The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation.
<h4>Purpose</h4>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 treatme...
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Public Library of Science (PLoS)
2018-01-01
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| author | 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 Nakamura Michiaki Kubo Gloria M Petersen William R Bamlet Robert R McWilliams |
| author_facet | 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 Nakamura Michiaki Kubo Gloria M Petersen William R Bamlet Robert R McWilliams |
| author_sort | Federico Innocenti |
| collection | DOAJ |
| description | <h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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. |
| format | Article |
| id | doaj-art-3e344ee31f6b477ca981d00ace30fd70 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-3e344ee31f6b477ca981d00ace30fd702025-08-20T02:36:18ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01138e020227210.1371/journal.pone.0202272The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation.Federico InnocentiKouros OwzarChen JiangAmy S EtheridgeRaluca GordânAlexander B SibleyFlora MulkeyDonna NiedzwieckiDylan GlubbNicole NeelMark S TalamontiDavid J BentremEric SeiserJen Jen YehKatherine Van LoonHoward McLeodMark J RatainHedy L KindlerAlan P VenookYusuke NakamuraMichiaki KuboGloria M PetersenWilliam R BamletRobert R McWilliams<h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0202272&type=printable |
| spellingShingle | 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 Nakamura Michiaki Kubo Gloria M Petersen William R Bamlet Robert R McWilliams The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. PLoS ONE |
| title | The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. |
| title_full | The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. |
| title_fullStr | The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. |
| title_full_unstemmed | The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. |
| title_short | The vitamin D receptor gene as a determinant of survival in pancreatic cancer patients: Genomic analysis and experimental validation. |
| title_sort | vitamin d receptor gene as a determinant of survival in pancreatic cancer patients genomic analysis and experimental validation |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0202272&type=printable |
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