle Furge in analyzing our microarray data. Using a program developed by his team, comparative genomic microarray analysis (CGMA), we correlated gene expression profiles with the predicted chromosomal imbalances for different RCC histological subtypes, which may facilitate our efforts in identifying RCC-related genes from these chromosomal regions. More information and details can be found in several of our review articles and book chapters. 45

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