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1. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

Author

Wang, Anqi, Shen, Jiayi, Rodriguez, Alex, Saunders, Edward, Chen, Fei, Janivara, Rohini, Darst, Burcu, Sheng, Xin, Xu, Yili, Chou, Alisha, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark, Plym, Anna, Sahimi, Ali, Hoffman, Thomas, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Laisk, Triin, Figuerêdo, Jéssica, Muir, Kenneth, Ito, Shuji, Liu, Xiaoxi, Uchio, Yuji, Kubo, Michiaki, Kamatani, Yoichiro, Lophatananon, Artitaya, Wan, Peggy, Andrews, Caroline, Lori, Adriana, Choudhury, Parichoy, Schleutker, Johanna, Tammela, Teuvo, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham, Southey, Melissa, MacInnis, Robert, Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher, Cho, Kelly, Mcmahon, Benjamin, Neal, David, Donovan, Jenny, Hamdy, Freddie, Martin, Richard, Nordestgaard, Borge, Nielsen, Sune, Weischer, Maren, Bojesen, Stig, Røder, Andreas, Stroomberg, Hein, Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith, Tilly, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, Tobias, Pashayan, Nora, Dunning, Alison, Ghoussaini, Maya, Travis, Ruth, Key, Tim, Riboli, Elio, Park, Jong, Sellers, Thomas, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie, Cook, Michael, Mucci, Lorelei, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David, Penney, Kathryn, Turman, Constance, Tangen, Catherine, Goodman, Phyllis, Thompson, Ian, Hamilton, Robert, Fleshner, Neil, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet, Ostrander, Elaine, Koutros, Stella, Beane Freeman, Laura, Stampfer, Meir, Wolk, Alicja, and Håkansson, Niclas

Subjects
Humans, Male, Black People, Genetic Predisposition to Disease, Genome-Wide Association Study, Hispanic or Latino, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Factors, White People, Asian People
Abstract

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Published
2023

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

Author

Chen, Fei, Madduri, Ravi K., Rodriguez, Alex A., Darst, Burcu F., Chou, Alisha, Sheng, Xin, Wang, Anqi, Shen, Jiayi, Saunders, Edward J., Rhie, Suhn K., Bensen, Jeannette T., Ingles, Sue A., Kittles, Rick A., Strom, Sara S., Rybicki, Benjamin A., Nemesure, Barbara, Isaacs, William B., Stanford, Janet L., Zheng, Wei, Sanderson, Maureen, John, Esther M., Park, Jong Y., Xu, Jianfeng, Wang, Ying, Berndt, Sonja I., Huff, Chad D., Yeboah, Edward D., Tettey, Yao, Lachance, Joseph, Tang, Wei, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Sellers, Thomas A., Yamoah, Kosj, Murphy, Adam B., Crawford, Dana C., Patel, Alpa V., Bush, William S., Aldrich, Melinda C., Cussenot, Olivier, Petrovics, Gyorgy, Cullen, Jennifer, Neslund-Dudas, Christine M., Stern, Mariana C., Kote-Jarai, Zsofia, Govindasami, Koveela, Cook, Michael B., Chokkalingam, Anand P., Hsing, Ann W., Goodman, Phyllis J., Hoffmann, Thomas J., Drake, Bettina F., Hu, Jennifer J., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Idowu, Michael O., Popoola, Olufemi, Adebiyi, Akindele O., Aisuodionoe-Shadrach, Oseremen I., Ajibola, Hafees O., Jamda, Mustapha A., Oluwole, Olabode P., Nwegbu, Maxwell, Adusei, Ben, Mante, Sunny, Darkwa-Abrahams, Afua, Mensah, James E., Diop, Halimatou, Van Den Eeden, Stephen K., Blanchet, Pascal, Fowke, Jay H., Casey, Graham, Hennis, Anselm J., Lubwama, Alexander, Thompson, Ian M., Jr., Leach, Robin, Easton, Douglas F., Preuss, Michael H., Loos, Ruth J., Gundell, Susan M., Wan, Peggy, Mohler, James L., Fontham, Elizabeth T., Smith, Gary J., Taylor, Jack A., Srivastava, Shiv, Eeles, Rosaline A., Carpten, John D., Kibel, Adam S., Multigner, Luc, Parent, Marie-Élise, Menegaux, Florence, Cancel-Tassin, Geraldine, Klein, Eric A., Andrews, Caroline, Rebbeck, Timothy R., Brureau, Laurent, Ambs, Stefan, Edwards, Todd L., Watya, Stephen, Chanock, Stephen J., Witte, John S., Blot, William J., Michael Gaziano, J., Justice, Amy C., Conti, David V., and Haiman, Christopher A.

Published
2023
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5. Two Novel Susceptibility Loci for Prostate Cancer in Men of African Ancestry

