A number of susceptibility genes in prostate tissue have been identified to be associated with prostate cancer (PCa) risk. However, the reported genes based on assessing prostate tissue could not fully explain PCa genetic susceptibility. It is believed that genes functioning in the immune system may fill in the gap of some missing heritability.
To study potential susceptibility genes acting in such pathways, we performed a transcriptome-wide association study (TWAS) of 79,194 PCa cases and 61,112 control of European ancestry by using three sets of gene expression prediction models of blood tissue.
A total of 470 genes were associated at false discovery rates-corrected p-value < 0.05, of which 51 were implicated as likely causal genes based on fine-mapping analysis. Compared with previous literature, 133 novel genes were reported for the first time. Of the identified genes, five (CREB3L4, GSTP1, MAPK3, NKX3-1, and PIK3C2B) were enriched in a PCa signaling pathway, and 128 genes were enriched in five PCa categories. Importantly, 13 genes (SCP2, LMNA, ZNF148, H2AFV, TACC1, FLII, SUPT4H1, CD300LF, MYO9B, COX6B1, CTSA, EP300, and TSPO) showed consistent effect directions for the measured levels in circulating immune cells between PCa cases and controls, and 14 genes (SLC39A1, ZBTB7B, TRIM59, NCEH1, N4BP2, TAGAP, TACC1, TRAF1, AIP, SECTM1, C18orf54, ZNF793, YIF1B, and TSPO) showed consistency for levels in blood exosomes between PCa patients and controls.
The identified blood-based candidate susceptibility genes provide further insights into the genetic basis of PCa risk.
The Prostate. 2025 Jan 29 [Epub ahead of print]
Yanfa Sun, Jingjing Zhu, Hua Zhong, Zichen Zhang, Fubo Wang, Akira Nakamura, Yanhui Liu, Jiawen Liu, Jie Yu, Guanghua Zeng, Xin Lin, Dan Zhou, Chong Wu, Liang Wang, Youping Deng, Lang Wu
College of Life Science, Fujian Provincial Key Laboratory for the Prevention and Control of Animal Infectious Diseases and Biotechnology, Fujian Provincial Universities Key Laboratory of Preventive Veterinary Medicine and Biotechnology (Longyan University), Longyan University, Longyan, Fujian, P. R. China., Department of Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA., Cancer Epidemiology Division, Population Sciences in the Pacific Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu, Hawaii, USA., Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Department of Urology, Shanghai Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, P. R. China., Division of Immunology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan., School of Public Health and the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China., Department of Tumor Biology, Moffitt Cancer Center, Tampa, Florida, USA.