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

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

doi:10.1371/journal.pone.0202272

Abstract

PurposeAdvanced 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 methodsGenome-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.ResultsThe 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.ConclusionOur 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.

Highlights

Advanced pancreatic cancer is rarely curable at the time of diagnosis and is typically associated with survival of little more than a year
The rs2853564 variant in vitamin D receptor gene (VDR) was associated with overall survival (OS) in patients from both the Mayo Clinic (HR 0.81, 95% CI 0.70–0.94, p = 0.0059) and Cancer and Leukemia Group B (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
Our findings propose VDR as a novel determinant of survival in advanced pancreatic cancer patients

Summary

Introduction

Advanced pancreatic cancer is rarely curable at the time of diagnosis and is typically associated with survival of little more than a year. Estimated new cases of advanced pancreatic cancer in the USA for 2017 is 53,670 and an estimated number of deaths at 43,090 [1]. Recent approved therapies conferring modest survival advantages include folfirinox, nab-paclitaxel, and others. Multidisciplinary efforts have focused on improving tools for early diagnosis and cataloging the architecture of somatic mutations. In conjunction with these efforts, the interrogation of the germline genome of patients [3] aims to characterize the constitutive basis of biological systems of fundamental importance for tumor biology, such as angiogenesis, inflammation, immunity, and others [4]. Scanning the entire genome for germline DNA variants results in the discovery of novel candidate genes worthy of further investigation [5]

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