Prostate cancer (PrCa) is the second most common cancer worldwide in males. While strongly warranted, the prediction of mortality risk due to PrCa, especially before its development, is challenging. Here, we address this issue by maximizing the statistical power of genetic data with multi-ancestry meta-analysis and focusing on binding sites of the androgen receptor (AR), which has a critical role in PrCa. Taking advantage of large Japanese samples ever, a multi-ancestry meta-analysis comprising more than 300,000 subjects in total identifies 9 unreported loci including ZFHX3, a tumor suppressor gene, and successfully narrows down the statistically finemapped variants compared to European-only studies, and these variants strongly enrich in AR binding sites. A polygenic risk scores (PRS) analysis restricting to statistically finemapped variants in AR binding sites shows among cancer-free subjects, individuals with a PRS in the top 10% have a strongly higher risk of the future death of PrCa (HR: 5.57, P = 4.2 × 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.
Nature communications. 2023 Aug 23*** epublish ***
Shuji Ito, Xiaoxi Liu, Yuki Ishikawa, David D Conti, Nao Otomo, Zsofia Kote-Jarai, Hiroyuki Suetsugu, Rosalind A Eeles, Yoshinao Koike, Keiko Hikino, Soichiro Yoshino, Kohei Tomizuka, Momoko Horikoshi, Kaoru Ito, Yuji Uchio, Yukihide Momozawa, Michiaki Kubo, BioBank Japan Project , Yoichiro Kamatani, Koichi Matsuda, Christopher A Haiman, Shiro Ikegawa, Hidewaki Nakagawa, Chikashi Terao
RIKEN Center for Integrative Medical Sciences, The Laboratory for Statistical and Translational Genetics, Yokohama, Japan., Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., The Institute of Cancer Research, London, UK., RIKEN Center for Integrative Medical Sciences, The Laboratory for Pharmacogenomics, Yokohama, Japan., RIKEN Center for Integrative Medical Sciences, The Laboratory for Genomics of Diabetes and Metabolism, Yokohama, Japan., RIKEN Center for Integrative Medical Sciences, The Cardiovascular Genomics and Informatics, Yokohama, Japan., Department of Orthopedic Surgery, Shimane University, Izumo, Japan., RIKEN Center for Integrative Medical Sciences, The Laboratory for Genotyping Development, Yokohama, Japan., Haradoi Hospital, Fukuoka, Japan., Laboratory of Complex Trait Genomics, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan., Institute of Medical Science, The University of Tokyo, Laboratory of Genome Technology, Human Genome Center, Tokyo, Japan., RIKEN Center for Integrative Medical Sciences, The Laboratory for Bone and Joint Diseases, Yokohama, Japan., RIKEN Center for Integrative Medical Sciences, Laboratory for Cancer Genomics, Yokohama, Japan., RIKEN Center for Integrative Medical Sciences, The Laboratory for Statistical and Translational Genetics, Yokohama, Japan. .