Study of messenger RNA regulatory mechanism reveals cancer risk genes

The Vanderbilt study used RNA-sequencing data generated in multiple normal tissues, along with matched genotype data from the Genotype-Tissue Expression Project as well as large-scale genomic data for cancers of the breast, ovary, prostate, colorectum, lung and pancreas.

Researchers investigating the association of cancer risk with alternative polyadenylation (APA) — a regulatory mechanism found in messenger RNA — have identified 58 susceptibility genes, including 25 new ones.

The study, published online May 17 in Cancer Research, revealed genetically predicted alternative polyadenylation levels with risk for breast, ovarian, prostate, colorectal, lung and pancreatic cancers. The research investigated a new frontier for assessing genomic risk factors for cancer because the interaction of alternative polyadenylation with messenger RNA has been largely unexplored.

Study design of APA-WAS in cancers of breast, ovary, prostate, colorectum, lung, and pancreas

A) Each box shows the reference data used to build models for breast, ovarian, pancreas, colorectal, prostate, and lung cancers. B) A workflow to illustrate our analytic framework, including model building for genetically predicted APA levels and association analyses to identify putative cancer susceptibility genes. C) Each box shows the reference GWAS data for each APA-WAS.

The findings by Xingyi Guo, PhD, associate professor of Medicine and of Biomedical Informatics at Vanderbilt University Medical Center, and research colleagues, may help identify drug candidates for these cancers.

“Genetic variants involved in posttranscriptional regulation, such as alternative polyadenylation (APA), are largely unexplored in association studies related to cancer risk. Our new approach, the APA-wide association study, leverages genetically predicted APA to provide additional insights into the discovery of cancer risk genes,” said Guo, the study’s corresponding author and a co-first author.

In their analysis, the team of researchers used RNA-sequencing data generated in multiple normal tissues, along with matched genotype data from the Genotype-Tissue Expression Project as well as large-scale genomic data for cancers of the breast, ovary, prostate, colorectum, lung and pancreas. A limitation of the study is that the datasets the researchers used were derived from people of European ancestry.

For breast cancer, the researchers found 14 susceptibility genes, including six that were newly identified. For ovarian cancer, they found two previously reported susceptibility genes.

For prostate cancer, they found 27 susceptibility genes, including 12 newly identified ones. For colorectal cancer, they found eight susceptibility genes, including four new ones. For lung cancer, they found seven susceptibility genes, including three that had not previously been linked to the cancer. The researchers found no susceptibility genes for pancreatic cancer.

Source – Vanderbilt University Medical Center

Guo X, Ping J, Yang Y, Su X, Shu XO, Wen W, Chen Z, Zhang Y, Tao R, Jia G, He J, Cai Q, Zhang Q, Giles GG, Pearlman R, Rennert G, Vodicka P, Phipps A, Gruber SB, Casey G, Peters U, Long J, Lin W, Zheng W. (2024) Large-scale alternative polyadenylation-wide association studies to identify putative cancer susceptibility genes. Cancer Res [Epub ahead of print]. [abstract]

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