Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes-Reference-Cited by-同舟云学术

Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Published:2024-05-17 Issue:16 Volume:84 Page:2707-2719
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Guo Xingyi¹²^ORCID,Ping Jie¹^ORCID,Yang Yaohua³⁴^ORCID,Su Xinwan⁵^ORCID,Shu Xiao-Ou¹^ORCID,Wen Wanqing¹^ORCID,Chen Zhishan¹^ORCID,Zhang Yunjing⁵^ORCID,Tao Ran⁶^ORCID,Jia Guochong¹^ORCID,He Jingni⁷⁸^ORCID,Cai Qiuyin¹^ORCID,Zhang Qingrun⁹^ORCID,Giles Graham G.¹⁰^ORCID,Pearlman Rachel¹¹^ORCID,Rennert Gad¹²^ORCID,Vodicka Pavel¹³¹⁴¹⁵^ORCID,Phipps Amanda¹⁶¹⁷^ORCID,Gruber Stephen B.¹⁸^ORCID,Casey Graham³^ORCID,Peters Ulrike¹⁶¹⁷^ORCID,Long Jirong¹^ORCID,Lin Weiqiang⁵^ORCID,Zheng Wei¹^ORCID

Affiliation:

1. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. 1

2. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee. 2

3. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia. 3

4. Department of Public Health Sciences, UVA Comprehensive Cancer Center, School of Medicine, University of Virginia, Charlottesville, Virginia. 4

5. International Institutes of Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, Zhejiang University, Yiwu, China. 5

6. Department of Biostatistics, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tennessee. 6

7. Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada. 7

8. Department of Medical Genetics, University of Calgary, Calgary, Canada. 8

9. Department of Mathematics and Statistics, Alberta Children’s Hospital Research Institute, Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada. 9

10. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia. 10

11. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. 11

12. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. 12

13. Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. 13

14. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. 14

15. Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. 15

16. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. 16

17. Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington. 17

18. Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California. 18

Abstract

Abstract Alternative polyadenylation (APA) modulates mRNA processing in the 3′-untranslated regions (3′ UTR), affecting mRNA stability and translation efficiency. Research into genetically regulated APA has the potential to provide insights into cancer risk. In this study, we conducted large APA-wide association studies to investigate associations between APA levels and cancer risk. Genetic models were built to predict APA levels in multiple tissues using genotype and RNA sequencing data from 1,337 samples from the Genotype-Tissue Expression project. Associations of genetically predicted APA levels with cancer risk were assessed by applying the prediction models to data from large genome-wide association studies of six common cancers among European ancestry populations: breast, ovarian, prostate, colorectal, lung, and pancreatic cancers. A total of 58 risk genes (corresponding to 76 APA sites) were associated with at least one type of cancer, including 25 genes previously not linked to cancer susceptibility. Of the identified risk APAs, 97.4% and 26.3% were supported by 3′-UTR APA quantitative trait loci and colocalization analyses, respectively. Luciferase reporter assays for four selected putative regulatory 3′-UTR variants demonstrated that the risk alleles of 3′-UTR variants, rs324015 (STAT6), rs2280503 (DIP2B), rs1128450 (FBXO38), and rs145220637 (LDHA), significantly increased the posttranscriptional activities of their target genes compared with reference alleles. Furthermore, knockdown of the target genes confirmed their ability to promote proliferation and migration. Overall, this study provides insights into the role of APA in the genetic susceptibility to common cancers. Significance: Systematic evaluation of associations of alternative polyadenylation with cancer risk reveals 58 putative susceptibility genes, highlighting the contribution of genetically regulated alternative polyadenylation of 3′UTRs to genetic susceptibility to cancer.

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Link

https://aacrjournals.org/cancerres/article-pdf/doi/10.1158/0008-5472.CAN-24-0521/3454210/can-24-0521.pdf

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