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A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT

Brown, Chad C.a; Havener, Tammy M.c; Medina, Marisa W.d; Auman, J. Toddc; Mangravite, Lara M.e; Krauss, Ronald M.d; McLeod, Howard L.c; Motsinger-Reif, Alison A.a,b,c

doi: 10.1097/FPC.0b013e3283589c50

Objective Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.

Methods In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.

Results Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10−8) with SNPs in the O6-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10–26) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.

Conclusion The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.

aDepartment of Statistics

bBioinformatics Research Center, North Carolina State University, Raleigh

cInstitute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

dChildren’s Hospital Oakland Research Institute, Oakland, California

eSage Bionetworks, Seattle, Washington, USA

Correspondence to Alison A. Motsinger-Reif, PhD, Department of Statistics, North Carolina State University, 307 Ricks Hall, 1 Lampe Dr., Raleigh, 27695-7566 North Carolina, USA Tel: +1 919 515 3574; fax: +1 919 515 7315; e-mail:

Received February 8, 2012

Accepted July 27, 2012

© 2012 Lippincott Williams & Wilkins, Inc.