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1. Agent orange exposure and prostate cancer risk in the million veteran program

Author

Pagadala, Meghana S, Lui, Asona J, Zhong, Allison Y, Lynch, Julie A, Karunamuni, Roshan, Lee, Kyung Min, Plym, Anna, Rose, Brent S, Carter, Hannah K, Kibel, Adam S, DuVall, Scott L, Gaziano, J Michael, Panizzon, Matthew S, Hauger, Richard L, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Urologic Diseases, Humans, Male, Agent Orange, Prostatic Neoplasms, Veterans, Middle Aged, Aged, Vietnam Conflict, United States, Defoliants, Chemical, Risk Factors, 2, 4, 5-Trichlorophenoxyacetic Acid, 2, 4-Dichlorophenoxyacetic Acid, Polychlorinated Dibenzodioxins, prostate cancer, MVP, race/ ethnicity, health disparities, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundThe US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk.Patients and methodsParticipants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models.Results and interpretationOn univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09,

Published
2024

2. Cluster effect for SNP–SNP interaction pairs for predicting complex traits

Author

Lin, Hui-Yi, Mazumder, Harun, Sarkar, Indrani, Huang, Po-Yu, Eeles, Rosalind A., Kote-Jarai, Zsofia, Muir, Kenneth R., Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Neal, David E., Nielsen, Sune F., Nordestgaard, Børge G., Grönberg, Henrik, Wiklund, Fredrik, MacInnis, Robert J., Haiman, Christopher A., Travis, Ruth C., Stanford, Janet L., Kibel, Adam S., Cybulski, Cezary, Khaw, Kay-Tee, Maier, Christiane, Thibodeau, Stephen N., Teixeira, Manuel R., Cannon-Albright, Lisa, Brenner, Hermann, Kaneva, Radka, Pandha, Hardev, and Park, Jong Y.

Published
2024
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4. Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants

Author

Wang, Anqi, Shen, Jiayi, Rodriguez, Alex A., Saunders, Edward J., Chen, Fei, Janivara, Rohini, Darst, Burcu F., Sheng, Xin, Xu, Yili, Chou, Alisha J., Benlloch, Sara, Dadaev, Tokhir, Brook, Mark N., Plym, Anna, Sahimi, Ali, Hoffman, Thomas J., 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 P., Schleutker, Johanna, Tammela, Teuvo L. J., Sipeky, Csilla, Auvinen, Anssi, Giles, Graham G., Southey, Melissa C., MacInnis, Robert J., Cybulski, Cezary, Wokolorczyk, Dominika, Lubinski, Jan, Rentsch, Christopher T., Cho, Kelly, Mcmahon, Benjamin H., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Martin, Richard M., Nordestgaard, Borge G., Nielsen, Sune F., Weischer, Maren, Bojesen, Stig E., Røder, Andreas, Stroomberg, Hein V., Batra, Jyotsna, Chambers, Suzanne, Horvath, Lisa, Clements, Judith A., Tilly, Wayne, Risbridger, Gail P., Gronberg, Henrik, Aly, Markus, Szulkin, Robert, Eklund, Martin, Nordstrom, 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, Cook, Michael B., 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., Koutros, Stella, Beane Freeman, Laura E., 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., Barnett, Gill, Maier, Christiane, Schnoeller, Thomas, Luedeke, Manuel, Kibel, Adam S., Drake, Bettina F., Cussenot, Olivier, Cancel-Tassin, Geraldine, 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., Butler, Ebonee N., Mohler, James L., Taylor, Jack A., Kogevinas, Manolis, Dierssen-Sotos, Trinidad, Castaño-Vinyals, Gemma, Cannon-Albright, Lisa, Teerlink, Craig C., Huff, Chad D., Pilie, Patrick, Yu, Yao, Bohlender, Ryan J., Gu, Jian, Strom, Sara S., Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Kaneva, Radka, Slavov, Chavdar, Mitev, Vanio, Leach, Robin J., Brenner, Hermann, Chen, Xuechen, Holleczek, Bernd, Schöttker, Ben, 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 M., Rybicki, Benjamin A., Gamulin, Marija, Lessel, Davor, Kulis, Tomislav, Usmani, Nawaid, Abraham, Aswin, 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, Petrovics, Gyorgy, Casey, Graham, Wang, Ying, Tettey, Yao, Lachance, Joseph, Tang, Wei, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Yamoah, Kosj, Govindasami, Koveela, Chokkalingam, Anand P., Keaton, Jacob M., Hellwege, Jacklyn N., Clark, Peter E., Jalloh, Mohamed, Gueye, Serigne M., Niang, Lamine, Ogunbiyi, Olufemi, Shittu, Olayiwola, Amodu, Olukemi, 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, Diop, Halimatou, Gundell, Susan M., Roobol, Monique J., Jenster, Guido, van Schaik, Ron H. N., Hu, Jennifer J., Sanderson, Maureen, Kachuri, Linda, Varma, Rohit, McKean-Cowdin, Roberta, Torres, Mina, Preuss, Michael H., Loos, Ruth J. F., Zawistowski, Matthew, Zöllner, Sebastian, Lu, Zeyun, Van Den Eeden, Stephen K., Easton, Douglas F., Ambs, Stefan, Edwards, Todd L., Mägi, Reedik, Rebbeck, Timothy R., Fritsche, Lars, Chanock, Stephen J., Berndt, Sonja I., Wiklund, Fredrik, Nakagawa, Hidewaki, Witte, John S., Gaziano, J. Michael, Justice, Amy C., Mancuso, Nick, Terao, Chikashi, Eeles, Rosalind A., Kote-Jarai, Zsofia, Madduri, Ravi K., Conti, David V., and Haiman, Christopher A.

