Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients
| Autor: | Lidija K. Gorsic, Raul C. Ribeiro, Stanley Pounds, Heather E. Wheeler, Jatinder K. Lamba, Imge Hulur, Eric R. Gamazon, Shan S. Wong, Jeffrey E. Rubnitz, Susana C. Raimondi, Dario Campana, Amit Kumar Mitra, Wei Zhang, Xueyuan Cao, M. Eileen Dolan, Nancy J. Cox, Marleen M. Welsh, Hae Kyung Im, Amy L. Stark, Christine Hartford, Kristine R. Crews |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Oncology
medicine.medical_specialty Antimetabolites Antineoplastic Myeloid Genotype Daunorubicin Immunology Apoptosis Biology Biochemistry Polymorphism Single Nucleotide Internal medicine hemic and lymphatic diseases medicine Humans Etoposide Myeloid Neoplasia Gene Expression Regulation Leukemic Cytarabine Myeloid leukemia Cell Biology Hematology medicine.disease Minimal residual disease Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Phenotype Treatment Outcome Drug Resistance Neoplasm medicine.drug Genome-Wide Association Study |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|