Integrating Cell-Based and Clinical Genome-Wide Studies to Identify Genetic Variants Contributing to Treatment Failure in Neuroblastoma Patients

Autor: Amy L. Stark, Wendy B. London, Navin Pinto, Sharon J. Diskin, Nancy J. Cox, M E Dolan, Susan L. Cohn, Hae Kyung Im, Nirav N. Antao, Eric R. Gamazon, Jamie Myers, Anuar Konkashbaev, John M. Maris, Susan M. Ludeman
Jazyk: angličtina
Rok vydání: 2014
Předmět:
Oncology
Quality Control
medicine.medical_specialty
ZPBP2
Single-nucleotide polymorphism
Genome-wide association study
Biology
Malignancy
Bioinformatics
Real-Time Polymerase Chain Reaction
Polymorphism
Single Nucleotide
Risk Assessment
Article
Disease-Free Survival
Cohort Studies
Neuroblastoma
Polymorphism (computer science)
Internal medicine
Cell Line
Tumor
Genetic variation
medicine
Humans
Pharmacology (medical)
Genetic Predisposition to Disease
Treatment Failure
RNA
Small Interfering
cell-based models
Child
Antineoplastic Agents
Alkylating
Cyclophosphamide
Genetic association
Pharmacology
pharmacogenomics
Cyclohexylamines
expression quantitative trait loci
Brain Neoplasms
Cancer
Genetic Variation
IKZF3
medicine.disease
3. Good health
Phenotype
Drug Resistance
Neoplasm
Genome-Wide Association Study
Zdroj: Clinical pharmacology and therapeutics
ISSN: 1532-6535
0009-9236
Popis: 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. Clinical Pharmacology & Therapeutics (2014); 95 6, 644–652. doi:10.1038/clpt.2014.37
Databáze: OpenAIRE
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