Published
2023
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5. Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score

Author

Huynh-Le, Minh-Phuong, Karunamuni, Roshan, Fan, Chun Chieh, Asona, Lui, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth R, Lophatananon, Artitaya, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Blot, William J, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Wiklund, Fredrik, Penney, Kathryn L, Huff, Chad D, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Ost, Piet, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Abraham, Aswin, Claessens, Frank, Castelao, Jose Esteban, Townsend, Paul A, Crawford, Dana C, Petrovics, Gyorgy, van Schaik, Ron HN, Parent, Marie-Élise, Hu, Jennifer J, Zheng, Wei, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Urologic Diseases, Prevention, Genetics, Good Health and Well Being, Male, Humans, Prostate-Specific Antigen, Prostatic Neoplasms, Early Detection of Cancer, Polymorphism, Single Nucleotide, Risk Factors, Risk Assessment, Genetic Predisposition to Disease, UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundProstate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets.MethodsIn total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured.ResultsThe final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively.ConclusionsWe demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Published
2022

7. MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study

Author

Ehdaie, Behfar, Tempany, Clare M, Holland, Ford, Sjoberg, Daniel D, Kibel, Adam S, Trinh, Quoc-Dien, Durack, Jeremy C, Akin, Oguz, Vickers, Andrew J, Scardino, Peter T, Sperling, Dan, Wong, Jeffrey YC, Yuh, Bertram, Woodrum, David A, Mynderse, Lance A, Raman, Steven S, Pantuck, Allan J, Schiffman, Marc H, McClure, Timothy D, Sonn, Geoffrey A, and Ghanouni, Pejman

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prevention, Biomedical Imaging, Prostate Cancer, Aging, Patient Safety, Clinical Research, Cancer, Urologic Diseases, Aged, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Prospective Studies, Prostate, Prostate-Specific Antigen, Prostatic Neoplasms, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundMen with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer.MethodsIn this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting.FindingsBetween May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths.Interpretation24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term.FundingInsightec and the National Cancer Institute.

Published
2022

8. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Lui, Asona, Martinez, Maria Elena, Rose, Brent S, Mahal, Brandon, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Taylor, Jack A, Bensen, Jeannette T, Mohler, James L, Fontham, Elizabeth TH, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay H, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Cullen, Jennifer, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Prevention, Genetics, Cancer, Urologic Diseases, Black People, Case-Control Studies, Chromosomes, Human, Pair 8, Genetic Predisposition to Disease, Humans, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk Assessment, White People, UKGPCS Collaborators, PRACTICAL Consortium, Urology & Nephrology, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2022

13. Prospective Multicenter Comparison of Open and Robotic Radical Prostatectomy: The PROST-QA/RP2 Consortium

Author

Chang, Peter, Wagner, Andrew A, Regan, Meredith M, Smith, Joseph A, Saigal, Christopher S, Litwin, Mark S, Hu, Jim C, Cooperberg, Matthew R, Carroll, Peter R, Klein, Eric A, Kibel, Adam S, Andriole, Gerald L, Han, Misop, Partin, Alan W, Wood, David P, Crociani, Catrina M, Greenfield, Thomas K, Patil, Dattatraya, Hembroff, Larry A, Davis, Kyle, Stork, Linda, Spratt, Daniel E, Wei, John T, Sanda, Martin G, and Consortium, and the PROST-QA RP2

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Pain Research, Chronic Pain, Urologic Diseases, Cancer, 6.4 Surgery, Evaluation of treatments and therapeutic interventions, Aged, Humans, Laparoscopy, Male, Middle Aged, Prospective Studies, Prostatectomy, Prostatic Neoplasms, Quality of Life, Robotic Surgical Procedures, Treatment Outcome, prostatectomy, robotic surgical procedures, quality of life, PROST-QA/RP2 Consortium
Abstract

PurposeOur goal was to evaluate the comparative effectiveness of robot-assisted laparoscopic prostatectomy (RALP) and open radical prostatectomy (ORP) in a multicenter study.Materials and methodsWe evaluated men with localized prostate cancer at 11 high-volume academic medical centers in the United States from the PROST-QA (2003-2006) and the PROST-QA/RP2 cohorts (2010-2013) with a pre-specified goal of comparing RALP (549) and ORP (545). We measured longitudinal patient-reported health-related quality of life (HRQOL) at pre-treatment and at 2, 6, 12, and 24 months, and pathological and perioperative outcomes/complications.ResultsDemographics, cancer characteristics, and margin status were similar between surgical approaches. ORP subjects were more likely to undergo lymphadenectomy (89% vs 47%; p

