title: 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.
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.
authors.affiliation: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Nifang
authors.initials: N
authors.lastname: Niu
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Abo
authors.forename: Krishna
authors.initials: K
authors.lastname: Kalari
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: Qiping
authors.initials: Q
authors.lastname: Feng
authors.forename: Gregory
authors.initials: G
authors.lastname: Jenkins
authors.forename: Anthony
authors.initials: A
authors.lastname: Batzler
authors.forename: Abra G
authors.initials: AG
authors.lastname: Brisbin
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.forename: Liang
authors.initials: L
authors.lastname: Li
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 / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001952:Bridged-Ring Compounds / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; D043823:Taxoids; C080625:taxane