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 Mc Williams, Liewei M Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
JournalPharmacogenetics and Genomics
DOIs
StateAccepted/In press - Oct 4 2016

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gemcitabine
Pancreatic Neoplasms
Single Nucleotide Polymorphism
Cell Line
Gene Knockdown Techniques
Chromosomes, Human, Pair 3
Survival
Chromosomes, Human, Pair 1

ASJC Scopus subject areas

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

Cite this

Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer. / Li, Liang; Zhang, Jian Wei; Jenkins, Gregory; Xie, Fang; Carlson, Erin E.; Fridley, Brooke L.; Bamlet, William R.; Petersen, Gloria M; Mc Williams, Robert R; Wang, Liewei M.

In: Pharmacogenetics and Genomics, 04.10.2016.

Research output: Contribution to journalArticle

Li, Liang ; Zhang, Jian Wei ; Jenkins, Gregory ; Xie, Fang ; Carlson, Erin E. ; Fridley, Brooke L. ; Bamlet, William R. ; Petersen, Gloria M ; Mc Williams, Robert R ; Wang, Liewei M. / Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer. In: Pharmacogenetics and Genomics. 2016.
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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.",
author = "Liang Li and Zhang, {Jian Wei} and Gregory Jenkins and Fang Xie and Carlson, {Erin E.} and Fridley, {Brooke L.} and Bamlet, {William R.} and Petersen, {Gloria M} and {Mc Williams}, {Robert R} and Wang, {Liewei M}",
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AU - Jenkins, Gregory

AU - Xie, Fang

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AU - Fridley, Brooke L.

AU - Bamlet, William R.

AU - Petersen, Gloria M

AU - Mc Williams, Robert R

AU - Wang, Liewei M

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N2 - 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.

AB - 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.

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