Systematic analysis on expression quantitative trait loci identifies a novel regulatory variant in ring finger and WD repeat domain 3 associated with prognosis of pancreatic cancer.
Systematic analysis on expression quantitative trait loci identifies a novel regulatory variant in ring finger and WD repeat domain 3 associated with prognosis of pancreatic cancer.
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对表达定量性状基因座的系统分析确定了环手指和WD重复域3中与胰腺癌预后相关的新调节变体。
DOI：
10.1097/cm9.0000000000002180
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发表时间：
2022-06-05
影响因子：
6.1
通讯作者：
Miao, Xiaoping
中科院分区：
文献类型：
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作者：
Zhu, Ying;Peng, Xiating;Wang, Xiaoyang;Ying, Pingting;Wang, Haoxue;Li, Bin;Li, Yue;Zhang, Ming;Cai, Yimin;Lu, Zequn;Niu, Siyuan;Yang, Nan;Zhong, Rong;Tian, Jianbo;Chang, Jiang;Miao, Xiaoping
胰腺癌是一种致死率极高的恶性肿瘤。鉴定与PAAD预后相关的功能基因和遗传变异是重要且具有挑战性的。以前确定的预后基因从几个表达谱分析是不一致的。影响PAAD预后的调节基因变异在很大程度上是未知的。首先，对7个已发表的数据集进行荟萃分析，系统地探索PAAD的候选预后基因。接下来，为了鉴定这些候选基因的调控变体，用来自癌症基因组图谱的PAAD数据资源实施表达定量性状基因座分析。然后，在总共893例PAAD患者中进行了两阶段关联研究，以询问调节变体并找到预后位点。最后，通过一系列的生化实验和表型分析，阐明了变异和基因在PAAD进展过程中的生物学功能。在荟萃分析中，共确定了128个与PAAD预后相关的基因。在128个基因中的12个基因中发现了14个调控位点，其中只有rs 4887783，即Ring Finger和WD Repeat Domain 3（RFWD 3）启动子中的功能变体，在两个群体研究阶段均与PAAD预后显著相关。双荧光素酶报告和电泳迁移率变动分析表明，rs 4887783-G等位基因，预测预后较差，增强了转录因子REST的结合，从而提高RFWD 3的表达。进一步的表型分析表明，RFWD 3的过度表达促进肿瘤细胞迁移，而不影响其增殖率。RFWD 3在PAAD中高表达，可能参与DNA修复过程中的基因调控。RFWD 3及其调控变异体是PAAD预后的新遗传因子。
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. 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. 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. Dual-luciferase 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. RFWD3 and its regulatory variant are novel genetic factors for PAAD prognosis.