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2005 Scientific Report

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Bioinformatics Special

Bioinformatics Special Program Kyle A. Furge, Ph.D. Dr. Furge received his Ph.D. in biochemistry from the Vanderbilt University School of Medicine in 2000. Prior to obtaining his degree, he worked as a software engineer at YSI, Inc., where he wrote operating systems for embedded computer devices. Dr. Furge did his postdoctoral work in the laboratory of Dr. George Vande Woude and became a Bioinformatics Scientist at VARI in June of 2001. Laboratory Members Staff Karl Dykema, B.A. Research Interests Ashigh-throughput biotechnologies such as DNA sequencing, gene expression microarrays, and genotyping become more available to researchers, analysis of the data produced by these technologies becomes increasingly difficult. Disciplines such as bioinformatics and computational biology have recently emerged to help develop methods that assist in the storage, distribution, integration, and analysis of these data sets. The bioinformatics program at VARI is currently focused on using computational approaches to understand how cancer cells differ from normal cells at the molecular level. In addition, VARI is also part of the overall bioinformatics effort in the state of Michigan through the Michigan Center for Biological Information. Laboratory members from the bioinformatics program have worked on a wide variety of projects to further the research efforts at VARI in 2004. Recently, we constructed a program to identify short sequences within genes that are likely to be responsive to siRNA interference. siRNAs are short, double-stranded DNA sequences that when introduced into living cells bind to the RNA produced from a gene of interest and inhibit expression of the gene. As such, the introduction of siRNAs is becoming a more widely used technique to examine the role of individual genes in both cancerous and noncancerous cells. The program we developed contained a new algorithm, developed by one of the VARI investigators, to identify potential sites within genes that would be sensitive to siRNAs. In another project, we assisted the Microarray Technology Laboratory in the placement of quality control markers on gene expression microarrays. These microarrays contain more than 20,000 unique DNA fragments that are robotically placed on a small glass slide. In order to ensure the DNA fragments are placed correctly, the quality control markers are robotically placed on the arrays in a very specific pattern as the arrays are constructed. As each array is produced, a quick visual inspection of the pattern of quality control markers can be used to verify that all the DNA fragments were placed on the arrays correctly. In addition to assisting other VARI research labs, our group has a special focus on understanding how cytogenetic abnormalities influence cancer development and progression. Many cancer types, including liver and kidney cancers, are associated with defined sets of DNA gains and losses. For example, the majority of hepatocellular carcinomas contain extra copies of chromosome 1p and lack copies of chromosome 4q. In contrast, the majority of clear cell renal cell carcinomas contain an extra copy of chromosome 5q and lack a copy of chromosome 3p. Interestingly, we and other groups have noticed that transcription is dramatically disrupted within regions of DNA copy number change. We are currently developing and testing a number of different algorithms to identify these disrupted regions using gene expression data. In addition, we are developing methods to identify key regulatory genes that lie within the abnormal region and may be involved in tumor development and/or progression. 26

External Collaborators Xin Chen, Stanford University, Stanford, California Recent Publications Yang, X.J., M.-H. Tan, H.L. Kim, J.A. Ditlev, M.W. Betten, C.E. Png, E.J. Kort, K. Futami, K.J. Dykema, K.A. Furge, M. Takahashi, H. Kanayama, P.H. Tan, B.S. Teh, C. Luan, et al. In press. A molecular classification of papillary renal cell carcinoma. Cancer Research. Dykema, K.J., and K.A. Furge. 2004. Diminished transcription of chromosome 4q is inversely related to local spread of hepatocellular carcinoma. Genes, Chromosomes and Cancer 41(4): 390–394. Furge, Kyle A., Kerry A. Lucas, Masayuki Takahashi, Jun Sugimura, Eric J. Kort, Hiro-omi Kanayama, Susumu Kagawa, Philip Hoekstra, John Curry, Ximing J. Yang, and Bin T. Teh. 2004. Robust classification of renal cell carcinoma based on gene expression data and predicted cytogenetic profiles. Cancer Research 64(12): 4117–4121. Haven, C.J., V.M. Howell, P.H.C. Eilers, R. Dunne, M. Takahashi, M. van Puijenbroek, K. Furge, J. Kievit, M.-H. Tan, G.J. Fleuren, B.G. Robinson, L.W. Delbridge, J. Philips, A.E. Nelson, U. Krause, et al. 2004. Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype. Cancer Research 64(20): 7405–7411. Lindvall, Charlotta, Kyle Furge, Magnus Björkholm, Xiang Guo, Brian Haab, Elisabeth Blennow, Magnus Nordenskjöld, and Bin Tean Teh. 2004. Combined genetic and transcriptional profiling of acute myeloid leukemia with normal and complex karyotypes. Haematologica 89(9): 1072–1081. Sugimura, Jun, Richard S. Foster, Oscar W. Cummings, Eric J. Kort, Masayuki Takahashi, Todd T. Lavery, Kyle A. Furge, Lawrence H. Einhorn, and Bin Tean Teh. 2004. Gene expression profiling of earlyand late-relapse nonseminomatous germ cell tumor and primitive neuroectodermal tumor of the testis. Clinical Cancer Research 10(7): 2368–2378. Tan, Min-Han, Craig G. Rogers, Jeffrey T. Cooper, Jonathon A. Ditlev, Thomas J. Maatman, Ximing Yang, Kyle A. Furge, and Bin Tean Teh. 2004. Gene expression profiling of renal cell carcinoma. Clinical Cancer Research 10(18): 6315S–6321S. Yang, Ximing J., Jun Sugimura, Maria S. Tretiakova, Kyle Furge, Gregory Zagaja, Mitchell Sokoloff, Michael Pins, Raymond Bergan, David J. Grignon, Walter M. Stadler, Nicholas J. Vogelzang, and Bin Tean Teh. 2004. Gene expression profiling of renal medullary carcinoma: potential clinical relevance. Cancer 100(5): 976–985. From left to right: Furge, Dykema 27

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