Author

Conti, David V, Wang, Kan, Sheng, Xin, Bensen, Jeannette T, Hazelett, Dennis J, Cook, Michael B, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Stanford, Janet L, Zheng, Wei, Sanderson, Maureen, John, Esther M, Park, Jong Y, Xu, Jianfeng, Stevens, Victoria L, Berndt, Sonja I, Huff, Chad D, Wang, Zhaoming, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Sellers, Thomas A, Yamoah, Kosj, Murphy, Adam B, Crawford, Dana C, Gapstur, Susan M, Bush, William S, Aldrich, Melinda C, Cussenot, Olivier, Petrovics, Gyorgy, Cullen, Jennifer, Neslund-Dudas, Christine, Stern, Mariana C, Jarai, Zsofia-Kote, Govindasami, Koveela, Chokkalingam, Anand P, Hsing, Ann W, Goodman, Phyllis J, Hoffmann, Thomas, Drake, Bettina F, Hu, Jennifer J, Clark, Peter E, Van Den Eeden, Stephen K, Blanchet, Pascal, Fowke, Jay H, Casey, Graham, Hennis, Anselm JM, Han, Ying, Lubwama, Alexander, Thompson, Ian M, Leach, Robin, Easton, Douglas F, Schumacher, Fredrick, Van den Berg, David J, Gundell, Susan M, Stram, Alex, Wan, Peggy, Xia, Lucy, Pooler, Loreall C, Mohler, James L, Fontham, Elizabeth TH, Smith, Gary J, Taylor, Jack A, Srivastava, Shiv, Eeles, Rosalind A, Carpten, John, Kibel, Adam S, Multigner, Luc, Parent, Marie-Elise, Menegaux, Florence, Cancel-Tassin, Geraldine, Klein, Eric A, Brureau, Laurent, Stram, Daniel O, Watya, Stephen, Chanock, Stephen J, Witte, John S, Blot, William J, Henderson, Brian E, and Haiman, Christopher A

Subjects
Aging, Human Genome, Cancer, Prevention, Prostate Cancer, Biotechnology, Clinical Research, Genetics, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Blacks, Case-Control Studies, Checkpoint Kinase 2, Chromosomes, Human, Pair 13, Chromosomes, Human, Pair 22, Gene Frequency, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Insulin Receptor Substrate Proteins, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, PRACTICAL/ELLIPSE Consortium, Black People, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

Prostate cancer incidence is 1.6-fold higher in African Americans than in other populations. The risk factors that drive this disparity are unknown and potentially consist of social, environmental, and genetic influences. To investigate the genetic basis of prostate cancer in men of African ancestry, we performed a genome-wide association meta-analysis using two-sided statistical tests in 10 202 case subjects and 10 810 control subjects. We identified novel signals on chromosomes 13q34 and 22q12, with the risk-associated alleles found only in men of African ancestry (13q34: rs75823044, risk allele frequency = 2.2%, odds ratio [OR] = 1.55, 95% confidence interval [CI] = 1.37 to 1.76, P = 6.10 × 10-12; 22q12.1: rs78554043, risk allele frequency = 1.5%, OR = 1.62, 95% CI = 1.39 to 1.89, P = 7.50 × 10-10). At 13q34, the signal is located 5' of the gene IRS2 and 3' of a long noncoding RNA, while at 22q12 the candidate functional allele is a missense variant in the CHEK2 gene. These findings provide further support for the role of ancestry-specific germline variation in contributing to population differences in prostate cancer risk.

Published
2017

6. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.

Published
2021
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7. Supplementary Figure 1 from Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry

Author

Hughley, Raymond W., primary, Matejcic, Marco, primary, Song, Ziwei, primary, Sheng, Xin, primary, Wan, Peggy, primary, Xia, Lucy, primary, Hart, Steven N., primary, Hu, Chunling, primary, Yadav, Siddhartha, primary, Lubmawa, Alexander, primary, Kiddu, Vicky, primary, Asiimwe, Frank, primary, Amanya, Colline, primary, Mutema, George, primary, Job, Kuteesa, primary, Ssebakumba, Mbaaga K., primary, Ingles, Sue A., primary, Hamilton, Ann S., primary, Couch, Fergus J., primary, Watya, Stephen, primary, Conti, David V., primary, Darst, Burcu F., primary, and Haiman, Christopher A., primary

Published
2023
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8. Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry

Author

Hughley, Raymond W., primary, Matejcic, Marco, additional, Song, Ziwei, additional, Sheng, Xin, additional, Wan, Peggy, additional, Xia, Lucy, additional, Hart, Steven N., additional, Hu, Chunling, additional, Yadav, Siddhartha, additional, Lubwama, Alexander, additional, Kiddu, Vicky, additional, Asiimwe, Frank, additional, Amanya, Colline, additional, Mutema, George, additional, Job, Kuteesa, additional, Ssebakumba, Mbaaga Kigongo, additional, Ingles, Sue Ann, additional, Hamilton, Ann S, additional, Couch, Fergus J, additional, Watya, Stephen, additional, Conti, David V., additional, Darst, Burcu F, additional, and Haiman, Christopher A, additional

Published
2023
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10. Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Author

