Androgen receptor binding sites enabling genetic prediction of mortality due to prostate cancer in cancer-free subjects.

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Authors

Ito, S
Liu, X
Ishikawa, Y
Conti, DD
Otomo, N
Kote-Jarai, Z
Suetsugu, H
Eeles, RA
Koike, Y
Hikino, K
Yoshino, S
Tomizuka, K
Horikoshi, M
Ito, K
Uchio, Y
Momozawa, Y
Kubo, M
BioBank Japan Project,
Kamatani, Y
Matsuda, K
Haiman, CA
Ikegawa, S
Nakagawa, H
Terao, C

Document Type

Journal Article

Date

2023-08-23

Date Accepted

2023-06-27

Abstract

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, Pā€‰=ā€‰4.2 Ɨ 10-10). Our findings demonstrate the potential utility of leveraging large-scale genetic data and advanced analytical methods in predicting the mortality of PrCa.

Citation

Nature Communications, 2023, 14 (1), pp. 4863 -

Source Title

Nature Communications

Publisher

NATURE PORTFOLIO

ISSN

2041-1723

eISSN

2041-1723
2041-1723
2041-1723

Research Team

Oncogenetics

Notes