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

Authors

Chen F, Sheng X, Wang A, Xu Y, Hughley R, Xiong W, Pooler L, Wan P, Gundell SM, Kigozi G, Nakigozi G, Nalugoda F, Kagaayi J, Kigozi GN, Mugamba S, Kyasanku E, Nkale J, Olwa VO, Lubwama A, Daama A, ...show more Nakajugo R, Adusei B, Jalloh M, Gueye SM, Adjei AA, Mensah J, Fernandez PW, Adebiyi AO, Olufemi Ogunbiyi J, Aisuodionoe-Shadrach OI, Petersen L, Chen WC, McBride J, Bensen JT, Mohler JL, Taylor JA, Andrews C, Kigongo M, Colline A, Kiddu V, Namugambe J, Owamaani S, Job K, Masaba BJ, Asiimwe F, Muwanga P, Namulondo J, Nagawa F, Kayiraba C, Ogwang M, Okidi R, Oweka D, Kitara E, Obonyo J, Lajul D, Matovu P, Muheki PA, Natumanya J, Agaba E, Aculokin E, Twongyeirwe A, Mutema G, Bitamazire D, Butler EN, Ingles SA, Rybicki BA, Stanford JL, Zheng W, Berndt SI, Chanock SJ, Huff CD, Lachance J, Multigner L, Darst BF, Rebbeck TR, Brureau L, Watya S, Conti DV, Haiman CA

Affiliations

• Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
• Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
• Africa Medical and Behavioural Sciences Organization, Wakiso, Uganda.
• 37 Military Hospital, Accra, Ghana.
• Department of Urology, University Cheikh Anta Diop de Dakar, Dakar, Senegal.
• Hôpital Général de Grand Yoff, Dakar, Senegal.
• Department of Pathology, University of Ghana Medical School College of Health Sciences Korle Bu Accra Ghana, Accra, Ghana.
• Department of surgery, Division of Urology, Korle-Bu Hospital, Accra, Ghana.
• Division of Urology, Stellenbosch University, Cape Town, South Africa.
• University College Hospital, Ibadan, Nigeria.

Abstract

BACKGROUND AND OBJECTIVE: 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.

METHODS: 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.

KEY FINDINGS AND LIMITATIONS: 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 aggressive PCa (odds ratio 2.18-5.96, p < 0.05). Lifetime absolute risk varied widely depending on PV carrier status, PRS, and family history, ranging from 3.0% to 74% for overall PCa, 0.6% to 41% for aggressive PCa, and 0.2% to 37% for metastatic PCa. PV carriers with a positive family history and a PRS in the 90th percentile had seven, 18, and 34 times the risks of overall, aggressive, and metastatic PCa, respectively, compared with average-risk individuals. Oversampling of aggressive cases may limit the generalizability of these findings to screening populations.

CONCLUSIONS AND CLINICAL IMPLICATIONS: Integration of PV status, PRS, and family history enables more refined PCa risk estimates. The wide range of PCa risk observed among men of African ancestry in our study supports future prospective studies in the development of risk-stratified cancer screening programs to identify high-risk individuals who may benefit from screening at an earlier age.