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Pancreatic Cancer – live a year longer if have high vitamin D and good Vitamin D Receptor – Aug 2018

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

PLoS One. 2018 Aug 14;13(8):e0202272. doi: 10.1371/journal.pone.0202272. eCollection 2018.
Innocenti F1, Owzar K2,3, Jiang C3, Etheridge AS1, Gordân R2, Sibley AB3, Mulkey F3, Niedzwiecki D3, Glubb D1, Neel N1, Talamonti MS4, Bentrem DJ5, Seiser E1, Yeh JJ1, Van Loon K6, McLeod H7, Ratain MJ8, Kindler HL8, Venook AP6, Nakamura Y8, Kubo M9, Petersen GM10, Bamlet WR10, McWilliams RR10.

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PURPOSE:
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.

PATIENTS AND METHODS:
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.

RESULTS:
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.

CONCLUSION:
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.

PMID: 30107003 DOI: 10.1371/journal.pone.0202272


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