种系多态性与癌症的不同生存结局有关,但在鼻咽癌(NPC)中并未得到很好的研究。这里,进行了两阶段关联研究,以发现与NPC预后相关的种系多态性.发现阶段包括来自中国南方的两个连续的NPC患者队列。确定了246173个单核苷酸多态性(SNP)的全外显子组基因型,然后在Cox比例风险回归模型下对每个SNP进行生存分析。候选SNP在来自中国南方和新加坡的另外两个独立队列中复制。所有样本(n=5553)的荟萃分析证实了rs1131636-T的存在,位于RPA1的3'-UTR中,总生存期较差(HR=1.33,95%CI=1.20-1.47,P=6.31×10-8)。生物信息学和生物测定表明,rs1131636对上游RPA1具有调节作用。功能研究进一步表明,RPA1促进生长,入侵,迁移,和NPC细胞的辐射抗性。此外,miR-1253被鉴定为RPA1表达的抑制剂,可能是通过调节其与rs1131636基因座的结合亲和力。总的来说,这些发现提供了一个有希望的生物标志物,帮助患者分层生存不佳,以及NPC的潜在药物靶标。
Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association
study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3\'-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.