Journal article
Genetic Variation Predicting Cisplatin Cytotoxicity Associated with Overall Survival in Lung Cancer Patients Receiving Platinum-Based Chemotherapy
Clinical cancer research, Vol.17(17), pp.5801-5811
09/01/2011
DOI: 10.1158/1078-0432.CCR-11-1133
PMCID: PMC3167019
PMID: 21775533
Abstract
Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients.
Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells.
Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells.
Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801-11. (C)2011 AACR.
Details
- Title: Subtitle
- Genetic Variation Predicting Cisplatin Cytotoxicity Associated with Overall Survival in Lung Cancer Patients Receiving Platinum-Based Chemotherapy
- Creators
- Xiang-Lin Tan - Mayo Clinic in FloridaAnn M. Moyer - Mayo Clinic in FloridaBrooke L. Fridley - Mayo Clinic in FloridaDaniel J. Schaid - Mayo Clinic in FloridaNifang Niu - Mayo Clinic in FloridaAnthony J. Batzler - Mayo Clinic in FloridaGregory D. Jenkins - Mayo Clinic in FloridaRyan P. Abo - Mayo Clinic in FloridaLiang Li - Mayo Clinic in FloridaJulie M. Cunningham - Mayo Clinic in FloridaZhifu Sun - Mayo Clinic in FloridaPing Yang - Mayo Clinic in FloridaLiewei Wang - Mayo Clinic in Florida
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.17(17), pp.5801-5811
- Publisher
- Amer Assoc Cancer Research
- DOI
- 10.1158/1078-0432.CCR-11-1133
- PMID
- 21775533
- PMCID
- PMC3167019
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Number of pages
- 11
- Grant note
- U19GM061388 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Mayo Foundation R01 CA80127; R01 CA84354; K22 CA130828; R01 CA138461; R25T CA92049; U19 GM61388 / U.S. NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA ASPET-Astellas PhRMA Foundation "Center of Excellence in Clinical Pharmacology" R01CA080127 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Language
- English
- Date published
- 09/01/2011
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701654302771
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