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Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer

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 polymo...

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Autores principales: Li, Liang, Zhang, Jian-Wei, Jenkins, Gregory, Xie, Fang, Carlson, Erin E., Fridley, Brooke L., Bamlet, William R., Petersen, Gloria M., McWilliams, Robert R., Wang, Liewei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083195/
https://www.ncbi.nlm.nih.gov/pubmed/27749787
http://dx.doi.org/10.1097/FPC.0000000000000241
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author Li, Liang
Zhang, Jian-Wei
Jenkins, Gregory
Xie, Fang
Carlson, Erin E.
Fridley, Brooke L.
Bamlet, William R.
Petersen, Gloria M.
McWilliams, Robert R.
Wang, Liewei
author_facet Li, Liang
Zhang, Jian-Wei
Jenkins, Gregory
Xie, Fang
Carlson, Erin E.
Fridley, Brooke L.
Bamlet, William R.
Petersen, Gloria M.
McWilliams, Robert R.
Wang, Liewei
author_sort Li, Liang
collection PubMed
description 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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spelling pubmed-50831952016-11-07 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. McWilliams, Robert R. Wang, Liewei Pharmacogenet Genomics Original Articles 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. Lippincott Williams & Wilkins 2016-12 2016-10-18 /pmc/articles/PMC5083195/ /pubmed/27749787 http://dx.doi.org/10.1097/FPC.0000000000000241 Text en Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Original Articles
Li, Liang
Zhang, Jian-Wei
Jenkins, Gregory
Xie, Fang
Carlson, Erin E.
Fridley, Brooke L.
Bamlet, William R.
Petersen, Gloria M.
McWilliams, Robert R.
Wang, Liewei
Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title_full Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title_fullStr Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title_full_unstemmed Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title_short Genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
title_sort genetic variations associated with gemcitabine treatment outcome in pancreatic cancer
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5083195/
https://www.ncbi.nlm.nih.gov/pubmed/27749787
http://dx.doi.org/10.1097/FPC.0000000000000241
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