UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, United States of America.
Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS One. 2018 Aug 14;13(8):e0202272. doi: 10.1371/journal.pone.0202272. eCollection 2018.
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.
晚期胰腺癌是一种高度难治性疾病，患者的生存时间通常不足一年。需要基于新靶点的新干预措施。我们旨在使用全基因组筛选生殖系 DNA 来鉴定吉西他滨治疗后患者总生存期 (OS) 的新遗传决定因素。我们还旨在通过体外功能分析来支持这些发现。
使用来自癌症和白血病组 B (CALGB) 80303 和梅奥诊所的两个独立胰腺癌患者队列的生殖系 DNA 全基因组筛选来选择与 OS 相关的新基因。选择维生素 D 受体基因 (VDR)，并评估 VDR 中遗传变异与循环维生素 D 水平和吉西他滨治疗的相互作用。还在人类细胞系的实验测定中评估了常见 VDR 变体的功能影响。
VDR 中的 rs2853564 变体与来自梅奥诊所 (HR 0.81，95%CI 0.70-0.94，p = 0.0059) 和 CALGB 80303 (HR 0.74，0.63-0.87，p = 0.0002) 的患者的 OS 相关。rs2853564 与高预处理 25-羟维生素 D（25(OH)D，内源性维生素 D 的衡量标准）水平（交互作用 p = 0.0079）和吉西他滨治疗（交互作用 p = 0.024）相互作用，以增加 OS。rs2853564 在荧光素酶测定中增加了转录活性，并减少了 IRF4 转录因子的结合。
我们的研究结果表明 VDR 是晚期胰腺癌患者生存的新决定因素。该基因的常见功能变异可能与内源性维生素 D 和吉西他滨治疗相互作用，以确定患者的生存获益。这些结果支持维生素 D 途径对晚期胰腺癌患者生存具有调节作用的证据。
