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

Abstract
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.
AuthorsN Pinto, E R Gamazon, N Antao, J Myers, A L Stark, A Konkashbaev, H K Im, S J Diskin, W B London, S M Ludeman, J M Maris, N J Cox, S L Cohn, M E Dolan
JournalClinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 95 Issue 6 Pg. 644-52 (Jun 2014) ISSN: 1532-6535 [Electronic] United States
PMID24549002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Antineoplastic Agents, Alkylating
  • Cyclohexylamines
  • RNA, Small Interfering
  • Cyclophosphamide
  • perfosfamide
Topics
  • Antineoplastic Agents, Alkylating (therapeutic use)
  • Brain Neoplasms (drug therapy, genetics, pathology)
  • Cell Line, Tumor
  • Child
  • Cohort Studies
  • Cyclohexylamines (metabolism)
  • Cyclophosphamide (analogs & derivatives, metabolism, therapeutic use)
  • Disease-Free Survival
  • Drug Resistance, Neoplasm
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Neuroblastoma (drug therapy, genetics, pathology)
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Quality Control
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Risk Assessment
  • Treatment Failure

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