Darst, Burcu F., primary, Shen, Jiayi, additional, Madduri, Ravi K., additional, Rodriguez, Alexis A., additional, Xiao, Yukai, additional, Sheng, Xin, additional, Saunders, Edward J., additional, Dadaev, Tokhir, additional, Brook, Mark N., additional, Hoffmann, Thomas J., additional, Muir, Kenneth, additional, Wan, Peggy, additional, Le Marchand, Loic, additional, Wilkens, Lynne, additional, Wang, Ying, additional, Schleutker, Johanna, additional, MacInnis, Robert J., additional, Cybulski, Cezary, additional, Neal, David E., additional, Nordestgaard, Børge G., additional, Nielsen, Sune F., additional, Batra, Jyotsna, additional, Clements, Judith A., additional, Cancer BioResource, Australian Prostate, additional, Grönberg, Henrik, additional, Pashayan, Nora, additional, Travis, Ruth C., additional, Park, Jong Y., additional, Albanes, Demetrius, additional, Weinstein, Stephanie, additional, Mucci, Lorelei A., additional, Hunter, David J., additional, Penney, Kathryn L., additional, Tangen, Catherine M., additional, Hamilton, Robert J., additional, Parent, Marie-Élise, additional, Stanford, Janet L., additional, Koutros, Stella, additional, Wolk, Alicja, additional, Sørensen, Karina D., additional, Blot, William J., additional, Yeboah, Edward D., additional, Mensah, James E., additional, Lu, Yong-Jie, additional, Schaid, Daniel J., additional, Thibodeau, Stephen N., additional, West, Catharine M., additional, Maier, Christiane, additional, Kibel, Adam S., additional, Cancel-Tassin, Géraldine, additional, Menegaux, Florence, additional, John, Esther M., additional, Grindedal, Eli Marie, additional, Khaw, Kay-Tee, additional, Ingles, Sue A., additional, Vega, Ana, additional, Rosenstein, Barry S., additional, Teixeira, Manuel R., additional, Kogevinas, Manolis, additional, Cannon-Albright, Lisa, additional, Huff, Chad, additional, Multigner, Luc, additional, Kaneva, Radka, additional, Leach, Robin J., additional, Brenner, Hermann, additional, Hsing, Ann W., additional, Kittles, Rick A., additional, Murphy, Adam B., additional, Logothetis, Christopher J., additional, Neuhausen, Susan L., additional, Isaacs, William B., additional, Nemesure, Barbara, additional, Hennis, Anselm J., additional, Carpten, John, additional, Pandha, Hardev, additional, De Ruyck, Kim, additional, Xu, Jianfeng, additional, Razack, Azad, additional, Teo, Soo-Hwang, additional, Newcomb, Lisa F., additional, Fowke, Jay H., additional, Neslund-Dudas, Christine, additional, Rybicki, Benjamin A., additional, Gamulin, Marija, additional, Usmani, Nawaid, additional, Claessens, Frank, additional, Gago-Dominguez, Manuela, additional, Castelao, Jose Esteban, additional, Townsend, Paul A., additional, Crawford, Dana C., additional, Petrovics, Gyorgy, additional, Casey, Graham, additional, Roobol, Monique J., additional, Hu, Jennifer F., additional, Berndt, Sonja I., additional, Van Den Eeden, Stephen K., additional, Easton, Douglas F., additional, Chanock, Stephen J., additional, Cook, Michael B., additional, Wiklund, Fredrik, additional, Witte, John S., additional, Eeles, Rosalind A., additional, Kote-Jarai, Zsofia, additional, Watya, Stephen, additional, Gaziano, John M., additional, Justice, Amy C., additional, Conti, David V., additional, and Haiman, Christopher A., additional

Published
2023
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11. Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry

Author

Darst, Burcu F, Shen, Jiayi, Madduri, Ravi K, Rodriguez, Alexis A, Xiao, Yukai, Sheng, Xin, Saunders, Edward J, Dadaev, Tokhir, Brook, Mark N, Hoffmann, Thomas J, Muir, Kenneth, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne, Wang, Ying, Schleutker, Johanna, MacInnis, Robert J, Cybulski, Cezary, Neal, David E, Nordestgaard, Børge G, Nielsen, Sune F, Batra, Jyotsna, Clements, Judith A, Cancer BioResource, Australian Prostate, Grönberg, Henrik, Pashayan, Nora, Travis, Ruth C, Park, Jong Y, Albanes, Demetrius, Weinstein, Stephanie, Mucci, Lorelei A, Hunter, David J, Penney, Kathryn L, Tangen, Catherine M, Hamilton, Robert J, Parent, Marie-Élise, Stanford, Janet L, Koutros, Stella, Wolk, Alicja, Sørensen, Karina D, Blot, William J, Yeboah, Edward D, Mensah, James E, Lu, Yong-Jie, Schaid, Daniel J, Thibodeau, Stephen N, West, Catharine M, Maier, Christiane, Kibel, Adam S, and Cancel-Tassin, Géraldine

Subjects
Male, Prostatic Neoplasms/genetics, Risk Factors, Humans, Black People/genetics, Genetic Predisposition to Disease, Multifactorial Inheritance/genetics, Genome-Wide Association Study
Abstract

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Published
2023

13. Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry

Author

Darst, Burcu F., Shen, Jiayi, Madduri, Ravi K., Rodriguez, Alexis A., Xiao, Yukai, Sheng, Xin, Saunders, Edward J., Dadaev, Tokhir, Brook, Mark N., Hoffmann, Thomas J., Muir, Kenneth, Wan, Peggy, Marchand, Loic Le, Wilkens, Lynne, Wang, Ying, Schleutker, Johanna, MacInnis, Robert J., Cybulski, Cezary, Neal, David E., G. Nordestgaard, Børge, Nielsen, Sune F., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Travis, Ruth C., Park, Jong Y., Albanes, Demetrius, Weinstein, Stephanie, Mucci, Lorelei A., Hunter, David J., Penney, Kathryn L., Tangen, Catherine M., Hamilton, Robert J., Parent, Marie-Élise, Stanford, Janet L., Koutros, Stella, Wolk, Alicja, Sørensen, Karina D., Blot, William J., Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Schaid, Daniel J., Thibodeau, Stephen N., West, Catharine M., Maier, Christiane, Kibel, Adam S., Cancel-Tassin, Géraldine, Menegaux, Florence, John, Esther M., Grindedal, Eli Marie, Khaw, Kay-Tee, Ingles, Sue A., Vega, Ana, Rosenstein, Barry S., Teixeira, Manuel R., Kogevinas, Manolis, Cannon-Albright, Lisa, Huff, Chad, Multigner, Luc, Kaneva, Radka, Leach, Robin J., Brenner, Hermann, Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Neuhausen, Susan L., Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J., Carpten, John, Pandha, Hardev, De Ruyck, Kim, Xu, Jianfeng, Razack, Azad, Teo, Soo-Hwang, Newcomb, Lisa F., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Townsend, Paul A., Crawford, Dana C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Hu, Jennifer F., Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, Watya, Stephen, Gaziano, John M., Justice, Amy C., Conti, David V., and Haiman, Christopher A.

