Document Detail


A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.
MedLine Citation:
PMID:  23047291     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
CONCLUSION: 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:
Chad C Brown; Tammy M Havener; Marisa W Medina; J Todd Auman; Lara M Mangravite; Ronald M Krauss; Howard L McLeod; Alison A Motsinger-Reif
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  22     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-10     Completed Date:  2013-04-04     Revised Date:  2014-06-12    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  796-802     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Alkylating / pharmacology*
Cell Line, Tumor
DNA Methylation
DNA Modification Methylases / genetics*
DNA Repair Enzymes / genetics*
Dacarbazine / analogs & derivatives*,  pharmacology
Gene Expression Regulation, Neoplastic
Genome, Human
Genome-Wide Association Study
Humans
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*,  genetics*,  pathology
Tumor Suppressor Proteins / genetics*
Grant Support
ID/Acronym/Agency:
R01 CA161608/CA/NCI NIH HHS; R01 CA161608-01/CA/NCI NIH HHS; R01 HL104133/HL/NHLBI NIH HHS; T32 ES007329/ES/NIEHS NIH HHS; T32GM081057/GM/NIGMS NIH HHS; U01 GM63340/GM/NIGMS NIH HHS; U19 HL069757/HL/NHLBI NIH HHS; U19 HL69757-10/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Tumor Suppressor Proteins; 7GR28W0FJI/Dacarbazine; 85622-93-1/temozolomide; EC 2.1.1.-/DNA Modification Methylases; EC 2.1.1.63/MGMT protein, human; EC 6.5.1.-/DNA Repair Enzymes
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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