PAAR Pharmacogenomics of Anticancer Agents Research Group PROJECT SUMMARY The overall goal is to identify functional relationships at the intersection of drug, gene, and phenotype, particularly those phenotypes that are affected by one or more functional polymorphisms when patients are treated with a specific anticancer drug (at a clinically relevant dose). Mathematically, this can be described by a multidimensional matrix, where we aim to understand the functional importance (mathematically depicted as a PGScore) of variation in a specific gene (or polymorphism) on the effects of a drug as measured by a specific well-characterized phenotype. PROJECTS SIX INTERRELATED THEMES Cytotoxicity Transcriptome Irinotecan Angiogenesis Uridine glucuronosyltransferases (UGT) Epidermal Growth Factor Receptor (EGFR) Supported by: TWO PLATFORMS Clinical Studies Functional Studies THREE CORES Management and Administrative (MAC) Genetics and Informatics using Statistics GENIUS) Lymphoblastoid Cell Line (LCL) THEMES The weight of the lines showing connections among PAAR Themes is proportional to the number of PAAR investigators working at the interface of the two Themes. INTERACTIONS AMONG PAAR THEMES PLATFORMS CLINICAL STUDIES PLATFORM (CSP) The CSP will utilize multiple established clinical trial infrastructures for translation of laboratory findings, replication of prior clinical studies, and discovery of new variants associated with clinical endpoints (e.g., adverse events, efficacy) and endophenotypes FUNCTIONAL STUDIES PLATFORM (FSP) Purpose of the FSP is to devise and apply systematic and state of the art approaches to functional studies of genes and genetic variants that emerge as candidates from our PAAR studiies CORES GENETICS & INFORMATICS USING STATISTICS (GENIUS) Responsible for working with investigators to develop studies that are optimal in terms for design and power and to conduct statistical and statistical genetic analysis of data for PAAR projects. LYMPHOBLASTOID CELL LINE (LCL) Responsible for the maintenance and distribution of LCLs for PAAR investigators. MANAGEMENT AND ADMINISTRATIVE (MAC) Responsible for budgetary administration, communication within PAAR and to the PGRN and its Program Director. KEY PERSONNEL PROGRAM DIRECTORS Mark J. Ratain, M.D. Nancy J. Cox, Ph.D. M. Eileen Dolan, Ph.D. The University of Chicago R. Stephanie Huang, Ph.D. The University of Chicago LCL Soma Das, Ph.D. The University of Chicago GENIUS Wanqing Liu, Ph.D. The University of Chicago Gene-Centric Themes and Functional Studies Platform Federico Innocenti, M.D., Ph.D. The University of Chicago UGT and Drug-Centric Themes Michael Maitland, M.D, Ph.D. The University of Chicago Angiogenesis Theme and Clinical Studies Platform Yves A. Lussier, M.D. The University of Chicago GENIUS Kouros Owzar, Ph.D. Duke University GENIUS CO-INVESTIGATORS POPULATIONS HapMap 88 CEU I (30 trios) 89 CEU II (26 trios, 5 duos, 2 singletons) 90 YRI I (30 trios) YRI II (28 trios, 2 duos, 2 singletons and 29 are replicates) 45 CHB I (unrelated) 45 JPT I (unrelated) 90 CHD (unrelated, also part of HVP) 90 MEX (30 trios, also part of HVP) 90 ASW (11 trios, 24 duos and 9 singletons) Non-HapMap 354 CEPH Family (various CEPH pedigrees) / RESOURCES/ TOOLS FOR SHARING PGScore - provides a comprehensive overview of results of studies in pharmacogenomics All PGScore data will be publicly available at PACdb - for use as a central repository of results of association studies on pharmacology-related phenotypes Publicly available at SCANdb - enables the annotation of single nucleotide and copy number genetic variants by combining approaches that involve not only physical and functional annotations currently distributed across several public databases, but also multi- locus measures of linkage disequilibrium (LD) calculated using TUNA as well as results of GWAS on association of HapMap variants to gene expression Publicly available at INSTITUTIONS