摘要
Background:Pancreatic adenocarcinoma(PAAD)is an extremely lethal malignancy.Identification of the functional genes and genetic variants related to PAAD prognosis is important and challenging.Previously identified prognostic genes from several expression profile analyses were inconsistent.The regulatory genetic variants that affect PAAD prognosis were largely unknown.Methods:Firstly,a meta-analysis was performed with seven published datasets to systematically explore the candidate prognostic genes for PAAD.Next,to identify the regulatory variants for those candidate genes,expression quantitative trait loci analysis was implemented with PAAD data resources from The Cancer Genome Atlas.Then,a two-stage association study in a total of 893 PAAD patients was conducted to interrogate the regulatory variants and find the prognostic locus.Finally,a series of biochemical experiments and phenotype assays were carried out to demonstrate the biological function of variation and genes in PAAD progression process.Results:A total of 128 genes were identified associated with the PAAD prognosis in the meta-analysis.Fourteen regulatory loci in 12 of the 128 genes were discovered,among which,only rs4887783,the functional variant in the promoter of Ring Finger and WD Repeat Domain 3(RFWD3),presented significant association with PAAD prognosis in both stages of the population study.Dualluciferase reporter and electrophoretic mobility shift assays demonstrated that rs4887783-G allele,which predicts the worse prognosis,enhanced the binding of transcript factor REST,thus elevating RFWD3 expression.Further phenotypic assays revealed that excess expression of RFWD3 promoted tumor cell migration without affecting their proliferation rate.RFWD3 was highly expressed in PAAD and might orchestrate the genes in the DNA repair process.Conclusions:RFWD3 and its regulatory variant are novel genetic factors for PAAD prognosis.
基金
This work was supported by grants from the Youth Program of National Natural Science Foundation of China (No. NSFC-82003547) , China Postdoctoral Science Foundation (No. 2019M662644) , and the Fundamental Research Funds for the Central Universities (No. WHU 2042022kf1031) for Ying Zhu, National Science Fund for Distinguished Young Scholars of China (No. NSFC-81925032) and Natural Science Foundation of Hubei Province (No. 2019CFA009) for Xiaoping Miao, National Program for Support of Top-notch Young Professionals and the Young Elite Scientist Sponsorship Program by CAST (No. 2018QNRC001) for Jiang Chang, Youth Program of National Natural Science Foundation of China (No. NSFC-82103929) and the Fundamental Research Funds for the Central Universities (No. WHU 2042022kf1205) for Jianbo Tian.
