title: Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.
abstract: A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced 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 from 1.7- 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-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10(-6)) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Lamba
authors.forename: Stanley
authors.initials: S
authors.lastname: Pounds
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stark
authors.forename: Heather E
authors.initials: HE
authors.lastname: Wheeler
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Cao
authors.forename: Hae K
authors.initials: HK
authors.lastname: Im
authors.forename: Amit K
authors.initials: AK
authors.lastname: Mitra
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Rubnitz
authors.forename: Raul C
authors.initials: RC
authors.lastname: Ribeiro
authors.forename: Susana
authors.initials: S
authors.lastname: Raimondi
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Shan S
authors.initials: SS
authors.lastname: Wong
authors.forename: Marleen
authors.initials: M
authors.lastname: Welsh
authors.forename: Imge
authors.initials: I
authors.lastname: Hulur
authors.forename: Lidija
authors.initials: L
authors.lastname: Gorsic
authors.forename: Christine M
authors.initials: CM
authors.lastname: Hartford
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Cox
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D003561:Cytarabine / Q000627:therapeutic use* / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; D003561:Cytarabine
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