Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer

Pharmacogenet Genomics. 2016 Dec;26(12):527-537. doi: 10.1097/FPC.0000000000000241.

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 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.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic / administration & dosage*
  • Antimetabolites, Antineoplastic / pharmacology
  • Cadherins / genetics*
  • Cell Line, Tumor
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Female
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pharmacogenomic Variants*
  • Survival Analysis
  • Treatment Outcome

Substances

  • Antimetabolites, Antineoplastic
  • Cadherins
  • R-cadherin
  • Deoxycytidine
  • gemcitabine