A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.
A genome-wide association analysis of temozolomide response using lymphoblastoid cell lines shows a clinically relevant association with MGMT.
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DOI：
10.1097/fpc.0b013e3283589c50
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发表时间：
2012-11
影响因子：
2.6
通讯作者：
Motsinger-Reif AA
中科院分区：
文献类型：
--
作者：
Brown CC;Havener TM;Medina MW;Auman JT;Mangravite LM;Krauss RM;McLeod HL;Motsinger-Reif AA
Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict dose response to chemotherapy drugs. In the current study, this strategy was expanded to the in vitro genome-wide association approach, using 516 LCLs derived from a Caucasian cohort to assess cytotoxic response to temozolamide. Genome-wide association analysis using approximately 2.1 million quality controlled单核苷酸多态性（SNP）鉴定出与O6-甲基鸟嘌呤 - DNA甲基转移酶（MGMT）基因中SNP的统计学意义（p <10-8），我们还证明了该区域的主要SNP与MGMT（P <10 -26）的差异化相关的基因（p <10-26）以前记录了MGMT和替莫唑胺反应之间的临床和功能关系，突显了LCL模型系统驱动的GWAS鉴定有意义的遗传关联的潜力。
Recently, lymphoblastoid cell lines (LCLs) have emerged as an innovative model system for mapping gene variants that predict dose response to chemotherapy drugs. In the current study, this strategy was expanded to the in vitro genome-wide association approach, using 516 LCLs derived from a Caucasian cohort to assess cytotoxic response to temozolomide. Genome-wide association analysis using approximately 2.1 million quality controlled single-nucleotide polymorphisms (SNPs) identified a statistically significant association (p < 10−8) with SNPs in the O6-methylguanine–DNA methyltransferase (MGMT) gene. We also demonstrate that the primary SNP in this region is significantly associated with differential gene expression of MGMT (p< 10−26) in LCLs, and differential methylation in glioblastoma samples from The Cancer Genome Atlas. The previously documented clinical and functional relationships between MGMT and temozolomide response highlight the potential of well-powered GWAS of the LCL model system to identify meaningful genetic associations.