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

Abstract

PurposeFKBP51, (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 DesignWe 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.ResultsIn-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.ConclusionThis comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.

RETRACTED: Hsp90‐binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity

“…Thus, FKBP51 positively regulates melanoma stemness and metastatic potential (Romano et al., 2013). FKBP51 is thought to be a key factor in the progression and chemotherapeutic response of pancreatic adenocarcinoma (Ellsworth et al., 2013), and it is close‐related to acute lymphoblastic leukemia and several variants of breast, ovary and lung tumor pathologies (Romano et al., 2010b).…”

Gene–environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism

“…A number of studies have investigated the FKBP5 locus by using a tagging approach to investigate variants that best cover the genetic diversity in different populations, but recently next‐generation sequencing projects that catalog all variants in this gene, including rare and private variants, have been described (Ellsworth et al 2013a,b; Pelleymounter et al ). The best investigated and characterized polymorphisms are within a haplotype spanning the whole gene (in Caucasians from the promoter area to the 3′UTR and in Africans from intron 1 to the 3′UTR) that is tagged by rs3800373, rs9296158 or rs1360780 and contains up to 18 single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium in Caucasians (when mapped to the 1000 genomes next‐generation sequencing project using r 2 threshold of 0.8 and distance of 500 kb).…”

Pharmacogenomics‐Driven Prediction of Antidepressant Treatment Outcomes: A Machine‐Learning Approach With Multi‐trial Replication

“…Crucially, we demonstrated cross‐trial replication of prediction performance across rating scales in both STAR*D (QIDS‐C scale) and ISPC (HDRS scale) trials with precision similar to that observed in training with PGRN‐AMPS data. This work also represents an advance over traditional pharmacogenetic candidate gene approaches that identify plausible genes and SNPs associated with outcomes . We achieved that advance by asking whether the application of machine‐learning approaches that combine clinical assessments with a group of functionally validated pharmacogenomic SNPs as predictor variables might make it possible to predict SSRI treatment outcomes.…”