A distinct class of pan-cancer susceptibility genes revealed by an alternative polyadenylation transcriptome-wide association study

Hui Chen, Zeyang Wang, Lihai Gong, Qixuan Wang, Wenyan Chen, Jia Wang, Xuelian Ma, Ruofan Ding, Xing Li, Xudong Zou, Mireya Plass, Cheng Lian, Ting Ni, Gong-Hong Wei, Wei Li (), Lin Deng () and Lei Li ()
Additional contact information
Hui Chen: Shenzhen Bay Laboratory
Zeyang Wang: Shenzhen Bay Laboratory
Lihai Gong: Shenzhen Bay Laboratory
Qixuan Wang: Shenzhen Bay Laboratory
Wenyan Chen: Shenzhen Bay Laboratory
Jia Wang: Shenzhen Bay Laboratory
Xuelian Ma: Shenzhen Bay Laboratory
Ruofan Ding: Shenzhen Bay Laboratory
Xing Li: Shenzhen Bay Laboratory
Xudong Zou: Shenzhen Bay Laboratory
Mireya Plass: L′Hospitalet de Llobregat
Cheng Lian: Shanghai Medical College of Fudan University
Ting Ni: Fudan University
Gong-Hong Wei: Shanghai Medical College of Fudan University
Wei Li: The University of California
Lin Deng: Shenzhen Bay Laboratory
Lei Li: Shenzhen Bay Laboratory

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Alternative polyadenylation plays an important role in cancer initiation and progression; however, current transcriptome-wide association studies mostly ignore alternative polyadenylation when identifying putative cancer susceptibility genes. Here, we perform a pan-cancer 3′ untranslated region alternative polyadenylation transcriptome-wide association analysis by integrating 55 well-powered (n > 50,000) genome-wide association studies datasets across 22 major cancer types with alternative polyadenylation quantification from 23,955 RNA sequencing samples across 7,574 individuals. We find that genetic variants associated with alternative polyadenylation are co-localized with 28.57% of cancer loci and contribute a significant portion of cancer heritability. We further identify 642 significant cancer susceptibility genes predicted to modulate cancer risk via alternative polyadenylation, 62.46% of which have been overlooked by traditional expression- and splicing- studies. As proof of principle validation, we show that alternative alleles facilitate 3′ untranslated region lengthening of CRLS1 gene leading to increased protein abundance and promoted proliferation of breast cancer cells. Together, our study highlights the significant role of alternative polyadenylation in discovering new cancer susceptibility genes and provides a strong foundational framework for enhancing our understanding of the etiology underlying human cancers.

Date: 2024
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DOI: 10.1038/s41467-024-46064-7

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