Abstract | BACKGROUND AND OBJECTIVE: METHODS: Eight of the 17 pathway genes were resequenced with DNA samples from Coriell lymphoblastoid cell lines (LCLs) using Sanger sequencing for all exons, exon-intron junctions, and 5'-, 3'-UTRs. A total of 107 tagging SNPs were selected on the basis of the resequencing data for the eight genes and on HapMap data for the remaining nine genes, followed by successful genotyping of 394 NSCLC patient DNA samples. Association of SNPs/haplotypes with OS was performed using the Cox regression model, followed by functional studies performed with LCLs and NSCLC cell lines. RESULTS: Five SNPs in four genes (CDA, NT5C2, RRM1, and SLC29A1) showed associations with OS of those patients with NSCLC, as well as nine haplotypes in four genes (RRM1, RRM2, SLC28A3, and SLC29A1) with a P value of less than 0.05. Genotype imputation using the LCLs was performed for a region of 200 kb surrounding those SNPs, followed by association studies with gemcitabine cytotoxicity. Functional studies demonstrated that downregulation of SLC29A1, NT5C2, and RRM1 in NSCLC cell lines altered cell susceptibility to gemcitabine. CONCLUSION:
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Authors | Liang Li, Daniel J Schaid, Brooke L Fridley, Krishna R Kalari, Gregory D Jenkins, Ryan P Abo, Anthony Batzler, Irene Moon, Linda Pelleymounter, Bruce W Eckloff, Eric D Wieben, Zhifu Sun, Ping Yang, Liewei Wang |
Journal | Pharmacogenetics and genomics
(Pharmacogenet Genomics)
Vol. 22
Issue 2
Pg. 105-16
(Feb 2012)
ISSN: 1744-6880 [Electronic] United States |
PMID | 22173087
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Biomarkers
- Deoxycytidine
- Gemcitabine
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Topics |
- Antimetabolites, Antineoplastic
(pharmacology, therapeutic use)
- Biomarkers
(metabolism)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics, mortality)
- Deoxycytidine
(analogs & derivatives, pharmacology, therapeutic use)
- Genotype
- HapMap Project
- Humans
- Lung Neoplasms
(drug therapy, genetics, mortality)
- Polymorphism, Genetic
- Signal Transduction
(genetics)
- Gemcitabine
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