The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation

• Published in: PloS one 2018-08, Vol.13 (8), p.e0202272-e0202272
• Main Authors: Innocenti, Federico, Owzar, Kouros, Jiang, Chen, Etheridge, Amy S, Gordân, Raluca, Sibley, Alexander B, Mulkey, Flora, Niedzwiecki, Donna, Glubb, Dylan, Neel, Nicole, Talamonti, Mark S, Bentrem, David J, Seiser, Eric, Yeh, Jen Jen, Van Loon, Katherine, McLeod, Howard, Ratain, Mark J, Kindler, Hedy L, Venook, Alan P, Nakamura, Yusuke, Kubo, Michiaki, Petersen, Gloria M, Bamlet, William R, McWilliams, Robert R
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D; Adenocarcinoma - blood; Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - mortality; Aged; Antimetabolites, Antineoplastic - therapeutic use; Antineoplastic Agents, Immunological - therapeutic use; Bevacizumab - therapeutic use; Binding sites; Bioinformatics; Biology and Life Sciences; Cancer; Cancer genetics; Cancer patients; Care and treatment; Cell cycle; Cell Line, Tumor; Cyclin-dependent kinases; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Deoxyribonucleic acid; DNA; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Functional analysis; Gemcitabine; Genes; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease; Genetic variation; Genome-Wide Association Study; Genomes; Genomic analysis; Health aspects; Humans; Interferon regulatory factor 4; Leukemia; Male; Medicine and Health Sciences; Middle Aged; Pancreatic cancer; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - mortality; Patients; Pharmacy; Physical sciences; Polymorphism, Single Nucleotide; Receptors, Calcitriol - genetics; Research and Analysis Methods; RNA interference; RNA, Messenger - metabolism; Screens; Survival; Vitamin D; Vitamin D - blood; Vitamin D receptors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0202272

Advanced pancreatic cancer is a highly refractory disease almost always associated with survival of little more than a year. New interventions based on novel targets are needed. We aim to identify new genetic determinants of overall survival (OS) in patients after treatment with gemcitabine using genome-wide screens of germline DNA. We aim also to support these findings with in vitro functional analysis. Genome-wide screens of germline DNA in two independent cohorts of pancreatic cancer patients (from the Cancer and Leukemia Group B (CALGB) 80303 and the Mayo Clinic) were used to select new genes associated with OS. The vitamin D receptor gene (VDR) was selected, and the interactions of genetic variation in VDR with circulating vitamin D levels and gemcitabine treatment were evaluated. Functional effects of common VDR variants were also evaluated in experimental assays in human cell lines. The rs2853564 variant in VDR was associated with OS in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70-0.94, p = 0.0059) and CALGB 80303 (HR 0.74, 0.63-0.87, p = 0.0002). rs2853564 interacted with high pre-treatment levels of 25-hydroxyvitamin D (25(OH)D, a measure of endogenous vitamin D) (p = 0.0079 for interaction) and with gemcitabine treatment (p = 0.024 for interaction) to confer increased OS. rs2853564 increased transcriptional activity in luciferase assays and reduced the binding of the IRF4 transcription factor. Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients. Common functional variation in this gene might interact with endogenous vitamin D and gemcitabine treatment to determine improved patient survival. These results support evidence for a modulatory role of the vitamin D pathway for the survival of advanced pancreatic cancer patients.