title: 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.
authors.affiliation: Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: N
authors.initials: N
authors.lastname: Pinto
authors.affiliation: Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: E R
authors.initials: ER
authors.lastname: Gamazon
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: N
authors.initials: N
authors.lastname: Antao
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: J
authors.initials: J
authors.lastname: Myers
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: A L
authors.initials: AL
authors.lastname: Stark
authors.affiliation: Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: A
authors.initials: A
authors.lastname: Konkashbaev
authors.affiliation: Department of Health Studies, The University of Chicago, Chicago, Illinois, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Im
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Diskin
authors.affiliation: 1] Boston Children's Hospital/Dana Farber Harvard Cancer Center, Harvard University, Boston, Massachusetts, USA [2] Children's Oncology Group Statistics and Data Center, Arcadia, California, USA.
authors.forename: W B
authors.initials: WB
authors.lastname: London
authors.affiliation: Department of Basic and Social Sciences, Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Ludeman
authors.affiliation: Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Maris
authors.affiliation: Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Cox
authors.affiliation: Section of Pediatric Hematology/Oncology, Department of Pediatrics, The University of Chicago, Chicago, Illinois, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Cohn
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Dolan
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D002648:Child; D015331:Cohort Studies; D003514:Cyclohexylamines / Q000378:metabolism; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000627:therapeutic use; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D018570:Risk Assessment; D017211:Treatment Failure
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003514:Cyclohexylamines; D034741:RNA, Small Interfering; D003520:Cyclophosphamide; C011272:perfosfamide