Subjects
Article
Abstract

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS (269) ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS (269) . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS (269) had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS (269) constructed with fine-mapping.

Published
2023

16. Supplementary Table 1 from Evaluating Genetic Risk for Prostate Cancer among Japanese and Latinos

Author

Cheng, Iona, primary, Chen, Gary K., primary, Nakagawa, Hidewaki, primary, He, Jing, primary, Wan, Peggy, primary, Laurie, Cathy C., primary, Shen, Jess, primary, Sheng, Xin, primary, Pooler, Loreall C., primary, Crenshaw, Andrew T., primary, Mirel, Daniel B., primary, Takahashi, Atsushi, primary, Kubo, Michiaki, primary, Nakamura, Yusuke, primary, Al Olama, Ali Amin, primary, Benlloch, Sara, primary, Donovan, Jenny L., primary, Guy, Michelle, primary, Hamdy, Freddie C., primary, Kote-Jarai, Zsofia, primary, Neal, David E., primary, Wilkens, Lynne R., primary, Monroe, Kristine R., primary, Stram, Daniel O., primary, Muir, Kenneth, primary, Eeles, Rosalind A., primary, Easton, Douglas F., primary, Kolonel, Laurence N., primary, Henderson, Brian E., primary, Le Marchand, Loïc, primary, and Haiman, Christopher A., primary

Published
2023
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18. Publisher Correction: Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V., Darst, Burcu F., Moss, Lilit C., Saunders, Edward J., Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R., Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Sahimi, Ali, Hoffmann, Thomas J., Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R., Stevens, Victoria L., Gapstur, Susan M., Carter, Brian D., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Børge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A., Tilley, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M., Ghoussaini, Maya, Travis, Ruth C., Key, Tim J., Riboli, Elio, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J., Mucci, Lorelei A., Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J., Penney, Kathryn L., Turman, Constance, Tangen, Catherine M., Goodman, Phyllis J., Thompson, Jr., Ian M., Hamilton, Robert J., Fleshner, Neil E., Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L., Ostrander, Elaine A., Geybels, Milan S., Koutros, Stella, Freeman, Laura E. Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L., Hoover, Robert N., Machiela, Mitchell J., Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J., Zheng, Wei, Yeboah, Edward D., Mensah, James E., Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Wu, Yudong, Zhao, Shan-Chao, Sun, Zan, Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., West, Catharine M. L., Burnet, Neil, Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Koudou, Yves Akoli, John, Esther M., Grindedal, Eli Marie, Maehle, Lovise, Khaw, Kay-Tee, Ingles, Sue A., Stern, Mariana C., Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Rosenstein, Barry S., Kerns, Sarah L., Ostrer, Harry, Teixeira, Manuel R., Paulo, Paula, Brandão, Andreia, Watya, Stephen, Lubwama, Alexander, Bensen, Jeannette T., Fontham, Elizabeth T. H., Mohler, James, Taylor, Jack A., Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Weaver, Brandi, Brenner, Hermann, Cuk, Katarina, Holleczek, Bernd, Saum, Kai-Uwe, Klein, Eric A., Hsing, Ann W., Kittles, Rick A., Murphy, Adam B., Logothetis, Christopher J., Kim, Jeri, Neuhausen, Susan L., Steele, Linda, Ding, Yuan Chun, Isaacs, William B., Nemesure, Barbara, Hennis, Anselm J. M., Carpten, John, Pandha, Hardev, Michael, Agnieszka, De Ruyck, Kim, De Meerleer, Gert, Ost, Piet, Xu, Jianfeng, Razack, Azad, Lim, Jasmine, Teo, Soo-Hwang, Newcomb, Lisa F., Lin, Daniel W., Fowke, Jay H., Neslund-Dudas, Christine, Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Singhal, Sandeep, Parliament, Matthew, Claessens, Frank, Joniau, Steven, Van den Broeck, Thomas, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Martinez, Maria Elena, Larkin, Samantha, Townsend, Paul A., Aukim-Hastie, Claire, Bush, William S., Aldrich, Melinda C., Crawford, Dana C., Srivastava, Shiv, Cullen, Jennifer C., Petrovics, Gyorgy, Casey, Graham, Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Mancuso, Nicholas, Berndt, Sonja I., Van Den Eeden, Stephen K., Easton, Douglas F., Chanock, Stephen J., Cook, Michael B., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Eeles, Rosalind A., Kote-Jarai, Zsofia, and Haiman, Christopher A.

