Journal article
Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study
BMC cancer, Vol.12(1), pp.422-422
09/24/2012
DOI: 10.1186/1471-2407-12-422
PMCID: PMC3573965
PMID: 23006423
Abstract
Background: Taxane is one of the first line treatments of lung cancer. In order to identify novel single nucleotide polymorphisms (SNPs) that might contribute to taxane response, we performed a genome-wide association study (GWAS) for two taxanes, paclitaxel and docetaxel, using 276 lymphoblastoid cell lines (LCLs), followed by genotyping of top candidate SNPs in 874 lung cancer patient samples treated with paclitaxel.
Methods: GWAS was performed using 1.3 million SNPs and taxane cytotoxicity IC50 values for 276 LCLs. The association of selected SNPs with overall survival in 76 small or 798 non-small cell lung cancer (SCLC, NSCLC) patients were analyzed by Cox regression model, followed by integrated SNP-microRNA-expression association analysis in LCLs and siRNA screening of candidate genes in SCLC (H196) and NSCLC (A549) cell lines.
Results: 147 and 180 SNPs were associated with paclitaxel or docetaxel IC50s with p-values < 10(-4) in the LCLs, respectively. Genotyping of 153 candidate SNPs in 874 lung cancer patient samples identified 8 SNPs (p-value < 0.05) associated with either SCLC or NSCLC patient overall survival. Knockdown of PIP4K2A, CCT5, CMBL, EXO1, KMO and OPN3, genes within 200 kb up-/downstream of the 3 SNPs that were associated with SCLC overall survival (rs1778335, rs2662411 and rs7519667), significantly desensitized H196 to paclitaxel. SNPs rs2662411 and rs1778335 were associated with mRNA expression of CMBL or PIP4K2A through microRNA (miRNA) hsa-miR-584 or hsa-miR-1468.
Conclusions: GWAS in an LCL model system, joined with clinical translational and functional studies, might help us identify genetic variations associated with overall survival of lung cancer patients treated paclitaxel.
Details
- Title: Subtitle
- Genetic association with overall survival of taxane-treated lung cancer patients - a genome-wide association study in human lymphoblastoid cell lines followed by a clinical association study
- Creators
- Nifang Niu - Mayo ClinicDaniel J. Schaid - Mayo ClinicRyan P. Abo - Massachusetts Institute of TechnologyKrishna Kalari - Mayo ClinicBrooke L. Fridley - Mayo ClinicQiping Feng - Vanderbilt University Medical CenterGregory Jenkins - Mayo ClinicAnthony Batzler - Mayo ClinicAbra G. Brisbin - Mayo ClinicJulie M. Cunningham - Mayo ClinicLiang Li - Mayo ClinicZhifu Sun - Mayo Clinic in FloridaPing Yang - Mayo Clinic in FloridaLiewei Wang - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- BMC cancer, Vol.12(1), pp.422-422
- Publisher
- Springer Nature
- DOI
- 10.1186/1471-2407-12-422
- PMID
- 23006423
- PMCID
- PMC3573965
- ISSN
- 1471-2407
- eISSN
- 1471-2407
- Number of pages
- 13
- Grant note
- R01CA138461 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) K22 CA130828; R01 CA138461; U19 GM61388; R01 CA80127; R01 CA84354; R01 CA105857 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA CA15083 / Mayo Comprehensive Cancer Center
- Language
- English
- Date published
- 09/24/2012
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701647002771
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