Transcriptome-wide association study of alternative polyadenylation identifies susceptibility genes in non-small cell lung cancer

被引：0

作者：

Xu, Xiaohang ^{[1
,2
,3
]}

Wang, Sicong ^{[1
,2
,3
]}

Zhou, Hanyi ^{[1
,2
]}

Tan, Qilong ^{[1
,2
,3
]}

Lang, Zeyong ^{[1
,2
]}

Zhu, Yun ^{[1
,2
]}

Yuan, Huadi ^{[4
]}

Wu, Zixiang ^{[4
]}

Zhu, Ling ^{[4
]}

Hu, Kejia ^{[1
,2
,5
]}

Li, Wenyuan ^{[1
,2
,3
]}

Zhou, Dan ^{[1
,2
,3
]}

Wu, Ming ^{[4
]}

Wu, Xifeng ^{[1
,2
,5
,6
,7
]}

机构：

[1] Zhejiang Univ, Affiliated Hosp 2, Ctr Clin Big Data & Analyt, Sch Med, Hangzhou, Peoples R China

[2] Zhejiang Univ, Sch Publ Hlth, Sch Med, Hangzhou, Peoples R China

[3] Zhejiang Key Lab Intelligent Prevent Med, Hangzhou, Peoples R China

[4] Zhejiang Univ, Affiliated Hosp 2, Sch Med, Dept Thorac Surg, Hangzhou, Peoples R China

[5] Zhejiang Univ, Natl Inst Data Sci Hlth & Med, Hangzhou, Zhejiang, Peoples R China

[6] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA

[7] Zhejiang Canc Hosp, Hangzhou, Peoples R China

来源：

ONCOGENE | 2025年 / 44卷 / 26期

关键词：

COMPREHENSIVE CHARACTERIZATION; MESSENGER-RNA; EXPRESSION; LOCI; RISK; VARIANTS; CLEAVAGE; REVEALS; TRAITS;

D O I：

10.1038/s41388-025-03338-8

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alternative polyadenylation (APA) plays a crucial role in cancer development and prognosis. However, the molecular characteristics of APA related to non-small cell lung cancer (NSCLC) susceptibility remain understudied, especially in East Asian populations. In this study, we constructed an atlas of APA-regulated 3 ' untranslated region (3 ' UTR) and profiled its genetic regulation in 747 lung tissue samples (including tumors and paired normal tissues) from 417 NSCLC Chinese patients. We verified a significant global shortening of 3 ' UTRs in tumor samples compared to normal samples and underscored the value of APA-regulation as a prognostic marker. The 3 ' UTR APA quantitative trait loci (3 ' aQTL) was identified by regressing the percentage of distal poly(A) site usage index (PDUI) value on genetic variants. We found that a significant proportion 3 ' aQTLs are independent of genetic regulation of expression and are specific in Chinese. We also conducted a 3 ' UTR APA transcriptome-wide association study (3 ' aTWAS) by integrating the APA regulation atlas with a genome-wide association study (GWAS) for NSCLC involving 7035 cases and 185,413 cancer-free controls. We identified NSCLC-associated genes, highlighting TUBB, TEAD3, and PPP1R10. Combining the consistent results from colocalization analysis, differential APA analysis, and survival analysis, we provide novel evidence for the role TUBB APA regulation in NSCLC and identified potential upstream regulators. Overall, our study profiled the APA regulation and highlighted the substantial role of APA in NSCLC carcinogenesis and prognosis in East Asian populations.

引用

页码：2127 / 2141

页数：15

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