Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer

Liang Li, Jian Wei Zhang, Gregory Jenkins, Fang Xie, Erin E. Carlson, Brooke L. Fridley, William R. Bamlet, Gloria M. Petersen, Robert R. McWilliams, Liewei Wang

Research output: Contribution to journalArticle

6 Scopus citations

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. Materials and 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. Conclusion: We identified SNPs with gemcitabinedependent 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. Pharmacogenetics and Genomics 26:527-537

Original languageEnglish (US)
Pages (from-to)527-537
Number of pages11
JournalPharmacogenetics and genomics
Volume26
Issue number12
DOIs
StatePublished - 2016

Keywords

  • R-cadherin)
  • cadherin-4 (CDH4
  • gemcitabine (dFdC)
  • genotype-phenotype association
  • lymphoblastoid cell lines
  • pancreatic cancer
  • pharmacogenomics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Fingerprint Dive into the research topics of 'Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer'. Together they form a unique fingerprint.

  • Cite this