Contribution of FKBP5 genetic variation to gemcitabine treatment and survival in pancreatic adenocarcinoma.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
This comprehensive FKBP5 resequencing study provides insights into the role of genetic variation in variation of gemcitabine response.
Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.
Katarzyna A
KA
Ellsworth
Bruce W
BW
Eckloff
Liang
L
Li
Irene
I
Moon
Brooke L
BL
Fridley
Gregory D
GD
Jenkins
Erin
E
Carlson
Abra
A
Brisbin
Ryan
R
Abo
William
W
Bamlet
Gloria
G
Petersen
Eric D
ED
Wieben
Liewei
L
Wang
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5
D003841:Deoxycytidine; D011965:Receptors, Glucocorticoid; D022021:Tacrolimus Binding Proteins; D000093542:Gemcitabine; D000099159:Tacrolimus Binding Protein 5