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.
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.
The study’s other co-first authors are Jie Ping, PhD, Yaohua Yang, PhD, and Xinwan Su. Vanderbilt authors on the study also included Xiao-ou Shu, MD, PhD, MPH; Wanqing Wen, MD, MPH; Zhishan Chen, PhD; Ran Tao, PhD; Guochong Jia, PhD, MPH; Qiuyin Cai, MD, PhD; Jirong Long, PhD; and Wei Zheng, MD, PhD, MPH (co-corresponding author).
The research received support from the National Institutes of Health (grants R37CA227130, R01CA269589, R01CA235553 and R01CA202981).
