Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients

Eric R. Gamazon, Jatinder K. Lamba, Stanley Pounds, Amy L. Stark, Heather E. Wheeler, Xueyuan Cao, Hae K. Im, Amit K Mitra, Jeffrey E. Rubnitz, Raul C. Ribeiro, Susana Raimondi, Dario Campana, Kristine R. Crews, Shan S. Wong, Marleen Welsh, Imge Hulur, Lidija Gorsic, Christine M. Hartford, Wei Zhang, Nancy J. CoxM. Eileen Dolan

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Awhole-genome approach was used to investigate the genetic determinants of cytarabineinduced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from1.7- to 26.6-fold in LCLs.A total of 33 SNPs ranked at the top of the meta-analysis (P < 10-5) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-relatedmortality). This count (n518) was significantly greater than expected by chance (P5 .016). For rs1203633, LCLs with AA genotype weremore sensitive to cytarabine-induced cytotoxicity (P 5 1.313106) andAA (vs GA or GG) genotype was associated with poorer OS (P 5 .015), likely as a result of greater treatment-related mortality (P 5 .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.

Original languageEnglish (US)
Pages (from-to)4366-4376
Number of pages11
JournalBlood
Volume121
Issue number21
DOIs
StatePublished - May 23 2013

Bibliographical note

Funding Information:
This work was supported by grants from: the Leukemia and Lymphoma Society, Specialized Center of Research grant (M.E.D.); the National Institutes of Health, National Institute of General Medical Sciences grant U01 GM61393 (M.E.D., N.J.C.); the National Human Genome Research Institute R21HG006367 (W.Z., M.E.D.); Clinical Therapeutics, Training grant 5T32GM007019 (C.M.H.); the Department of Defense, Breast Cancer Research Program grant BC087674 (M.W.); the National Institutes of Health, National Cancer Institute, Cancer Biology Training grants T32CA009594 (H.E.W.) and R01CA132946 (J.K.L.); and the Cancer Research Foundation of the University of Chicago Comprehensive Cancer Center (M.E.D.).

Publisher Copyright:
© 2013 by The American Society of Hematology.

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