Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci

Author:

Li Bin123ORCID,Cai Yimin123ORCID,Chen Can123ORCID,Li Gaoyuan1ORCID,Zhang Ming1ORCID,Lu Zequn1ORCID,Zhang Fuwei1ORCID,Huang Jinyu1ORCID,Fan Linyun1ORCID,Ning Caibo1ORCID,Li Yanmin1ORCID,Wang Wenzhuo1ORCID,Geng Hui1ORCID,Liu Yizhuo1ORCID,Chen Shuoni1ORCID,Li Hanting1ORCID,Yang Shuhui1ORCID,Zhang Heng1ORCID,Tian Wen1ORCID,Zhu Zhongchao4ORCID,Xu Bin5ORCID,Li Heng6ORCID,Li Haijie7ORCID,Jin Meng8ORCID,Wang Xiaoyang9ORCID,Zhang Shaokai9ORCID,Liu Jiuyang10ORCID,Huang Chaoqun10ORCID,Yang Xiaojun10ORCID,Wei Yongchang11ORCID,Zhu Ying123ORCID,Tian Jianbo123ORCID,Miao Xiaoping12341213ORCID

Affiliation:

1. 1Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.

2. 2Department of Gastrointestinal Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.

3. 3Department of Radiation Oncology, Renmin Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.

4. 4Department of Pancreatic Surgery Department, Renmin Hospital of Wuhan University, Wuhan, China.

5. 5Cancer Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, China.

6. 6Department of Urology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

7. 7Department of Gastrointestinal Cancer Research Institute, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

8. 8Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

9. 9Department of Cancer Epidemiology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Cancer Prevention and Control, Henan International Joint Laboratory of Cancer Prevention, Zhengzhou, China.

10. 10Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.

11. 11Department of Gastrointestinal Oncology, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.

12. 12Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Sciences and Technology, Wuhan, China.

13. 13Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.

Abstract

Abstract Alternative polyadenylation (APA) is emerging as a major mechanism of posttranscriptional regulation. APA can impact the development and progression of cancer, suggesting that the genetic determinants of APA might play an important role in regulating cancer risk. Here, we depicted a pan-cancer atlas of human APA quantitative trait loci (apaQTL), containing approximately 0.7 million apaQTLs across 32 cancer types. Systematic multiomics analyses indicated that cancer apaQTLs could contribute to APA regulation by altering poly(A) motifs, RNA-binding proteins (RBP), and chromatin regulatory elements and were preferentially enriched in genome-wide association studies (GWAS)–identified cancer susceptibility loci. Moreover, apaQTL-related genes (aGene) were broadly related to cancer signaling pathways, high mutational burden, immune infiltration, and drug response, implicating their potential as therapeutic targets. Furthermore, apaQTLs were mapped in Chinese colorectal cancer tumor tissues and then screened for functional apaQTLs associated with colorectal cancer risk in 17,789 cases and 19,951 controls using GWAS-ChIP data, with independent validation in a large-scale population consisting of 6,024 cases and 10,022 controls. A multi-ancestry–associated apaQTL variant rs1020670 with a C>G change in DNM1L was identified, and the G allele contributed to an increased risk of colorectal cancer. Mechanistically, the risk variant promoted aberrant APA and facilitated higher usage of DNM1L proximal poly(A) sites mediated by the RBP CSTF2T, which led to higher expression of DNM1L with a short 3′UTR. This stabilized DNM1L to upregulate its expression, provoking colorectal cancer cell proliferation. Collectively, these findings generate a resource for understanding APA regulation and the genetic basis of human cancers, providing insights into cancer etiology. Significance: Cancer risk is mediated by alternative polyadenylation quantitative trait loci, including the rs1020670-G variant that promotes alternative polyadenylation of DNM1L and increases colorectal cancer risk.

Funder

Program of National Natural Science Foundation of China

Young Elite Scientists Sponsorship Program by CAST

National Science Fund for Distinguished Young Scholars of Hubei Province of China

Fundamental Research Funds for the Central Universities

Knowledge Innovation Program of Wuhan

National Science Fund for Distinguished Young Scholars of China

Key Program of National Natural Science Foundation of China

Natural Science Foundation of Hubei Province

the Fundamental Research Funds for the Central Universities

Youth Program of National Natural Science Foundation of China

National Science Fund for Excellent Young Scholars

the Leading Talent Program of the Health Commission of Hubei Province, Knowledge Innovation Program of Wuhan

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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