Published
2022

15. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis

Author

Landi, Maria Teresa, Stevens, Victoria, Wang, Ying, Albanes, Demetrios, Caporaso, Neil, Brennan, Paul, Amos, Christopher I., Shete, Sanjay, Hung, Rayjean J., Bickeböller, Heike, Risch, Angela, Houlston, Richard, Lam, Stephen, Tardon, Adonina, Chen, Chu, Bojesen, Stig E., Johansson, Mattias, Wichmann, H-Erich, Christiani, David, Rennert, Gadi, Arnold, Susanne, Field, John K., Le Marchand, Loic, Melander, Olle, Brunnström, Hans, Liu, Geoffrey, Andrew, Angeline, Kiemeney, Lambertus A., Shen, Hongbing, Zienolddiny, Shan, Grankvist, Kjell, Johansson, Mikael, Teare, M. Dawn, Hong, Yun-Chul, Yuan, Jian-Min, Lazarus, Philip, Schabath, Matthew B., Aldrich, Melinda C., Eeles, Rosalind A., Haiman, Christopher A., Kote-Jarai, Zsofia, Schumacher, Fredrick R., Benlloch, Sara, Al Olama, Ali Amin, Muir, Kenneth R., Berndt, Sonja I., Conti, David V., Wiklund, Fredrik, Chanock, Stephen, Tangen, Catherine M., Batra, Jyotsna, Clements, Judith A., Grönberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Albanes, Demetrius, Weinstein, Stephanie J., Wolk, Alicja, West, Catharine M.L., Mucci, Lorelei A., Cancel-Tassin, Géraldine, Koutros, Stella, Sørensen, Karina Dalsgaard, Grindedal, Eli Marie, Neal, David E., Hamdy, Freddie C., Donovan, Jenny L., Travis, Ruth C., Hamilton, Robert J., Ingles, Sue Ann, Rosenstein, Barry S., Lu, Yong-Jie, Giles, Graham G., MacInnis, Robert J., Kibel, Adam S., Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L., Park, Jong Y., Stanfrod, Janet L., Cybulski, Cezary, Nordestgaard, Børge G., Nielsen, Sune F., Brenner, Hermann, Maier, Christiane, Logothetis, Christopher J., John, Esther M., Teixeira, Manuel R., Neuhausen, Susan L., De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F., Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A., Castelao, Jose Esteban, Roobol, Monique J., Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa, Pandha, Hardev, Thibodeau, Stephen N., Hunter, David J., Kraft, Peter, Blot, William J., Riboli, Elio, Yarmolinsky, James, Robinson, Jamie W., Mariosa, Daniela, Karhunen, Ville, Huang, Jian, Dimou, Niki, Murphy, Neil, Burrows, Kimberley, Bouras, Emmanouil, Smith-Byrne, Karl, Lewis, Sarah J., Galesloot, Tessel E., Vermeulen, Sita, Martin, Paul, Hou, Lifang, Newcomb, Polly A., White, Emily, Wu, Anna H., Le Marchand, Loïc, Phipps, Amanda I., Buchanan, Daniel D., Zhao, Sizheng Steven, Gill, Dipender, Chanock, Stephen J., Purdue, Mark P., Davey Smith, George, Herzig, Karl-Heinz, Järvelin, Marjo-Riitta, Amos, Chris I., Dehghan, Abbas, Gunter, Marc J., Tsilidis, Kostas K., and Martin, Richard M.

Published
2024
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19. Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Lui, Asona, Martinez, Maria Elena, Rose, Brent S, Mahal, Brandon, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, UKGPCS Collaborators, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Taylor, Jack A, Bensen, Jeannette T, Mohler, James L, Fontham, Elizabeth TH, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay H, Bush, William S, Aldrich, Melinda C, Crawford, Dana C, Cullen, Jennifer, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, PRACTICAL Consortium, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
UKGPCS Collaborators, PRACTICAL Consortium, Urologic Diseases, Prevention, Genetics, Prostate Cancer, Cancer, Urology & Nephrology, Oncology and Carcinogenesis
Abstract

BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

Published
2021

20. Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Lophatananon, Artitaya, UKGPCS collaborators, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, APCB BioResource (Australian Prostate Cancer BioResource), Grönberg, Henrik, Walsh, Eleanor I, Turner, Emma L, Lane, Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Nordestgaard, Børge G, Tangen, Catherine M, MacInnis, Robert J, Wolk, Alicja, Albanes, Demetrius, Haiman, Christopher A, Travis, Ruth C, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Nielsen, Sune F, Kibel, Adam S, Wiklund, Fredrik, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Rosenstein, Barry S, Vega, Ana, IMPACT Study Steering Committee and Collaborators, Kogevinas, Manolis, Penney, Kathryn L, Teixeira, Manuel R, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, Razack, Azad, Newcomb, Lisa F, Canary PASS Investigators, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Roobol, Monique J, Zheng, Wei, Profile Study Steering Committee, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB BioResource, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Prevention, Urologic Diseases, Cancer, Prostate Cancer, Aging, Urology & Nephrology, Oncology and Carcinogenesis
Abstract

BackgroundPolygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).Materials and method180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.Results166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.ConclusionsIncorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

Published
2021

22. Reply by Authors

Author

Lucas, Mayra I., Qian, Zhiyu, Lipsitz, Stuart R., Chen, Xi, Alkhatib, Khalid, Kibel, Adam S., Cole, Alexander P., Iyer, Hari S., and Trinh, Quoc-Dien

Published
2024
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24. Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Thompson, Wesley K, Martinez, Maria Elena, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, Schleutker, Johanna, Pashayan, Nora, Batra, Jyotsna, Grönberg, Henrik, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Nielsen, Sune F, Nordestgaard, Børge G, Wiklund, Fredrik, Tangen, Catherine M, Giles, Graham G, Wolk, Alicja, Albanes, Demetrius, Travis, Ruth C, Blot, William J, Zheng, Wei, Sanderson, Maureen, Stanford, Janet L, Mucci, Lorelei A, West, Catharine ML, Kibel, Adam S, Cussenot, Olivier, Berndt, Sonja I, Koutros, Stella, Sørensen, Karina Dalsgaard, Cybulski, Cezary, Grindedal, Eli Marie, Menegaux, Florence, Khaw, Kay-Tee, Park, Jong Y, Ingles, Sue A, Maier, Christiane, Hamilton, Robert J, Thibodeau, Stephen N, Rosenstein, Barry S, Lu, Yong-Jie, Watya, Stephen, Vega, Ana, Kogevinas, Manolis, Penney, Kathryn L, Huff, Chad, Teixeira, Manuel R, Multigner, Luc, Leach, Robin J, Cannon-Albright, Lisa, Brenner, Hermann, John, Esther M, Kaneva, Radka, Logothetis, Christopher J, Neuhausen, Susan L, De Ruyck, Kim, Pandha, Hardev, Razack, Azad, Newcomb, Lisa F, Fowke, Jay H, Gamulin, Marija, Usmani, Nawaid, Claessens, Frank, Gago-Dominguez, Manuela, Townsend, Paul A, Bush, William S, Roobol, Monique J, Parent, Marie-Élise, Hu, Jennifer J, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, UKGPCS collaborators, APCB (Australian Prostate Cancer BioResource), NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, and PRACTICAL Consortium

Subjects
UKGPCS collaborators, APCB, NC-LA PCaP Investigators, IMPACT Study Steering Committee and Collaborators, Canary PASS Investigators, Profile Study Steering Committee, PRACTICAL Consortium, Humans, Prostatic Neoplasms, Neoplasm Invasiveness, Multivariate Analysis, Multifactorial Inheritance, Aged, Middle Aged, Ethnic Groups, Male, Self Report, Aging, Urologic Diseases, Cancer, Prostate Cancer
Abstract

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p

Published
2021

25. African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Thompson, Wesley, Eeles, Rosalind A, Kote-Jarai, Zsofia, Muir, Kenneth, UKGPCS Collaborators, Lophatananon, Artitaya, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Blot, William J, Zheng, Wei, Kibel, Adam S, Drake, Bettina F, Cussenot, Olivier, Cancel-Tassin, Géraldine, Menegaux, Florence, Truong, Thérèse, Park, Jong Y, Lin, Hui-Yi, Bensen, Jeannette T, Fontham, Elizabeth TH, Mohler, James L, Taylor, Jack A, Multigner, Luc, Blanchet, Pascal, Brureau, Laurent, Romana, Marc, Leach, Robin J, John, Esther M, Fowke, Jay, Bush, William S, Aldrich, Melinda, Crawford, Dana C, Srivastava, Shiv, Cullen, Jennifer C, Petrovics, Gyorgy, Parent, Marie-Élise, Hu, Jennifer J, Sanderson, Maureen, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and PRACTICAL Consortium

Subjects
UKGPCS Collaborators, PRACTICAL Consortium, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Proportional Hazards Models, Case-Control Studies, Age Factors, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Models, Genetic, Middle Aged, African Continental Ancestry Group, Male, Genotyping Techniques, African, genome wide association study, genomics, genotypic ancestry, health disparities, polygenic risk, prostate cancer, Aging, Genetics, Urologic Diseases, Cancer, Prostate Cancer, Prevention, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

Published
2021

27. 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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28. The effect of sample size on polygenic hazard models for prostate cancer

Author

Karunamuni, Roshan A, Huynh-Le, Minh-Phuong, Fan, Chun C, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Amin Al Olama, Ali, Benlloch Garcia, Sara, Muir, Kenneth, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge G, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and Seibert, Tyler M

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Cancer, Aging, Urologic Diseases, Clinical Trials as Topic, Genome-Wide Association Study, Humans, Male, Models, Genetic, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Proportional Hazards Models, Prostatic Neoplasms, Sample Size, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Genetics, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR98/50 (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.

