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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.

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