Published
2021
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19. Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men

Author

Wang, Anqi, primary, Xu, Yili, additional, Yu, Yao, additional, Nead, Kevin T, additional, Kim, TaeBeom, additional, Xu, Keren, additional, Dadaev, Tokhir, additional, Saunders, Ed, additional, Sheng, Xin, additional, Wan, Peggy, additional, Pooler, Loreall, additional, Xia, Lucy Y, additional, Chanock, Stephen, additional, Berndt, Sonja I, additional, Gapstur, Susan M, additional, Stevens, Victoria, additional, Albanes, Demetrius, additional, Weinstein, Stephanie J, additional, Gnanapragasam, Vincent, additional, Giles, Graham G, additional, Nguyen-Dumont, Tu, additional, Milne, Roger L, additional, Pomerantz, Mark M, additional, Schmidt, Julie A, additional, Stopsack, Konrad H, additional, Mucci, Lorelei A, additional, Catalona, William J, additional, Hetrick, Kurt N, additional, Doheny, Kimberly F, additional, MacInnis, Robert J, additional, Southey, Melissa C, additional, Eeles, Rosalind A, additional, Wiklund, Fredrik, additional, Kote-Jarai, Zsofia, additional, de Smith, Adam J, additional, Conti, David V, additional, Huff, Chad, additional, Haiman, Christopher A, additional, and Darst, Burcu F, additional

Published
2022
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21. Abstract 688: Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases

Author

Darst, Burcu F., primary, Saunders, Ed, additional, Dadaev, Tokhir, additional, Sheng, Xin, additional, Wan, Peggy, additional, Pooler, Loreall, additional, Xia, Lucy Y., additional, Chanock, Stephen, additional, Berndt, Sonja I., additional, Gapstur, Susan M., additional, Stevens, Victoria, additional, Albanes, Demetrius, additional, Weinstein, Stephanie J., additional, Gnanapragasam, Vincent, additional, Giles, Graham G., additional, Nguyen-Dumont, Tu, additional, Milne, Roger L., additional, Pomerantz, Mark M., additional, Schmidt, Julie A., additional, Travis, Ruth C., additional, Key, Timothy J., additional, Stopsack, Konrad H., additional, Mucci, Lorelei A., additional, Catalona, William J., additional, Marosy, Beth, additional, Hetrick, Kurt N., additional, Doheny, Kimberly F., additional, MacInnis, Robert J., additional, Southey, Melissa C., additional, Eeles, Rosalind A., additional, Wiklund, Fredrik, additional, Kote-Jarai, Zsofia, additional, Conti, David V., additional, and Haiman, Christopher A., additional

Published
2022
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22. A Rare Germline HOXB13 Variant Contributes to Risk of Prostate Cancer in Men of African Ancestry

Author

Darst, Burcu F., primary, Hughley, Raymond, additional, Pfennig, Aaron, additional, Hazra, Ujani, additional, Fan, Caoqi, additional, Wan, Peggy, additional, Sheng, Xin, additional, Xia, Lucy, additional, Andrews, Caroline, additional, Chen, Fei, additional, Berndt, Sonja I., additional, Kote-Jarai, Zsofia, additional, Govindasami, Koveela, additional, Bensen, Jeannette T., additional, Ingles, Sue A., additional, Rybicki, Benjamin A., additional, Nemesure, Barbara, additional, John, Esther M., additional, Fowke, Jay H., additional, Huff, Chad D., additional, Strom, Sara S., additional, Isaacs, William B., additional, Park, Jong Y., additional, Zheng, Wei, additional, Ostrander, Elaine A., additional, Walsh, Patrick C., additional, Carpten, John, additional, Sellers, Thomas A., additional, Yamoah, Kosj, additional, Murphy, Adam B., additional, Sanderson, Maureen, additional, Crawford, Dana C., additional, Gapstur, Susan M., additional, Bush, William S., additional, Aldrich, Melinda C., additional, Cussenot, Olivier, additional, Petrovics, Gyorgy, additional, Cullen, Jennifer, additional, Neslund-Dudas, Christine, additional, Kittles, Rick A., additional, Xu, Jianfeng, additional, Stern, Mariana C., additional, Chokkalingam, Anand P., additional, Multigner, Luc, additional, Parent, Marie-Elise, additional, Menegaux, Florence, additional, Cancel-Tassin, Geraldine, additional, Kibel, Adam S., additional, Klein, Eric A., additional, Goodman, Phyllis J., additional, Stanford, Janet L., additional, Drake, Bettina F., additional, Hu, Jennifer J., additional, Clark, Peter E., additional, Blanchet, Pascal, additional, Casey, Graham, additional, Hennis, Anselm J.M., additional, Lubwama, Alexander, additional, Thompson, Ian M., additional, Leach, Robin J., additional, Gundell, Susan M., additional, Pooler, Loreall, additional, Mohler, James L., additional, Fontham, Elizabeth T.H., additional, Smith, Gary J., additional, Taylor, Jack A., additional, Brureau, Laurent, additional, Blot, William J., additional, Biritwum, Richard, additional, Tay, Evelyn, additional, Truelove, Ann, additional, Niwa, Shelley, additional, Tettey, Yao, additional, Varma, Rohit, additional, McKean-Cowdin, Roberta, additional, Torres, Mina, additional, Jalloh, Mohamed, additional, Magueye Gueye, Serigne, additional, Niang, Lamine, additional, Ogunbiyi, Olufemi, additional, Oladimeji Idowu, Michael, additional, Popoola, Olufemi, additional, Adebiyi, Akindele O., additional, Aisuodionoe-Shadrach, Oseremen I., additional, Nwegbu, Maxwell, additional, Adusei, Ben, additional, Mante, Sunny, additional, Darkwa-Abrahams, Afua, additional, Yeboah, Edward D., additional, Mensah, James E., additional, Anthony Adjei, Andrew, additional, Diop, Halimatou, additional, Cook, Michael B., additional, Chanock, Stephen J., additional, Watya, Stephen, additional, Eeles, Rosalind A., additional, Chiang, Charleston W.K., additional, Lachance, Joseph, additional, Rebbeck, Timothy R., additional, Conti, David V., additional, and Haiman, Christopher A., additional