Published
2020

29. A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data

Author

Huynh-Le, Minh-Phuong, Fan, Chun Chieh, Karunamuni, Roshan, Walsh, Eleanor I, Turner, Emma L, Lane, J Athene, Martin, Richard M, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo LJ, Nordestgaard, Børge Grønne, Key, Timothy J, Travis, Ruth C, Pharoah, Paul DP, Pashayan, Nora, Khaw, Kay-Tee, Thibodeau, Stephen N, McDonnell, Shannon K, Schaid, Daniel J, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa A, Brenner, Hermann, Schöttker, Ben, Holleczek, Bernd, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar Kroumov, Kaneva, Radka P, Mitev, Vanio I, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda B, BioResource, for the Australian Prostate Cancer, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, Seibert, Tyler M, and Consortium, for the PRACTICAL

Subjects
Biomedical and Clinical Sciences, Health Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Prostate Cancer, Cancer, Prevention, Urologic Diseases, Good Health and Well Being, Aged, Early Detection of Cancer, Humans, Male, Middle Aged, Neoplasm Grading, Population Control, Prostatic Neoplasms, Australian Prostate Cancer BioResource, PRACTICAL Consortium, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundA polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.ResultsThe expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.ImpactPersonalized genetic risk assessments could inform prostate cancer screening decisions.

Published
2020

30. Predictors of Recurrence, and Progression-Free and Overall Survival following Open versus Robotic Radical Cystectomy: Analysis from the RAZOR Trial with a 3-Year Followup.

Author

Venkatramani, Vivek, Reis, Isildinha M, Castle, Erik P, Gonzalgo, Mark L, Woods, Michael E, Svatek, Robert S, Weizer, Alon Z, Konety, Badrinath R, Tollefson, Mathew, Krupski, Tracey L, Smith, Norm D, Shabsigh, Ahmad, Barocas, Daniel A, Quek, Marcus L, Dash, Atreya, Kibel, Adam S, Pruthi, Raj S, Montgomery, Jeffrey Scott, Weight, Christopher J, Sharp, David S, Chang, Sam S, Cookson, Michael S, Gupta, Gopal N, Gorbonos, Alex, Uchio, Edward M, Skinner, Eila, Soodana-Prakash, Nachiketh, Becerra, Maria F, Swain, Sanjaya, Kendrick, Kerri, Smith, Joseph A, Thompson, Ian M, and Parekh, Dipen J

Subjects
Prevention, Cancer, Clinical Trials and Supportive Activities, Comparative Effectiveness Research, Clinical Research, Aged, Cystectomy, Disease Progression, Female, Humans, Male, Middle Aged, Neoplasm Recurrence, Local, Robotic Surgical Procedures, Survival Rate, United States, Urinary Bladder Neoplasms, bladder neoplasms, cystectomy, neoplasm recurrence, robotic surgical procedures, mortality
Abstract

PurposeThe RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for 3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival.Materials and methodsWe analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis.ResultsEstimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome.ConclusionsThis analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.

Published
2020

31. Effect of a Behavioral Intervention to Increase Vegetable Consumption on Cancer Progression Among Men With Early-Stage Prostate Cancer

Author

Parsons, J Kellogg, Zahrieh, David, Mohler, James L, Paskett, Electra, Hansel, Donna E, Kibel, Adam S, Liu, Heshan, Seisler, Drew K, Natarajan, Loki, White, Martha, Hahn, Olwen, Taylor, John, Hartman, Sheri J, Stroup, Sean P, Van Veldhuizen, Peter, Hall, Lannis, Small, Eric J, Morris, Michael J, Pierce, John P, and Marshall, James

Subjects
Clinical Research, Rehabilitation, Clinical Trials and Supportive Activities, Prevention, Aging, Cancer, Urologic Diseases, Prostate Cancer, Aged, Aged, 80 and over, Counseling, Disease Progression, Humans, Male, Middle Aged, Neoplasm Staging, Prostate-Specific Antigen, Prostatic Neoplasms, Telephone, Vegetables, Watchful Waiting, Medical and Health Sciences, General & Internal Medicine
Abstract

ImportanceGuidelines endorsing vegetable-enriched diets to improve outcomes for prostate cancer survivors are based on expert opinion, preclinical studies, and observational data.ObjectiveTo determine the effect of a behavioral intervention that increased vegetable intake on cancer progression in men with early-stage prostate cancer.Design, setting, and participantsThe Men's Eating and Living (MEAL) Study (CALGB 70807 [Alliance]) was a randomized clinical trial conducted at 91 US urology and medical oncology clinics that enrolled 478 men aged 50 to 80 years with biopsy-proven prostate adenocarcinoma (International Society of Urological Pathology grade group = 1 in those

Published
2020

37. Healthy lifestyle and prostate cancer risk in the Million Veteran Program

Author

Pagadala, Meghana S., primary, Lui, Asona, additional, Lynch, Julie, additional, Karunamuni, Roshan, additional, Lee, Kyung Min, additional, Plym, Anna, additional, Rose, Brent S., additional, Carter, Hannah, additional, Kibel, Adam S., additional, DuVall, Scott L., additional, Vassy, Jason, additional, Gaziano, J. Michael, additional, Panizzon, Matthew S., additional, Hauger, Richard L., additional, and Seibert, Tyler M., additional

Published
2024
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38. Prognostic impact of residual cancer burden (RCB) on long-term outcomes after neoadjuvant (neo) androgen receptor pathway inhibitor (ARPI) and radical prostatectomy (RP) for high-risk localized prostate cancer (HRLPC): A pooled analysis of phase 2 trials.

Author

Ravi, Praful, primary, Kwak, Lucia, additional, Acosta, Andrew, additional, Rastogi, Saahil, additional, Xie, Wanling, additional, Einstein, David Johnson, additional, Chang, Peter K., additional, Wagner, Andrew, additional, McKay, Rana R., additional, Kibel, Adam S., additional, and Taplin, Mary-Ellen, additional

Published
2024
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40. Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

Author

Matejcic, Marco, Saunders, Edward J, Dadaev, Tokhir, Brook, Mark N, Wang, Kan, Sheng, Xin, Olama, Ali Amin Al, Schumacher, Fredrick R, Ingles, Sue A, Govindasami, Koveela, Benlloch, Sara, Berndt, Sonja I, Albanes, Demetrius, Koutros, Stella, Muir, Kenneth, Stevens, Victoria L, Gapstur, Susan M, Tangen, Catherine M, Batra, Jyotsna, Clements, Judith, Gronberg, Henrik, Pashayan, Nora, Schleutker, Johanna, Wolk, Alicja, West, Catharine, Mucci, Lorelei, Kraft, Peter, Cancel-Tassin, Géraldine, Sorensen, Karina D, Maehle, Lovise, Grindedal, Eli M, Strom, Sara S, Neal, David E, Hamdy, Freddie C, Donovan, Jenny L, Travis, Ruth C, Hamilton, Robert J, Rosenstein, Barry, Lu, Yong-Jie, Giles, Graham G, Kibel, Adam S, Vega, Ana, Bensen, Jeanette T, Kogevinas, Manolis, Penney, Kathryn L, Park, Jong Y, Stanford, Janet L, Cybulski, Cezary, Nordestgaard, Børge G, Brenner, Hermann, Maier, Christiane, Kim, Jeri, Teixeira, Manuel R, Neuhausen, Susan L, De Ruyck, Kim, Razack, Azad, Newcomb, Lisa F, Lessel, Davor, Kaneva, Radka, Usmani, Nawaid, Claessens, Frank, Townsend, Paul A, Gago-Dominguez, Manuela, Roobol, Monique J, Menegaux, Florence, Khaw, Kay-Tee, Cannon-Albright, Lisa A, Pandha, Hardev, Thibodeau, Stephen N, Schaid, Daniel J, PRACTICAL Consortium, Wiklund, Fredrik, Chanock, Stephen J, Easton, Douglas F, Eeles, Rosalind A, Kote-Jarai, Zsofia, Conti, David V, and Haiman, Christopher A

Subjects
PRACTICAL Consortium
Abstract

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Published
2019

43. Insulin resistance during androgen deprivation therapy in men with prostate cancer.

Author

Basaria, Shehzad, Taplin, Mary‐Ellen, McDonnell, Marie, Simonson, Donald C., Lin, Alexander P., Dufour, Alyssa B., Habtemariam, Daniel, Nguyen, Paul L., Ravi, Praful, Kibel, Adam S., Sweeney, Christopher J., D'Amico, Anthony V., Roberts, Daniel A., Xu, Wenxin, Wei, Xiao X., Sunkara, Rajitha, Choudhury, Atish D., Mantia, Charlene, Beltran, Himisha, and Pomerantz, Mark

Subjects
ANDROGEN deprivation therapy, INSULIN resistance, ADIPOSE tissues, PROSTATE cancer patients, BODY composition
Abstract

Background: Androgen deprivation therapy (ADT) in prostate cancer (PCa) has been associated with development of insulin resistance. However, the predominant site of insulin resistance remains unclear. Methods: The ADT & Metabolism Study was a single‐center, 24‐week, prospective observational study that enrolled ADT‐naive men without diabetes who were starting ADT for at least 24 weeks (ADT group, n = 42). The control group comprised men without diabetes with prior history of PCa who were in remission after prostatectomy (non‐ADT group, n = 23). Prevalent diabetes mellitus was excluded in both groups using all three laboratory criteria defined in the American Diabetes Association guidelines. All participants were eugonadal at enrollment. The primary outcome was to elucidate the predominant site of insulin resistance (liver or skeletal muscle). Secondary outcomes included assessments of body composition, and hepatic and intramyocellular fat. Outcomes were assessed at baseline, 12, and 24 weeks. Results: At 24 weeks, there was no change in hepatic (1.2; 95% confidence interval [CI], −2.10 to 4.43; p =.47) or skeletal muscle (−3.2; 95% CI, −7.07 to 0.66; p =.10) insulin resistance in the ADT group. No increase in hepatic or intramyocellular fat deposition or worsening of glucose was seen. These changes were mirrored by those observed in the non‐ADT group. Men undergoing ADT gained 3.7 kg of fat mass. Conclusions: In men with PCa and no diabetes, 24 weeks of ADT did not change insulin resistance despite adverse body composition changes. These findings should be reassuring for treating physicians and for patients who are being considered for short‐term ADT. In this prospective study of hormone‐naive men who were eugonadal and did not have diabetes, 24 weeks of androgen deprivation therapy (ADT) for prostate cancer (PCa) was not associated with worsening of hepatic or skeletal muscle insulin resistance despite a substantial increase in fat mass. These findings have relevance for both physicians and patients when determining treatment for PCa and suggest that a short course of ADT may not worsen metabolic risk in patients without pre‐existing diabetes. [ABSTRACT FROM AUTHOR]

Published
2024
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45. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author

Schumacher, Fredrick R, Al Olama, Ali Amin, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Saunders, Edward J, Dadaev, Tokhir, Leongamornlert, Daniel, Anokian, Ezequiel, Cieza-Borrella, Clara, Goh, Chee, Brook, Mark N, Sheng, Xin, Fachal, Laura, Dennis, Joe, Tyrer, Jonathan, Muir, Kenneth, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis J, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail P, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Håkansson, Niclas, West, Catharine ML, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei A, Giovannucci, Edward, Andriole, Gerald L, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Beane Freeman, Laura E, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry S, Kerns, Sarah L, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Stanford, Janet L, and Cybulski, Cezary

Subjects
Cancer, Aging, Prostate Cancer, Genetics, Urologic Diseases, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Risk, Profile Study, Australian Prostate Cancer BioResource, IMPACT Study, Canary PASS Investigators, Breast and Prostate Cancer Cohort Consortium, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Cancer of the Prostate in Sweden, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

Published
2018

46. Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts.

Author

Seibert, Tyler M, Fan, Chun Chieh, Wang, Yunpeng, Zuber, Verena, Karunamuni, Roshan, Parsons, J Kellogg, Eeles, Rosalind A, Easton, Douglas F, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Garcia, Sara Benlloch, Muir, Kenneth, Grönberg, Henrik, Wiklund, Fredrik, Aly, Markus, Schleutker, Johanna, Sipeky, Csilla, Tammela, Teuvo Lj, Nordestgaard, Børge G, Nielsen, Sune F, Weischer, Maren, Bisbjerg, Rasmus, Røder, M Andreas, Iversen, Peter, Key, Tim J, Travis, Ruth C, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S, Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Cuk, Katarina, Saum, Kai-Uwe, Park, Jong Y, Sellers, Thomas A, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Clements, Judith A, Spurdle, Amanda, Teixeira, Manuel R, Paulo, Paula, Maia, Sofia, Pandha, Hardev, Michael, Agnieszka, Kierzek, Andrzej, Karow, David S, Mills, Ian G, Andreassen, Ole A, Dale, Anders M, and PRACTICAL Consortium*

Subjects
PRACTICAL Consortium*, Humans, Prostatic Neoplasms, Kallikreins, Prostate-Specific Antigen, Disease-Free Survival, Risk Assessment, Survival Analysis, Cohort Studies, Predictive Value of Tests, Age of Onset, Genotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, European Continental Ancestry Group, Male, Early Detection of Cancer, Outcome Assessment, Health Care, Polymorphism, Single Nucleotide, Outcome Assessment, Health Care, Aging, Urologic Diseases, Cancer, Genetic Testing, Prevention, Prostate Cancer, Genetics, 2.1 Biological and endogenous factors, General & Internal Medicine, Public Health and Health Services, Clinical Sciences
Abstract

ObjectivesTo develop and validate a genetic tool to predict age of onset of aggressive prostate cancer (PCa) and to guide decisions of who to screen and at what age.DesignAnalysis of genotype, PCa status, and age to select single nucleotide polymorphisms (SNPs) associated with diagnosis. These polymorphisms were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (that is, not eligible for surveillance according to National Comprehensive Cancer Network guidelines; any of Gleason score ≥7, stage T3-T4, PSA (prostate specific antigen) concentration ≥10 ng/L, nodal metastasis, distant metastasis). The resulting polygenic hazard score is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and PSA screening data. The hazard score was calculated for these men to test prediction of survival free from PCa.SettingMultiple institutions that were members of international PRACTICAL consortium.ParticipantsAll consortium participants of European ancestry with known age, PCa status, and quality assured custom (iCOGS) array genotype data. The development dataset comprised 31 747 men; the validation dataset comprised 6411 men.Main outcome measuresPrediction with hazard score of age of onset of aggressive cancer in validation set.ResultsIn the independent validation set, the hazard score calculated from 54 single nucleotide polymorphisms was a highly significant predictor of age at diagnosis of aggressive cancer (z=11.2, P98th centile) were compared with those with average scores (30th-70th centile), the hazard ratio for aggressive cancer was 2.9 (95% confidence interval 2.4 to 3.4). Inclusion of family history in a combined model did not improve prediction of onset of aggressive PCa (P=0.59), and polygenic hazard score performance remained high when family history was accounted for. Additionally, the positive predictive value of PSA screening for aggressive PCa was increased with increasing polygenic hazard score.ConclusionsPolygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.

