Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk
Aberrant RNA Splicing Is a Primary Link between Genetic Variation and Pancreatic Cancer Risk
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DOI：
10.1158/0008-5472.can-21-4367
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发表时间：
2022-06-01
期刊：
影响因子：
11.2
通讯作者：
Miao, Xiaoping
中科院分区：
文献类型：
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作者：
Tian, Jianbo;Chen, Can;Miao, Xiaoping
了解转录物剪接背后的遗传变异对于全面剖析常见疾病的分子机制至关重要。使用胰腺导管腺癌（PDAC）组织进行剪接数量性状位点（sQTL）研究的现有证据仅限于小样本量。在此，我们提出了一项全基因组sQTL分析，以确定来自TCGA的176个PDAC样本中控制mRNA剪接的SNP。通过分析，发现16,175个sqtl显著富集于rna结合蛋白（RBP）结合位点和染色质调控元件，并与PDAC全基因组关联研究（GWAS）中已知的位点重叠。sqtl和表达数量性状位点（eQTL）大多显示非重叠模式，表明sqtl为疾病的病因提供了额外的见解。受sqtl影响的靶基因与肿瘤信号通路、高突变负担、免疫浸润和药物靶点密切相关，有助于临床应用。由2782名PDAC患者和7983名健康对照组成的大规模人群整合发现了一个sQTL变异rs1785932-T等位基因，该等位基因促进ELP2外显子6的选择性剪接，导致ELP2全长亚型（ELP2_V1）水平降低，ELP2截断亚型（ELP2_V2）水平升高，从而降低PDAC的风险[OR = 0.83；95%置信区间（CI）， 0.77 ~ 0.89；P = 1.16 × 10(-6)]。ELP2_V2亚型作为一种潜在的肿瘤抑制基因，通过表现出比ELP2_V1更强的与JAK1/STAT3的结合亲和力，进而阻断磷酸化STAT3 （pSTAT3）通路的病理激活，从而抑制PDAC细胞的增殖。总的来说，这些发现提供了一个信息丰富的sQTL资源，并深入了解了将剪接变异体与PDAC风险联系起来的调控机制。
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 x 10(-6)]. The ELP2_V2 isoform functioned as a potential tumor suppressor gene, inhibiting PDAC cell proliferation by exhibiting stronger binding affinity to JAK1/STAT3 than ELP2_V1 and subsequently blocking the pathologic activation of the phosphorylated STAT3 (pSTAT3) pathway. Collectively, these findings provide an informative sQTL resource and insights into the regulatory mechanisms linking splicing variants to PDAC risk.