Published
2022
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27. Genome-wide association study of colorectal cancer in Hispanics

Author

Schmit, Stephanie L., Schumacher, Fredrick R., Edlund, Christopher K., Conti, David V., Ihenacho, Ugonna, Wan, Peggy, Van Den Berg, David, Casey, Graham, Fortini, Barbara K., Lenz, Heinz-Josef, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Moreno-Macías, Hortensia, Huerta-Chagoya, Alicia, Ordóñez-Sánchez, María Luisa, Rodríguez-Guillén, Rosario, Cruz-Bautista, Ivette, Rodríguez-Torres, Maribel, Muñóz-Hernández, Linda Liliana, Arellano-Campos, Olimpia, Gómez, Donají, Alvirde, Ulices, González-Villalpando, Clicerio, González-Villalpando, María Elena, Le Marchand, Loic, Haiman, Christopher A., and Figueiredo, Jane C.

Published
2016
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29. Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction

Author

Conti, David V, Darst, Burcu F, Moss, Lilit C, Saunders, Edward J, Sheng, Xin, Chou, Alisha, Schumacher, Fredrick R, Olama, Ali Amin Al, Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N, Sahimi, Ali, Hoffmann, Thomas J, Takahashi, Atushi, Matsuda, Koichi, Momozawa, Yukihide, Fujita, Masashi, Muir, Kenneth, Lophatananon, Artitaya, Wan, Peggy, Le Marchand, Loic, Wilkens, Lynne R, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, Cybulski, Cezary, Wokołorczyk, Dominika, Lubiński, Jan, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bojesen, Stig E, Røder, Martin Andreas, Iversen, Peter, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Horvath, Lisa, Clements, Judith A, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordström, Tobias, Pashayan, Nora, Dunning, Alison M, Ghoussaini, Maya, Travis, Ruth C, Key, Tim J, Riboli, Elio, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Albanes, Demetrius, Weinstein, Stephanie J, Mucci, Lorelei A, Giovannucci, Edward, Lindstrom, Sara, Kraft, Peter, Hunter, David J, Penney, Kathryn L, Turman, Constance, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Parent, Marie-Élise, Stanford, Janet L, Ostrander, Elaine A, Geybels, Milan S, Koutros, Stella, Freeman, Laura E Beane, Stampfer, Meir, Wolk, Alicja, Håkansson, Niclas, Andriole, Gerald L, Hoover, Robert N, Machiela, Mitchell J, Sørensen, Karina Dalsgaard, Borre, Michael, Blot, William J, Zheng, Wei, Yeboah, Edward D, Mensah, James E, and Lu, Yong-Jie

Subjects
Male, Urologic Diseases, Aging, Quantitative Trait Loci, Medical and Health Sciences, Risk Factors, Clinical Research, Odds Ratio, Genetics, Humans, 2.1 Biological and endogenous factors, Neoplasm Invasiveness, Genetic Predisposition to Disease, Aetiology, Cancer, Prevention, Prostate Cancer, Racial Groups, Human Genome, Prostatic Neoplasms, Molecular Sequence Annotation, Genomics, Middle Aged, Biological Sciences, Phenotype, Good Health and Well Being, Genetic Loci, Software, Genome-Wide Association Study, Statistical Distributions, Developmental Biology
Abstract

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Published
2021

31. A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry

Author

Darst, Burcu F., primary, Wan, Peggy, additional, Sheng, Xin, additional, Bensen, Jeannette T., additional, Ingles, Sue A., additional, Rybicki, Benjamin A., additional, Nemesure, Barbara, additional, John, Esther M., additional, Fowke, Jay H., additional, Stevens, Victoria L., additional, Berndt, Sonja I., additional, Huff, Chad D., additional, Strom, Sara S., additional, Park, Jong Y., additional, Zheng, Wei, additional, Ostrander, Elaine A., additional, Walsh, Patrick C., additional, Srivastava, Shiv, additional, Carpten, John, additional, Sellers, Thomas A., additional, Yamoah, Kosj, additional, Murphy, Adam B., additional, Sanderson, Maureen, additional, Crawford, Dana C., additional, Gapstur, Susan M., additional, Bush, William S., additional, Aldrich, Melinda C., additional, Cussenot, Olivier, additional, Yeager, Meredith, additional, Petrovics, Gyorgy, additional, Cullen, Jennifer, additional, Neslund-Dudas, Christine, additional, Kittles, Rick A., additional, Xu, Jianfeng, additional, Stern, Mariana C., additional, Kote-Jarai, Zsofia, additional, Govindasami, Koveela, additional, Chokkalingam, Anand P., additional, Multigner, Luc, additional, Parent, Marie-Elise, additional, Menegaux, Florence, additional, Cancel-Tassin, Geraldine, additional, Kibel, Adam S., additional, Klein, Eric A., additional, Goodman, Phyllis J., additional, Drake, Bettina F., additional, Hu, Jennifer J., additional, Clark, Peter E., additional, Blanchet, Pascal, additional, Casey, Graham, additional, Hennis, Anselm J.M., additional, Lubwama, Alexander, additional, Thompson, Ian M., additional, Leach, Robin, additional, Gundell, Susan M., additional, Pooler, Loreall, additional, Xia, Lucy, additional, Mohler, James L., additional, Fontham, Elizabeth T.H., additional, Smith, Gary J., additional, Taylor, Jack A., additional, Eeles, Rosalind A., additional, Brureau, Laurent, additional, Chanock, Stephen J., additional, Watya, Stephen, additional, Stanford, Janet L., additional, Mandal, Diptasri, additional, Isaacs, William B., additional, Cooney, Kathleen, additional, Blot, William J., additional, Conti, David V., additional, and Haiman, Christopher A., additional

