title: Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer.
abstract: BACKGROUND
  Pancreatic cancer is a rapidly fatal disease with gemcitabine remaining the first-line therapy. We performed a genotype-phenotype association study to identify biomarkers for predicting gemcitabine treatment outcome.
  
  
  METHODS
  We selected the top 200 single nucleotide polymorphisms (SNPs) identified from our previous genome-wide association study to associate with overall survival using 400 patients treated with/or without gemcitabine, followed by imputation analysis for regions around the identified SNPs and a replication study using an additional 537 patients by the TaqMan genotyping assay. Functional validation was performed using quantitative reverse transcription-PCR for gemcitabine-induced expression in genotyped lymphoblastoid cell lines and siRNA knockdown for candidate genes in pancreatic cancer cell lines.
  
  
  RESULTS
  Four SNPs in chromosome 1, 3, 9, and 20 showed an interaction with gemcitabine from the discovery cohort of 400 patients (P<0.01). Subsequently, we selected those four genotyped plus four imputed SNPs for SNP×gemcitabine interaction analysis using the secondary validation cohort. Two imputed SNPs in CDH4 and KRT8P35 showed a trend in interaction with gemcitabine treatment. The lymphoblastoid cell lines with the variant sequences showed increased CDH4 expression compared with the wild-type cells after gemcitabine exposure. Knockdown of CDH4 significantly desensitized pancreatic cancer cells to gemcitabine cytotoxicity. The CDH4 SNPs that interacted with treatment are more predictive than prognostic.
  
  
  CONCLUSIONS
  We identified SNPs with gemcitabine-dependent effects on overall survival. CDH4 might contribute to variations in gemcitabine response. These results might help us to better predict gemcitabine response in pancreatic cancer.
authors.affiliation: aDepartment of Oncology bKey Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology cDepartment of Abdominal Surgery, Cancer Hospital, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China dDepartment of Molecular Pharmacology and Experimental Therapeutics, Division of Clinical Pharmacology eDepartment of Health Sciences Research, Division of Biomedical Statistics and Informatics fDepartment of Oncology, Mayo Clinic, Rochester, Minnesota gDepartment of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhang
authors.forename: Gregory
authors.initials: G
authors.lastname: Jenkins
authors.forename: Fang
authors.initials: F
authors.lastname: Xie
authors.forename: Erin E
authors.initials: EE
authors.lastname: Carlson
authors.forename: Brooke L
authors.initials: BL
authors.lastname: Fridley
authors.forename: William R
authors.initials: WR
authors.lastname: Bamlet
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000071184:Pharmacogenomic Variants; D016019:Survival Analysis; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; C083970:R-cadherin; D003841:Deoxycytidine; D000093542:Gemcitabine