Abstract
Abstract 1285: Genetic variations predicting cisplatin cytotoxicity associated with the overall survival in lung cancer patients receiving platinum-based chemotherapy
Cancer research (Chicago, Ill.), Vol.71(8_Supplement), pp.1285-1285
04/15/2011
DOI: 10.1158/1538-7445.AM2011-1285
Abstract
Abstract
Background: Candidate gene and candidate pathway-based pharmacogenomic studies have been used to investigate the inherited variability of prognosis of lung cancer treated with platinum-based chemoptherapy. In order to make it possible to conduct an ‘unbiased’ query across the entire genome, a genome-wide association study (GWAS) in 283 lymphoblastoid cell lines (LCLs) was carried out to help identify candidate SNPs associated with variation in cisplatin cytotoxicity. Furthermore, we set out to test the hypothesis that genetic variation resulting in differences in cisplatin cytotoxicity might influence the overall survival of patients with lung cancer treated with platinum-based antineoplastic agents.
Material and Methods: We applied ethnically diverse Coriell “Human Variation Panel” LCLs for GWAS. Then, we picked 168 top significant SNPs selected from GWAS in 283 LCLs and genotyped these SNPs in 1183 lung cancer patients (222 SCLC and 961 NSCLC) who received platinum-based chemotherapy. Genotyping was performed using the Illumina Golden Gate platform. The association of SNPs with lung cancer overall survival was analyzed by Cox regression model after adjusting for disease stage. Functional validation of candidate genes was performed by siRNA screening in NSCLC cell lines CRL5872, H1299 and SCLC cell line CRL5823.
Results: A total of 157 SNPs were successfully genotyped for 1183 lung cancer patient samples. The Cox regression analysis indicated that 9 and 10 different SNPs were associated with overall survival for NSCLC and SCLC patients, respectively (p value <0.05). Fifteen genes including 7 genes located in the region of 200kb up or downstream of 4 SNPs (rs11169748, rs2440915, rs5952066 and rs7620841) and 8 genes for which the expression was correlated with three SNPs (rs11169748, rs2440915 and rs5952066) were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which the expression levels were correlated with the SNPs rs11169748 and rs2440915, significantly decreased cisplatin sensitivity in lung cancer cell lines CRL5872, H1299 and CRL5823.
Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes and SNPs that might help predict treatment outcomes of platinum-based therapy in lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1285. doi:10.1158/1538-7445.AM2011-1285
Details
- Title: Subtitle
- Abstract 1285: Genetic variations predicting cisplatin cytotoxicity associated with the overall survival in lung cancer patients receiving platinum-based chemotherapy
- Creators
- Xiang-Lin TanAnn M. Moyer - Mayo ClinicDaniel J. Schaid - Mayo ClinicNifang Niu - Mayo ClinicAnthony Batzler - Mayo ClinicLiang Li - Mayo ClinicZhifu Sun - Mayo ClinicPing Yang - Mayo ClinicLiewei Wang - Mayo Clinic
- Resource Type
- Abstract
- Publication Details
- Cancer research (Chicago, Ill.), Vol.71(8_Supplement), pp.1285-1285
- Publisher
- AMER ASSOC CANCER RESEARCH
- DOI
- 10.1158/1538-7445.AM2011-1285
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 04/15/2011
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984701748602771
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