Published
2020
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32. Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer

Author

Darst, Burcu F, primary, Dadaev, Tokhir, additional, Saunders, Ed, additional, Sheng, Xin, additional, Wan, Peggy, additional, Pooler, Loreall, additional, Xia, Lucy Y, additional, Chanock, Stephen, additional, Berndt, Sonja I, additional, Gapstur, Susan M, additional, Stevens, Victoria, additional, Albanes, Demetrius, additional, Weinstein, Stephanie J, additional, Gnanapragasam, Vincent, additional, Giles, Graham G, additional, Nguyen-Dumont, Tu, additional, Milne, Roger L, additional, Pomerantz, Mark, additional, Schmidt, Julie A, additional, Mucci, Lorelei, additional, Catalona, William J, additional, Hetrick, Kurt N, additional, Doheny, Kimberly F, additional, MacInnis, Robert J, additional, Southey, Melissa C, additional, Eeles, Rosalind A, additional, Wiklund, Fredrik, additional, Kote-Jarai, Zsofia, additional, Conti, David V, additional, and Haiman, Christopher A, additional

Published
2020
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33. The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population

Author

Darst, Burcu F., primary, Chou, Alisha, additional, Wan, Peggy, additional, Pooler, Loreall, additional, Sheng, Xin, additional, Vertosick, Emily A., additional, Conti, David V., additional, Wilkens, Lynne R., additional, Le Marchand, Loïc, additional, Vickers, Andrew J., additional, Lilja, Hans G., additional, and Haiman, Christopher A., additional

Published
2020
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34. Population-specific reference panels are crucial for genetic analyses: an example of the CREBRF locus in Native Hawaiians

Author

Lin, Meng, primary, Caberto, Christian, additional, Wan, Peggy, additional, Li, Yuqing, additional, Lum-Jones, Annette, additional, Tiirikainen, Maarit, additional, Pooler, Loreall, additional, Nakamura, Brooke, additional, Sheng, Xin, additional, Porcel, Jacqueline, additional, Lim, Unhee, additional, Setiawan, Veronica Wendy, additional, Le Marchand, Loïc, additional, Wilkens, Lynne R, additional, Haiman, Christopher A, additional, Cheng, Iona, additional, and Chiang, Charleston W K, additional

Published
2020
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36. Population specific reference panels are crucial for the genetic analyses of Native Hawai’ians: an example of theCREBRFlocus

Author

Lin, Meng, primary, Caberto, Christian, additional, Wan, Peggy, additional, Li, Yuqing, additional, Lum-Jones, Annette, additional, Tiirikainen, Maarit, additional, Pooler, Loreall, additional, Nakamura, Brooke, additional, Sheng, Xin, additional, Porcel, Jacqueline, additional, Lim, Unhee, additional, Setiawan, Veronica Wendy, additional, Marchand, Loïc Le, additional, Wilkens, Lynne R., additional, Haiman, Christopher A., additional, Cheng, Iona, additional, and Chiang, Charleston W. K., additional

Published
2019
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37. Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

Author

Darst, Burcu F, Dadaev, Tokhir, Saunders, Ed, Sheng, Xin, Wan, Peggy, Pooler, Loreall, Xia, Lucy Y, Chanock, Stephen, Berndt, Sonja I, Gapstur, Susan M, Stevens, Victoria, Albanes, Demetrius, Weinstein, Stephanie J, Gnanapragasam, Vincent, Giles, Graham G, Nguyen-Dumont, Tu, Milne, Roger L, Pomerantz, Mark, Schmidt, Julie A, and Mucci, Lorelei

Subjects
DNA repair, GENES, HEREDITARY nonpolyposis colorectal cancer, GERM cells, PROSTATE cancer, ALLELES, BRCA genes, RESEARCH, GENETIC mutation, DNA, RESEARCH methodology, EVALUATION research, COMPARATIVE studies, DISEASE susceptibility, PROSTATE tumors
Abstract

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease.Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided.Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4).Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations. [ABSTRACT FROM AUTHOR]

Published
2021
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39. Abstract 1305: A genome-wide association study of prostate cancer in Uganda

Author

Du, Zhaohui, primary, Lubmawa, Alexander, additional, Gundell, Susan, additional, Wan, Peggy, additional, Cissy, Nalukenge, additional, Proscovia, Muwanga, additional, Moses, Lutalo, additional, Deborah, Nansereko, additional, Olivia, Ndaruhutse, additional, Molly, Katuku, additional, Alexander, Lubwama, additional, Nassanga, Rosemary, additional, Masaba, Benson, additional, Kaggwa, Sam, additional, Namuguzi, Dan, additional, Kiddu, Vicky, additional, Luke, Asiimwe, additional, J, Kuteesa, additional, Henry, Dabanja M., additional, Conti, David, additional, Haiman, Christopher A., additional, and Watya, Stephen, additional

Published
2017
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40. Genetic risk of prostate cancer in Ugandan men.

