title: A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.
abstract: OBJECTIVE
  Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict the dose response to chemotherapy drugs.
  
  
  METHODS
  In the current study, this strategy was expanded to the in-vitro genome-wide association approach, using 516 LCLs derived from a White cohort to assess the cytotoxic response to temozolomide.
  
  
  RESULTS
  Genome-wide association analysis using ∼2.1 million quality-controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (P<10(-8)) with SNPs in the O(6)-methylguanine-DNA methyltransferase (MGMT) gene. We also show that the primary SNP in this region is significantly associated with the differential gene expression of MGMT (P<10(-26)) in LCLs and differential methylation in glioblastoma samples from The Cancer Genome Atlas.
  
  
  CONCLUSIONS
  The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered genome-wide association studies of the LCL model system to identify meaningful genetic associations.
authors.affiliation: Department of Statistics, North Carolina State University, Raleigh, North Carolina 27695-7566, USA.
authors.forename: Chad C
authors.initials: CC
authors.lastname: Brown
authors.forename: Tammy M
authors.initials: TM
authors.lastname: Havener
authors.forename: Marisa W
authors.initials: MW
authors.lastname: Medina
authors.forename: J Todd
authors.initials: JT
authors.lastname: Auman
authors.forename: Lara M
authors.initials: LM
authors.lastname: Mangravite
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Krauss
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Alison A
authors.initials: AA
authors.lastname: Motsinger-Reif
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide