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Randomized Controlled Trial
, 121 (21), 4366-76

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

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Randomized Controlled Trial

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

Eric R Gamazon et al. Blood.

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.

Figures

Figure 1
Figure 1
Cellular sensitivity to cytarabine in 523 HapMap LCLs. LCLs from world populations (ASN, ASW, CEU, and YRI) were phenotyped for the growth inhibitory effects of cytarabine. The mean (standard deviation) log2 AUC was 10.81 (±0.30 μM) for ASN, 10.78 (±0.27 μM) for ASW, 10.83 (±0.30 μM) for CEU, and 10.78 (±0.29 μM) for YRI.
Figure 2
Figure 2
Meta-analysis of GWAS in CEU, YRI, ASW, and ASN populations. (A) The Manhattan plot shows the meta-analysis results on GWAS of cellular susceptibility to cytarabine in 4 world populations (n = 523 individual samples). The highest-ranked SNP was rs7729269 (P = 3.67 × 10−7) in the gene MCC. (B) The plot shows P values from the meta-analysis of GWAS in CEU, YRI, ASW, and ASN populations for the top SNP associations with cytarabine log2 AUC in a specific region on chromosome 5. The colors, as indicated in the legend, denote the extent of LD between the SNPs; for this purpose, we use only the CEU reference population. The bottom panel illustrates the chromosomal region and genes that these SNPs fall on. The figure was made in LocusZoom.
Figure 3
Figure 3
Association of SNPs within MCC with cytarabine sensitivity in LCLs and in leukemic blasts. MCC SNPs plotted against log2 AUC in LCLs for (A) rs7729269 and (B) rs13171482, and MCC SNPs plotted against IC50 (dose required to inhibit growth of 50% of cells) in leukemic blasts for (C) rs7729269 and (D) rs13171482.
Figure 4
Figure 4
SNP rs2897047 association with log2 AUC in LCLs and association with MRD and RFS in all AML patients. Association of SNP rs2897047 with (A) log2 AUC for cellular sensitivity to cytarabine in a cell-based model (meta-analysis P = 4.06 × 10−6) illustrated in CEU, YRI, and ASN; (B) MRD at day 22 in all AML patients (P = .0218), where the numbers in each box represent MRD levels <0.1, 0.1 to 1, or ≥1 and the numbers in parentheses indicate fraction of patients within each MRD category; and (C) RFS (P = .043) in all AML patients.
Figure 5
Figure 5
SNP rs12036333 association with log2 AUC in LCLs and association with OS and TRM. Association of SNP rs12036333 (AA versus GA/GG) with (A) log2 AUC for cellular sensitivity to cytarabine in cell-based model in all populations (P = .007), (B) OS (P = .0146), and (C) TRM in white AML patients (P = .0037).
Figure 6
Figure 6
Top SNPs identified in LCLs are enriched for top associations with clinical phenotypes. Of the 33 SNPs tested that had an association with cytarabine-induced cytotoxicity in LCLs (P < 1 × 10−5), 18 were associated (P < .05) with cytarabine IC50 in leukemia cells, day 22 MRD, RFS, OS, or TRM. The number of clinically validated SNPs is highly significant (P = .016) given the correlation structure of the genotypes evaluated and that of the phenotypes examined.

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