Author

Du, Zhaohui, Lubmawa, Alexander, Gundell, Susan, Wan, Peggy, Nalukenge, Cissy, Muwanga, Proscovia, Lutalo, Moses, Nansereko, Deborah, Ndaruhutse, Olivia, Katuku, Molly, Nassanga, Rosemary, African Ancestry Prostate Cancer Consortium (AAPC), Asiimwe, Frank, Masaba, Benon, Kaggwa, Sam, Namuguzi, Dan, Kiddu, Vicky, Mutema, George, Conti, David V., and Luke, Asiimwe

Published
2018
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42. The Four-Kallikrein Panel Is Effective in Identifying Aggressive Prostate Cancer in a Multiethnic Population.

Author

Darst, Burcu F., Chou, Alisha, Wan, Peggy, Pooler, Loreall, Xin Sheng, Vertosick, Emily A., Conti, David V., Wilkens, Lynne R., Le Marchand, Loïc, Vickers, Andrew J., Lilja, Hans G., and Haiman, Christopher A.

Abstract

Background: The four-kallikrein (4K) panel has been demonstrated to improve prediction of aggressive prostate cancer compared with prostate-specific antigen (PSA) among men with moderately elevated PSA levels. However, the development and testing of the 4K panel has been conducted primarily in White men, with limited data in African Americans and no studies in other racial and ethnic groups. Methods: We evaluated the 4K panel in a nested case-control study among African American, Latino, Japanese, Native Hawaiian, and White men in the Multiethnic Cohort. Prediagnostic blood levels of free, intact, and total PSA and human kallikrein-related peptidase 2 were measured among 1,667 incident prostate cancer cases and 691 controls with PSA ≥2 ng/mL. We evaluated the discriminative ability of the 4K panel within and across all racial/ethnic groups. Results: The 4K panel enhanced discrimination of overall prostate cancer compared with free plus total PSA and total PSA alone (AUC 0.748 vs. 0.711 and 0.669, respectively). Discrimination was further enhanced for Gleason 8+ prostate cancer, aggressive prostate cancer, and death due to prostate cancer, and to a lesser degree for nonaggressive prostate cancer. Improvement of the 4K panel over PSA was observed in each population. Adding a prostate cancer polygenic risk score slightly improved upon the discriminative ability of the 4K panel. Conclusions: The superior discriminative ability of the 4K panel over PSA for overall and aggressive prostate cancer across multiethnic populations indicates the broad clinical applicability of the 4K panel. Impact: Our multiethnic investigation suggests potential for the 4K panel to improve current prostate cancer screening practices. [ABSTRACT FROM AUTHOR]

Published
2020
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43. Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.

Author

Darst BF, Shen J, Madduri RK, Rodriguez AA, Xiao Y, Sheng X, Saunders EJ, Dadaev T, Brook MN, Hoffmann TJ, Muir K, Wan P, Le Marchand L, Wilkens L, Wang Y, Schleutker J, MacInnis RJ, Cybulski C, Neal DE, Nordestgaard BG, Nielsen SF, Batra J, Clements JA, Grönberg H, Pashayan N, Travis RC, Park JY, Albanes D, Weinstein S, Mucci LA, Hunter DJ, Penney KL, Tangen CM, Hamilton RJ, Parent MÉ, Stanford JL, Koutros S, Wolk A, Sørensen KD, Blot WJ, Yeboah ED, Mensah JE, Lu YJ, Schaid DJ, Thibodeau SN, West CM, Maier C, Kibel AS, Cancel-Tassin G, Menegaux F, John EM, Grindedal EM, Khaw KT, Ingles SA, Vega A, Rosenstein BS, Teixeira MR, Kogevinas M, Cannon-Albright L, Huff C, Multigner L, Kaneva R, Leach RJ, Brenner H, Hsing AW, Kittles RA, Murphy AB, Logothetis CJ, Neuhausen SL, Isaacs WB, Nemesure B, Hennis AJ, Carpten J, Pandha H, De Ruyck K, Xu J, Razack A, Teo SH, Newcomb LF, Fowke JH, Neslund-Dudas C, Rybicki BA, Gamulin M, Usmani N, Claessens F, GagoDominguez M, Castelao JE, Townsend PA, Crawford DC, Petrovics G, Casey G, Roobol MJ, Hu JF, Berndt SI, Van Den Eeden SK, Easton DF, Chanock SJ, Cook MB, Wiklund F, Witte JS, Eeles RA, Kote-Jarai Z, Watya S, Gaziano JM, Justice AC, Conti DV, and Haiman CA

Abstract

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

Published
2023
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44. Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

Author

Darst BF, Dadaev T, Saunders E, Sheng X, Wan P, Pooler L, Xia LY, Chanock S, Berndt SI, Gapstur SM, Stevens V, Albanes D, Weinstein SJ, Gnanapragasam V, Giles GG, Nguyen-Dumont T, Milne RL, Pomerantz M, Schmidt JA, Mucci L, Catalona WJ, Hetrick KN, Doheny KF, MacInnis RJ, Southey MC, Eeles RA, Wiklund F, Kote-Jarai Z, Conti DV, and Haiman CA

Subjects
DNA Repair genetics, Genes, BRCA2, Genetic Predisposition to Disease, Germ Cells pathology, Humans, Male, Germ-Line Mutation, Prostatic Neoplasms pathology
Abstract

Background: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease., Methods: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided., Results: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4)., Conclusions: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Published
2021
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45. A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer.

Author

Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, Wokołorczyk D, Kluźniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Cook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, and Haiman CA

Subjects
Genome-Wide Association Study, Genotype, Humans, Male, Risk Assessment, Risk Factors, Genetic Loci genetics, Genetic Predisposition to Disease genetics, Polymorphism, Single Nucleotide, Prostatic Neoplasms genetics
Abstract

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Published
2014
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