Contribution of FKBP5 Genetic Variation to Gemcitabine Treatment and Survival in Pancreatic Adenocarcinoma

Katarzyna A. Ellsworth, Bruce W. Eckloff, Liang Li, Irene Moon, Brooke L. Fridley, Gregory D. Jenkins, Erin Carlson, Abra Brisbin, Ryan Abo, William Bamlet, Gloria M Petersen, Eric D Wieben, Liewei M Wang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Purpose:FKBP51, (FKBP5), is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.Experimental Design:We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies.Results:In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs) in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 "A(T)" SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR). The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing.Conclusion:This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

Original languageEnglish (US)
Article numbere70216
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2013

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gemcitabine
pancreatic neoplasms
adenocarcinoma
Pancreatic Neoplasms
Tumors
Adenocarcinoma
Polymorphism
single nucleotide polymorphism
Single Nucleotide Polymorphism
genetic variation
neoplasms
Survival
Nucleotides
DNA
Glucocorticoid Receptors
Neoplasms
Association reactions
genomics
DNA-binding proteins
DNA-Binding Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Contribution of FKBP5 Genetic Variation to Gemcitabine Treatment and Survival in Pancreatic Adenocarcinoma. / Ellsworth, Katarzyna A.; Eckloff, Bruce W.; Li, Liang; Moon, Irene; Fridley, Brooke L.; Jenkins, Gregory D.; Carlson, Erin; Brisbin, Abra; Abo, Ryan; Bamlet, William; Petersen, Gloria M; Wieben, Eric D; Wang, Liewei M.

In: PLoS One, Vol. 8, No. 8, e70216, 01.08.2013.

Research output: Contribution to journalArticle

Ellsworth, KA, Eckloff, BW, Li, L, Moon, I, Fridley, BL, Jenkins, GD, Carlson, E, Brisbin, A, Abo, R, Bamlet, W, Petersen, GM, Wieben, ED & Wang, LM 2013, 'Contribution of FKBP5 Genetic Variation to Gemcitabine Treatment and Survival in Pancreatic Adenocarcinoma', PLoS One, vol. 8, no. 8, e70216. https://doi.org/10.1371/journal.pone.0070216
Ellsworth, Katarzyna A. ; Eckloff, Bruce W. ; Li, Liang ; Moon, Irene ; Fridley, Brooke L. ; Jenkins, Gregory D. ; Carlson, Erin ; Brisbin, Abra ; Abo, Ryan ; Bamlet, William ; Petersen, Gloria M ; Wieben, Eric D ; Wang, Liewei M. / Contribution of FKBP5 Genetic Variation to Gemcitabine Treatment and Survival in Pancreatic Adenocarcinoma. In: PLoS One. 2013 ; Vol. 8, No. 8.
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abstract = "Purpose:FKBP51, (FKBP5), is a negative regulator of Akt. Variability in FKBP5 expression level is a major factor contributing to variation in response to chemotherapeutic agents including gemcitabine, a first line treatment for pancreatic cancer. Genetic variation in FKBP5 could influence its function and, ultimately, treatment response of pancreatic cancer.Experimental Design:We set out to comprehensively study the role of genetic variation in FKBP5 identified by Next Generation DNA resequencing on response to gemcitabine treatment of pancreatic cancer by utilizing both tumor and germline DNA samples from 43 pancreatic cancer patients, including 19 paired normal-tumor samples. Next, genotype-phenotype association studies were performed with overall survival as well as with FKBP5 gene expression in tumor using the same samples in which resequencing had been performed, followed by functional genomics studies.Results:In-depth resequencing identified 404 FKBP5 single nucleotide polymorphisms (SNPs) in normal and tumor DNA. SNPs with the strongest associations with survival or FKBP5 expression were subjected to functional genomic study. Electromobility shift assay showed that the rs73748206 {"}A(T){"} SNP altered DNA-protein binding patterns, consistent with significantly increased reporter gene activity, possibly through its increased binding to Glucocorticoid Receptor (GR). The effect of rs73748206 was confirmed on the basis of its association with FKBP5 expression by affecting the binding to GR in lymphoblastoid cell lines derived from the same patients for whom DNA was used for resequencing.Conclusion:This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.",
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AU - Carlson, Erin

AU - Brisbin, Abra

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