Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk

作者：Jianbo Tian, Can Chen, Meilin Rao, Ming Zhang, Zequn Lu, Yimin Cai, Pingting Ying, Bin Li, Haoxue Wang, Lu Wang, Yao Li, Jinyu Huang, Linyun Fan, Xiaomin Cai, Caibo Ning, Yanmin Li, Fuwei Zhang, Wenzhuo Wang, Yuan Jiang, Yizhuo Liu, Min Wang, Heng Li, Chaoqun Huang, Zhiyong Yang, Jiang Chang, Ying Zhu, Xiaojun Yang, Xiaoping Miao · 发表于：Cancer Research · 年份：2022 · DOI：10.1158/0008-5472.can-21-4367 · 被引用次数：34 · 研究领域：Genetic Associations and Epidemiology、Protein Tyrosine Phosphatases、Genetic Syndromes and Imprinting

Understanding the genetic variation underlying transcript splicing is essential for fully dissecting the molecular mechanisms of common diseases. The available evidence from splicing quantitative trait locus (sQTL) studies using pancreatic ductal adenocarcinoma (PDAC) tissues have been limited to small sample sizes. Here we present a genome-wide sQTL analysis to identify SNP that control mRNA splicing in 176 PDAC samples from TCGA. From this analysis, 16,175 sQTLs were found to be significantly enriched in RNA-binding protein (RBP) binding sites and chromatin regulatory elements and overlapped with known loci from PDAC genome-wide association studies (GWAS). sQTLs and expression quantitative trait loci (eQTL) showed mostly nonoverlapping patterns, suggesting sQTLs provide additional insights into the etiology of disease. Target genes affected by sQTLs were closely related to cancer signaling pathways, high mutational burden, immune infiltration, and pharmaceutical targets, which will be helpful for clinical applications. Integration of a large-scale population consisting of 2,782 patients with PDAC and 7,983 healthy controls identified an sQTL variant rs1785932-T allele that promotes alternative splicing of ELP2 exon 6 and leads to a lower level of the ELP2 full-length isoform (ELP2_V1) and a higher level of a truncated ELP2 isoform (ELP2_V2), resulting in decreased risk of PDAC [OR = 0.83; 95% confidence interval (CI), 0.77-0.89; P = 1.16 × 10-6]. The ELP2_V2 isoform functio...