Comprehensive Genetic Analysis of Cytarabine Sensitivity in a Cell-based Model Identifies Polymorphisms Associated with Outcome in AML Patients

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2013 Mar 30

PMID 23538338

Citations 23

Authors

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 Cox

M Eileen Dolan

Affiliations

Soon will be listed here.

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.

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