PAARPharmacogenomics of Anticancer Agents Research Group

www.paarpharmacogenomics.org

PROJECT SUMMARYThe 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.

PROJECTSSIX 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 workingat the interface ofthe two Themes.

INTERACTIONS AMONG PAAR THEMES

PLATFORMSCLINICAL 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

CORESGENETICS & 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 PERSONNELPROGRAM 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 ChicagoGene-Centric Themes and

Functional Studies Platform

Federico Innocenti, M.D., Ph.D.The University of ChicagoUGT and Drug-Centric Themes

Michael Maitland, M.D, Ph.D.The University of ChicagoAngiogenesis Theme andClinical Studies Platform

Yves A. Lussier, M.D.The University of Chicago

GENIUS

Kouros Owzar, Ph.D.Duke University

GENIUS

CO-INVESTIGATORS

POPULATIONSHapMap

•88 CEU I (30 trios)•89 CEU II (26 trios, 5 duos, 2 singletons)•90 YRI I (30 trios)•90+29 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)

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RESOURCES/TOOLS FOR SHARING

PGScore - provides a comprehensive overview of results of studies in pharmacogenomics

All PGScore data will be publicly available at http://pgscore.orgPACdb - for use as a central repository of results of association studies on pharmacology-related phenotypesPublicly available at http://pacdb.org

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 expressionPublicly available at http://scandb.org

INSTITUTIONS