Published
2018

47. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author

Dadaev, Tokhir, Saunders, Edward J, Newcombe, Paul J, Anokian, Ezequiel, Leongamornlert, Daniel A, Brook, Mark N, Cieza-Borrella, Clara, Mijuskovic, Martina, Wakerell, Sarah, Olama, Ali Amin Al, Schumacher, Fredrick R, Berndt, Sonja I, Benlloch, Sara, Ahmed, Mahbubl, Goh, Chee, Sheng, Xin, Zhang, Zhuo, Muir, Kenneth, Govindasami, Koveela, Lophatananon, Artitaya, Stevens, Victoria L, Gapstur, Susan M, Carter, Brian D, Tangen, Catherine M, Goodman, Phyllis, Thompson, Ian M, Batra, Jyotsna, Chambers, Suzanne, Moya, Leire, Clements, Judith, Horvath, Lisa, Tilley, Wayne, Risbridger, Gail, Gronberg, Henrik, Aly, Markus, Nordström, Tobias, Pharoah, Paul, Pashayan, Nora, Schleutker, Johanna, Tammela, Teuvo LJ, Sipeky, Csilla, Auvinen, Anssi, Albanes, Demetrius, Weinstein, Stephanie, Wolk, Alicja, Hakansson, Niclas, West, Catharine, Dunning, Alison M, Burnet, Neil, Mucci, Lorelei, Giovannucci, Edward, Andriole, Gerald, Cussenot, Olivier, Cancel-Tassin, Géraldine, Koutros, Stella, Freeman, Laura E Beane, Sorensen, Karina Dalsgaard, Orntoft, Torben Falck, Borre, Michael, Maehle, Lovise, Grindedal, Eli Marie, Neal, David E, Donovan, Jenny L, Hamdy, Freddie C, Martin, Richard M, Travis, Ruth C, Key, Tim J, Hamilton, Robert J, Fleshner, Neil E, Finelli, Antonio, Ingles, Sue Ann, Stern, Mariana C, Rosenstein, Barry, Kerns, Sarah, Ostrer, Harry, Lu, Yong-Jie, Zhang, Hong-Wei, Feng, Ninghan, Mao, Xueying, Guo, Xin, Wang, Guomin, Sun, Zan, Giles, Graham G, Southey, Melissa C, MacInnis, Robert J, FitzGerald, Liesel M, Kibel, Adam S, Drake, Bettina F, Vega, Ana, Gómez-Caamaño, Antonio, Fachal, Laura, Szulkin, Robert, Eklund, Martin, Kogevinas, Manolis, Llorca, Javier, Castaño-Vinyals, Gemma, Penney, Kathryn L, Stampfer, Meir, Park, Jong Y, and Sellers, Thomas A

Subjects
Genetics, Aging, Urologic Diseases, Prostate Cancer, Prevention, Human Genome, Cancer, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Algorithms, Bayes Theorem, Black People, Chromosome Mapping, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Molecular Sequence Annotation, Multivariate Analysis, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Risk, White People, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium
Abstract

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

Published
2018

48. Estimating the impact of enhanced care at minority‐serving hospitals on disparities in the treatment of breast, prostate, lung, and colon cancers

Author

Beatrici, Edoardo, primary, Paciotti, Marco, additional, Nguyen, David‐Dan, additional, Filipas, Dejan K., additional, Qian, Zhiyu, additional, Lughezzani, Giovanni, additional, Daniels, Danesha, additional, Lipsitz, Stuart R., additional, Kibel, Adam S., additional, Cole, Alexander P., additional, and Trinh, Quoc‐Dien, additional

Published
2024
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49. Agent orange exposure and prostate cancer risk in the million veteran program

Author

Pagadala, Meghana S., primary, Lui, Asona J., additional, Zhong, Allison Y., additional, Lynch, Julie A., additional, Karunamuni, Roshan, additional, Lee, Kyung Min, additional, Plym, Anna, additional, Rose, Brent S., additional, Carter, Hannah K., additional, Kibel, Adam S., additional, DuVall, Scott L., additional, Gaziano, J. Michael, additional, Panizzon, Matthew S., additional, Hauger, Richard L., additional, and Seibert, Tyler M., additional

Published
2024
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50. MP08-15 SMOKING STATUS IS ASSOCIATED WITH POOR MENTAL HEALTH IN BLADDER CANCER PATIENTS AND SURVIVORS

Author

Alkhatib, Khalid Y., primary, Koelker, Mara, additional, Nolazco, Jose I., additional, Steele, Graeme, additional, Preston, Mark A., additional, Harmatz, Ian Mitchell, additional, Clinton, Timothy N., additional, Lee, Daniel J., additional, Chang, Steve L., additional, Bivalacqua, Trinity J., additional, Gore, John L., additional, Guzzo, Thomas, additional, Kibel, Adam S., additional, Trinh, Quoc-Dien, additional, and Mossanen, Matthew, additional

Published
2024
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