SplicerAV: a tool for mining microarray expression data for changes in RNA processing.
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2010-02-25
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BACKGROUND: Over the past two decades more than fifty thousand unique clinical and biological samples have been assayed using the Affymetrix HG-U133 and HG-U95 GeneChip microarray platforms. This substantial repository has been used extensively to characterize changes in gene expression between biological samples, but has not been previously mined en masse for changes in mRNA processing. We explored the possibility of using HG-U133 microarray data to identify changes in alternative mRNA processing in several available archival datasets. RESULTS: Data from these and other gene expression microarrays can now be mined for changes in transcript isoform abundance using a program described here, SplicerAV. Using in vivo and in vitro breast cancer microarray datasets, SplicerAV was able to perform both gene and isoform specific expression profiling within the same microarray dataset. Our reanalysis of Affymetrix U133 plus 2.0 data generated by in vitro over-expression of HRAS, E2F3, beta-catenin (CTNNB1), SRC, and MYC identified several hundred oncogene-induced mRNA isoform changes, one of which recognized a previously unknown mechanism of EGFR family activation. Using clinical data, SplicerAV predicted 241 isoform changes between low and high grade breast tumors; with changes enriched among genes coding for guanyl-nucleotide exchange factors, metalloprotease inhibitors, and mRNA processing factors. Isoform changes in 15 genes were associated with aggressive cancer across the three breast cancer datasets. CONCLUSIONS: Using SplicerAV, we identified several hundred previously uncharacterized isoform changes induced by in vitro oncogene over-expression and revealed a previously unknown mechanism of EGFR activation in human mammary epithelial cells. We analyzed Affymetrix GeneChip data from over 400 human breast tumors in three independent studies, making this the largest clinical dataset analyzed for en masse changes in alternative mRNA processing. The capacity to detect RNA isoform changes in archival microarray data using SplicerAV allowed us to carry out the first analysis of isoform specific mRNA changes directly associated with cancer survival.
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Robinson, Timothy J, Michaela A Dinan, Mark Dewhirst, Mariano A Garcia-Blanco and James L Pearson (2010). SplicerAV: a tool for mining microarray expression data for changes in RNA processing. BMC Bioinformatics, 11. p. 108. 10.1186/1471-2105-11-108 Retrieved from https://hdl.handle.net/10161/4332.
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Michaela Ann Dinan
Dr. Dinan is a health services researcher by training and she specializes in using econometric and epidemiologic methodologies to analyze complex datasets. Specifically, Dr. Dinan's research involves issues related to advances in cancer care technologies, such as emerging treatments and diagnostics, and how these advances in technologies impact different cancer outcomes and experiences such as access, quality of care, cost of care, and health disparities.
Dr. Dinan has led studies funded by the National Institutes of Health, the American Cancer Society, and the Agency for Healthcare Research and Quality. She is currently leading an NCI-funded R01 study examining multi-level factors that contribute to disparities in access and adherence to oral anticancer agents for patients with kidney cancer. Dr. Dinan is also leading a study funded by the ACS to develop and validate risk prediction algorithms to inform efficient and high-quality care for long-term cancer survivors.
Areas of expertise: Health Economics, Health Policy, and Health Services Research
Mark Wesley Dewhirst
Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposome that has been successfully translated to human clinical trials. He has utilized the thermal characteristics of this liposome to develop an MR imageable form that can accurately reflect drug concentrations in tumors, which then is related to the extent of anti-tumor effect in pre-clinical models. This property has been widely used by other investigators, world-wide, particularly in the area of high intensity focused ultrasound, where it would be possible to literally paint drug to a target zone and visualize this process in real time, during heating. For his work in this area, Dr. Dewhirst was named a Fellow in the AAAS. Dr. Dewhirst has well over 500 peer-reviewed publications, book chapters and reviews, with >20,000 citations and an H-index of 73. He has given named lectures at the University of Western Ontario, Thomas Jefferson University and the New Zealand Cancer Society. He was awarded the Failla Medal and Lecture at the Radiation Research Society in 2008, the Eugene Robinson award for excellence hyperthermia research in 1992 and a similar award from the European Society for Hyperthermic Oncology in 2009. He was named a fellow of ASTRO in 2009 and was awarded the prestigious Gold Medal from the same society in 2012. He is a Senior Editor of Cancer Research and Editor-in-Chief of the International Journal of Hyperthermia. He has mentored 24 graduate students, and many postdoctoral fellows, residents, junior faculty and medical students. He has been particularly skillful in assisting those he has mentored to obtain DOD and NIH fellowships, K awards and first R01 grants. His skill in mentoring has been recognized by the Duke Comprehensive Cancer Center, the Medical Physics Graduate Training programs and the School of Medicine, where he has received “Mentor of the Year” awards. In 2011 he was selected to become the first Associate Dean of Faculty Mentoring in the Duke School of Medicine. In this position, he is implementing a comprehensive program to enhance success in obtaining NIH funding. He graduated from the University of Arizona in 1971 with a degree in Chemistry and Colorado State University in 1975 and 1979 with DVM and PhD degrees, respectively.
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