Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry

被引：23

作者：

Chen, Fei ^{[1
]}

Madduri, Ravi K. ^{[2
]}

Rodriguez, Alex A. ^{[2
]}

Darst, Burcu F. ^{[1
,3
]}

Chou, Alisha ^{[1
]}

Sheng, Xin ^{[1
]}

Wang, Anqi ^{[1
]}

Shen, Jiayi ^{[1
]}

Saunders, Edward J. ^{[4
]}

Rhie, Suhn K. ^{[5
]}

Bensen, Jeannette T. f ^{[6
,7
]}

Ingles, Sue A. ^{[1
]}

Kittles, Rick A. ^{[8
]}

Strom, Sara S. ^{[9
]}

Rybicki, Benjamin A. ^{[10
]}

Nemesure, Barbara ^{[11
]}

Isaacs, William B. ^{[12
]}

Stanford, Janet L. ^{[3
]}

Zheng, Wei ^{[13
]}

Sanderson, Maureen ^{[14
]}

John, Esther M. ^{[15
]}

Park, Jong Y. ^{[16
]}

Xu, Jianfeng ^{[17
,18
]}

Wang, Ying ^{[19
]}

Berndt, Sonja I. ^{[20
]}

Huff, Chad D. ^{[9
]}

Yeboah, Edward D. ^{[21
]}

Tettey, Yao ^{[22
,23
]}

Lachance, Joseph ^{[24
]}

Tang, Wei ^{[25
]}

Rentsch, Christopher T. ^{[26
,27
,28
]}

Cho, Kelly ^{[29
,30
]}

Mcmahon, Benjamin H. ^{[31
]}

Biritwum, Richard B. ^{[23
]}

Adjei, Andrew A. ^{[32
]}

Tay, Evelyn ^{[23
]}

Truelove, Ann ^{[33
]}

Niwa, Shelley ^{[33
]}

Sellers, Thomas A. ^{[16
]}

Yamoah, Kosj ^{[16
,34
]}

Murphy, Adam B. ^{[35
]}

Crawford, Dana C. ^{[36
]}

Patel, Alpa V. ^{[19
]}

Bush, William S. ^{[36
]}

Aldrich, Melinda C. ^{[37
]}

Cussenot, Olivier ^{[38
,39
,40
,41
]}

Petrovics, Gyorgy ^{[42
]}

Cullen, Jennifer ^{[36
,42
]}

Neslund-Dudas, Christine M. ^{[10
]}

Stern, Mariana C. ^{[1
]}

机构：

[1] Univ Southern Calif, Keck Sch Med, Dept Populat & Publ Hlth Sci, Los Angeles, CA USA

[2] Argonne Natl Lab, Lemont, IL USA

[3] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA

[4] Inst Canc Res, London, England

[5] Univ Southern Calif, Keck Sch Med, Dept Biochem & Mol Med, Los Angeles, CA USA

[6] Univ North Carolina Chapel Hill, Dept Epidemiol, Chapel Hill, NC USA

[7] Univ North Carolina Chapel Hill, Lineberger Comprehens Canc Ctr, Chapel Hill, NC USA

[8] City Hope Comprehens Canc Ctr, Dept Populat Sci, Duarte, CA USA

[9] Univ Texas A&M Anderson Canc Ctr, Dept Epidemiol, Houston, TX USA

[10] Henry Ford Hosp, Dept Publ Hlth Sci, Detroit, MI USA

[11] SUNY Stony Brook, Dept Family Populat & Prevent Med, Stony Brook, NY USA

[12] Johns Hopkins Hosp & Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD USA

[13] Vanderbilt Univ, Dept Med, Div Epidemiol, Med Ctr, Nashville, TN USA

[14] Meharry Med Coll, Dept Family & Community Med, Nashville, TN USA

[15] Stanford Univ, Sch Med, Dept Med, Stanford Canc Inst, Stanford, CA USA

[16] H Lee Moffitt Canc Ctr & Res Inst, Dept Canc Epidemiol, Tampa, FL USA

[17] NorthShore Univ HealthSyst, Program Personalized Canc Care, Evanston, IL USA

[18] NorthShore Univ HealthSyst, Dept Surg, Evanston, IL USA

[19] Amer Canc Soc, Dept Populat Sci, Kennesaw, GA USA

[20] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA

[21] Univ Ghana, Med Sch, Accra, Ghana

[22] Univ Ghana, Dept Pathol, Accra, Ghana

[23] Korle Bu Teaching Hosp, Atlanta, GA USA

[24] Georgia Inst Technol, Sch Biol Sci, Atlanta, GA USA

[25] NCI, Human Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD USA

[26] Yale Sch Med, New Haven, CT USA

[27] VA Connecticut Healthcare Syst, West Haven, CT USA

[28] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London, England

[29] Harvard Med Sch, Brigham & Womens Hosp, Div Aging, Boston, MA USA

[30] VA Boston Healthcare Syst, Jamaica, MA USA

[31] Los Alamos Natl Lab, Theoret Biol Div, Los Alamos, NM USA

[32] Univ Ghana, Dept Pathol, Med Sch, Accra, Ghana

[33] Westat Corp, Rockville, MD USA

[34] H Lee Moffitt Canc Ctr & Res Inst, Dept Radiat Oncol, Tampa, FL USA

[35] Northwestern Univ, Dept Urol, Chicago, IL USA

[36] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland Inst Computat Biol, Cleveland, OH USA

[37] Vanderbilt Univ, Div Epidemiol, Dept Thorac Surg, Med Ctr, Nashville, TN USA

[38] Sorbonne Univ, Dept Urol, Paris, France

[39] Sorbonne Univ, Predict Onco Urol Grp, Paris, France

[40] Sorbonne Univ, APHP, GRC Predict Onco Urol 5, Paris, France

[41] Tenon Hosp, CeRePP, Paris, France

[42] Uniformed Serv Univ Hlth Sci, Dept Surg Ctr Prostate Dis Res, Bethesda, MD USA

[43] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA USA

[44] Fred Hutchinson Canc Res Ctr, SWOG Stat Ctr, Seattle, WA USA

[45] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

[46] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, MO USA

[47] Univ Miami, Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL USA

[48] Natl Human Genome Res Inst, Ctr Precis Hlth Res, NIH, Bethesda, MD USA

[49] Vanderbilt Genet Inst, Div Med Genet, Dept Med, Nashville, TN USA

[50] Atrium Hlth, Levine Canc Inst, Charlotte, NC USA

来源：

EUROPEAN UROLOGY | 2023年 / 84卷 / 01期

基金：

美国国家卫生研究院;

关键词：

African ancestry; Aggressive prostate cancer; Polygenic risk score; Prostate cancer; Susceptibility loci; GENOME-WIDE ASSOCIATION; LOCI; METAANALYSIS; TRANSCRIPTION; EXPRESSION;

D O I：

10.1016/j.eururo.2023.01.022

中图分类号：

R5 [内科学]; R69 [泌尿科学（泌尿生殖系疾病）];

学科分类号：

1002 ; 100201 ;

摘要：

Background: Genetic factors play an important role in prostate cancer (PCa) susceptibility.Objective: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.Design, setting, and participants: We conducted a meta-analysis of ten genome-wide association studies consisting of 19 378 cases and 61 620 controls of African ancestry. Outcome measurements and statistical analysis: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.Results and limitations: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 x 10-4). Conclusions: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high -risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry.Patient summary: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.& COPY; 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

引用

页码：13 / 21

页数：9

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