Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry

作者：Fei Chen, Xin Sheng, Anqi Wang, Yili Xu, Raymond W. Hughley, Wei Xiong, Loreall Pooler, Peggy Wan, Susan Gundell, Godfrey Kigozi, Gertrude Nakigozi, Fred Nalugoda, Joseph Kagaayi, Grace Kigozi, Stephen Mugamba, Emmanuel Kyasanku, James Nkale, Vitalis Ofumbi Olwa, Alexander Lubwama, Alex Daama, Resty Nakajugo, Ben Adusei, Mohamed Jalloh, Sérigne Maguèye Gueye, Andrew A. Adjei, James E. Mensah, P. Fernandez, Akindele O. Adebiyi, Olufemi J. Ogunbiyi, Oseremen I. Aisuodionoe-Shadrach, Lindsay Petersen, Wenlong Carl Chen, Jo McBride, Jeannette T. Bensen, James L. Mohler, Jack A. Taylor, Caroline Andrews, Mbaaga Kigongo, Amanya Colline, Vicky Kiddu, Juliet Sanyu Namugambe, Shallot Owamaani, Kuteesa Job, Benon Masaba, Frank Asiimwe, Proscovia Muwanga, Joyce Namulondo, Florence Nagawa, Charity Kayiraba, Martin Ogwang, Ronald Okidi, David Oweka, Elio Kitara, James Obonyo, Daniel Lajul, Paul Matovu, Precious Arinda Muheki, Johnson Natumanya, Emmanuel I. Agaba, Emmanuel Aculokin, Amos Twongyeirwe, George Mutema, Denis Bitamazire, Eboneé N. Butler, Sue A. Ingles, Benjamin A. Rybicki, Janet L. Stanford, Wei Zheng, Sonja I Berndt, Stephen J. Chanock, Chad D. Huff, Joseph Lachance, Luc Multigner, Burcu F. Darst, Timothy R. Rebbeck, Laurent Brureau, Stephen Watya, David V. Conti, Christopher A. Haiman · 发表于：European Urology · 年份：2025 · DOI：10.1016/j.eururo.2025.09.4161 · 被引用次数：2 · 研究领域：Prostate Cancer Diagnosis and Treatment、BRCA gene mutations in cancer、Genetic Associations and Epidemiology

In this largest to date exome sequencing study in men of African ancestry, germline pathogenic variants (PVs) in ATM , BRCA2 , CHEK2 , HOXB13 , and PALB2 genes were associated with an increasing risk of aggressive prostate cancer (PCa). By combing PV carrier status, polygenic risk score, and family history of PCa, we observed substantial gradients of lifetime absolute risk for overall, aggressive, and metastatic PCa in African American men, which supports future development of more personalized risk-stratified cancer screening programs in contrast to the current recommendation of a uniformed screening strategy for this population. The impact of germline pathogenic variants (PVs) in cancer predisposition genes on risk of prostate cancer (PCa) remains understudied in large populations of African ancestry. This study aims to characterize the range of genetic risk of PCa and aggressive disease phenotypes in men of African ancestry. We analyzed 7176 PCa cases and 4873 controls from seven countries across North America and Africa to assess the association between PVs in 37 cancer predisposition genes and the risk of overall, aggressive, and metastatic PCa. Genes significantly associated with PCa risk were used to estimate lifetime absolute risk based on family history, polygenic risk score (PRS), and PV carrier status. PVs in ATM , BRCA2 , CHEK2 , HOXB13 , and PALB2 were presented in 4% of aggressive/metastatic PCa cases and were significantly associated with an increased risk of a...