Discovery of Novel Susceptibility Loci and Genes for Prostate Cancer Risk

Results from a transcriptome-wide association study in over 140,000 European descendants

To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, the researchers performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. They published their findings in July 2019 issue of the Cancer Research and concluded that their study provides substantial new information to advance understanding of prostate cancer genetics and biology.

The research team from the Vanderbilt University Medical Center, Nashville, Tennessee; University of Hawaii at Manoa, Honolulu, Hawaii; The Fifth People's Hospital of Shanghai, Shanghai, China; University of California, San Francisco, California; Harvard T.H. Chan School of Public Health, Boston, Massachusetts; The Institute of Cancer Research, and The Royal Marsden NHS Foundation Trust, London, United Kingdom; University of Southern California, Los Angeles, California; and the CRUK, BPC3, CAPS, PEGASUS consortia PRACTICAL wrote in study background that genome-wide association studies have identified genetic variants associated with prostate cancer risk.

However, these variants explain only a small fraction of the heritable component of prostate cancer risk, and the genes responsible for many of the identified associations remain unknown.

By using data from the Genotype-Tissue Expression Project, they established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets.

The study team identified significant associations for 137 genes at p < 2.61×10-6, a Bonferroni-corrected threshold, including 9 genes that remained significant at p < 2.61×10-6 after adjusting for all known prostate cancer risk variants in nearby regions.

Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. In addition, the study team silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines.

Wei Zheng of the Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee and colleagues concluded that their study provides substantial new information in terms of prostate cancer genetics and biology.

Reference

Wu L, Wang J, Cai Q, et al. Identification of novel susceptibility loci and genes for prostate cancer risk: A transcriptome-wide association study in over 140,000 European descendants. Cancer Res 2019; 79(13):3192-3204. doi: 10.1158/0008-5472.CAN-18-3536.