Journal
BLOOD
Volume 121, Issue 21, Pages 4366-4376Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-10-464149
Keywords
-
Categories
Funding
- Leukemia and Lymphoma Society, Specialized Center of Research grant
- National Institutes of Health, National Institute of General Medical Sciences grant [U01 GM61393]
- National Human Genome Research Institute [R21HG006367]
- Clinical Therapeutics, Training grant [5T32GM007019]
- Department of Defense, Breast Cancer Research Program grant [BC087674]
- National Institutes of Health, National Cancer Institute, Cancer Biology Training grants [T32CA009594, R01CA132946]
- Cancer Research Foundation of the University of Chicago Comprehensive Cancer Center
- CDMRP [BC087674, 544848] Funding Source: Federal RePORTER
Ask authors/readers for more resources
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 linvolving 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 x 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
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available