title: Genetic variation predicting cisplatin cytotoxicity associated with overall survival in lung cancer patients receiving platinum-based chemotherapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: Xiang-Lin
authors.initials: XL
authors.lastname: Tan
authors.forename: Ann M
authors.initials: AM
authors.lastname: Moyer
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Nifang
authors.initials: N
authors.lastname: Niu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Batzler
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Jenkins
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D002945:Cisplatin / Q000009:adverse effects / Q000627:therapeutic use*; D064550:Death-Associated Protein Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008780:Methyltransferases / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D021122:Protein Subunits / Q000096:biosynthesis / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D021122:Protein Subunits; D034741:RNA, Small Interfering; D008780:Methyltransferases; C579101:DAPK3 protein, human; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002945:Cisplatin