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

Federico Innocenti, Kouros Owzar, Chen Jiang, Amy S. Etheridge, Raluca Gordân, Alexander B. Sibley, Flora Mulkey, Donna Niedzwiecki, Dylan Glubb, Nicole Neel, Mark S. Talamonti, David J. Bentrem, Eric Seiser, Jen Jen Yeh, Katherine Van Loon, Howard McLeod, Mark J. Ratain, Hedy L. Kindler, Alan P. Venook, Yusuke NakamuraMichiaki Kubo, Gloria M. Petersen, William R. Bamlet, Robert R. McWilliams

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere0202272
JournalPloS one
Volume13
Issue number8
DOIs
Publication statusPublished - 08-2018

Fingerprint

pancreatic neoplasms
Calcitriol Receptors
gemcitabine
vitamin D
Pancreatic Neoplasms
Genes
genomics
receptors
Survival
Vitamin D
genes
leukemia
Leukemia
Assays
germ cells
Genome
Therapeutics
DNA
Functional analysis
neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Innocenti, F., Owzar, K., Jiang, C., Etheridge, A. S., Gordân, R., Sibley, A. B., ... McWilliams, R. R. (2018). The Vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. PloS one, 13(8), [e0202272]. https://doi.org/10.1371/journal.pone.0202272
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. / The Vitamin D receptor gene as a determinant of survival in pancreatic cancer patients : Genomic analysis and experimental validation. In: PloS one. 2018 ; Vol. 13, No. 8.
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title = "The Vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation",
abstract = "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.",
author = "Federico Innocenti and Kouros Owzar and Chen Jiang and Etheridge, {Amy S.} and Raluca Gord{\^a}n and Sibley, {Alexander B.} and Flora Mulkey and Donna Niedzwiecki and Dylan Glubb and Nicole Neel and Talamonti, {Mark S.} and Bentrem, {David J.} and Eric Seiser and Yeh, {Jen Jen} and {Van Loon}, Katherine and Howard McLeod and Ratain, {Mark J.} and Kindler, {Hedy L.} and Venook, {Alan P.} and Yusuke Nakamura and Michiaki Kubo and Petersen, {Gloria M.} and Bamlet, {William R.} and McWilliams, {Robert R.}",
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month = "8",
doi = "10.1371/journal.pone.0202272",
language = "English",
volume = "13",
journal = "PLoS One",
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Innocenti, F, Owzar, K, Jiang, C, Etheridge, AS, Gordân, R, Sibley, AB, Mulkey, F, Niedzwiecki, D, Glubb, D, Neel, N, Talamonti, MS, Bentrem, DJ, Seiser, E, Yeh, JJ, Van Loon, K, McLeod, H, Ratain, MJ, Kindler, HL, Venook, AP, Nakamura, Y, Kubo, M, Petersen, GM, Bamlet, WR & McWilliams, RR 2018, 'The Vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation', PloS one, vol. 13, no. 8, e0202272. https://doi.org/10.1371/journal.pone.0202272

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

In: PloS one, Vol. 13, No. 8, e0202272, 08.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The Vitamin D receptor gene as a determinant of survival in pancreatic cancer patients

T2 - Genomic analysis and experimental validation

AU - Innocenti, Federico

AU - Owzar, Kouros

AU - Jiang, Chen

AU - Etheridge, Amy S.

AU - Gordân, Raluca

AU - Sibley, Alexander B.

AU - Mulkey, Flora

AU - Niedzwiecki, Donna

AU - Glubb, Dylan

AU - Neel, Nicole

AU - Talamonti, Mark S.

AU - Bentrem, David J.

AU - Seiser, Eric

AU - Yeh, Jen Jen

AU - Van Loon, Katherine

AU - McLeod, Howard

AU - Ratain, Mark J.

AU - Kindler, Hedy L.

AU - Venook, Alan P.

AU - Nakamura, Yusuke

AU - Kubo, Michiaki

AU - Petersen, Gloria M.

AU - Bamlet, William R.

AU - McWilliams, Robert R.

PY - 2018/8

Y1 - 2018/8

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pone.0202272

DO - 10.1371/journal.pone.0202272

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