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Genetic Variants That Impact Alternative Polyadenylation in Cancer Represent Candidate Causal Risk Loci
Bin Li1,2,3, Yimin Cai1,2,3, Can Chen1,2,3
1Department of Epidemiology and Biostatistics, School of Public Health, Wuhan University, Wuhan, China.
Cancer Research
|September 5, 2023
Summary
Genetic factors influencing alternative polyadenylation (APA) impact cancer risk. A study identified a specific variant (rs1020670-G) linked to colorectal cancer by altering DNM1L gene expression through APA.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Biology
Background:
- Alternative polyadenylation (APA) is a key posttranscriptional regulatory mechanism.
- APA dysregulation is implicated in cancer development and progression.
- Genetic determinants of APA may influence cancer risk.
Purpose of the Study:
- To create a comprehensive atlas of human APA quantitative trait loci (apaQTL) across diverse cancer types.
- To investigate the role of apaQTLs in cancer etiology and identify functional variants associated with cancer risk.
- To elucidate the molecular mechanisms by which specific apaQTLs contribute to cancer development.
Main Methods:
- Construction of a pan-cancer atlas of approximately 0.7 million apaQTLs across 32 cancer types.
- Multiomics analyses integrating apaQTL data with genomic, transcriptomic, and epigenomic information.
- Genome-wide association studies (GWAS) and functional validation in colorectal cancer cohorts to identify and confirm risk-associated apaQTLs.
Main Results:
- Cancer apaQTLs were found to regulate APA by affecting poly(A) motifs, RNA-binding proteins, and chromatin elements.
- apaQTLs were enriched in known cancer susceptibility loci identified by GWAS.
- A novel multi-ancestry apaQTL variant, rs1020670-G in DNM1L, was identified, increasing colorectal cancer risk by promoting aberrant APA and DNM1L expression.
Conclusions:
- The study provides a valuable resource for understanding APA regulation in cancer.
- Genetic variants influencing APA are significant contributors to cancer risk and etiology.
- The identified DNM1L-associated apaQTL offers potential therapeutic targets for colorectal cancer intervention.
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