Integrating Pathogenic Variants, Polygenic Risk Score, and Family History for Prostate Cancer Risk Estimation in Men of African Ancestry.
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Chen Fei, Sheng Xin, Wang Anqi, Xu Yili, Hughley Raymond, Xiong Wei, Pooler Loreall, Wan Peggy, Gundell Susan M, Kigozi Godfrey, Nakigozi Gertrude, Nalugoda Fred, Kagaayi Joseph, Kigozi Grace Nalwoga, Mugamba Stephen, Kyasanku Emmanuel, Nkale James, Olwa Vitalis Ofumbi, Lubwama Alexander, Daama Alex, Nakajugo Resty, Adusei Ben, Jalloh Mohamed, Gueye Serigne Magueye, Adjei Andrew A, Mensah James, Fernandez Pedro W, Adebiyi Akindele Olupelumi, Olufemi Ogunbiyi J, Aisuodionoe-Shadrach Oseremen Inokhoife, Petersen Lindsay, Chen Wenlong Carl, McBride Jo, Bensen Jeannette T, Mohler James L, Taylor Jack A, Andrews Caroline, Kigongo Mbaaga, Colline Amanya, Kiddu Vicky, Namugambe Juliet, Owamaani Shallot, Job Kuteesa, Masaba Benon Joseph, Asiimwe Frank, Muwanga Proscovia, Namulondo Joy, Nagawa Florence, Kayiraba Charity, Ogwang Martin, Okidi Ronald, Oweka David, Kitara Elio, Obonyo James, Lajul Daniel, Matovu Paul, Muheki Precious Arinda, Natumanya Johnson, Agaba Emmanuel, Aculokin Emmanuel, Twongyeirwe Amos, Mutema George, Bitamazire Denis, Butler Eboneé N, Ingles Sue Ann, Rybicki Benjamin A, Stanford Janet L, Zheng Wei, Berndt Sonja I, Chanock Stephen J, Huff Chad D, Lachance Joseph, Multigner Luc, Darst Burcu F, Rebbeck Timothy R, Brureau Laurent, Watya Stephen, Conti David V, Haiman Christopher A
Аннотация
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.