Integrating cell-based and clinical genome-wide studies to identify genetic variants contributing to treatment failure in neuroblastoma patients.

Pinto N, Gamazon ER, Antao N, Myers J, Stark AL, Konkashbaev A, Im HK, Diskin SJ, London WB, Ludeman SM, Maris JM, Cox NJ, Cohn SL, Dolan ME
Clin Pharmacol Ther. 2014 95 (6): 644-52

PMID: 24549002 · PMCID: PMC4029857 · DOI:10.1038/clpt.2014.37

High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428). Genome-wide association studies were performed to identify single-nucleotide polymorphisms (SNPs) associated with sensitivity to 4HC and PM. SNPs consistently associated with LCL sensitivity were analyzed for associations with event-free survival (EFS) in patients. Two linked SNPs, rs9908694 and rs1453560, were found to be associated with (i) sensitivity to PM in LCLs across populations and (ii) EFS in all patients (P = 0.01) and within the high-risk subset (P = 0.05). Our study highlights the value of cell-based models to identify candidate variants that may predict response to treatment in patients with cancer.

MeSH Terms (21)

Antineoplastic Agents, Alkylating Brain Neoplasms Cell Line, Tumor Child Cohort Studies Cyclohexylamines Cyclophosphamide Disease-Free Survival Drug Resistance, Neoplasm Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Humans Neuroblastoma Phenotype Polymorphism, Single Nucleotide Quality Control Real-Time Polymerase Chain Reaction Risk Assessment RNA, Small Interfering Treatment Failure

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