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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. Cancer origin tracing and timing in two high-risk prostate cancers using multisample whole genome analysis: prospects for personalized medicine

Author

Nurminen, Anssi, Jaatinen, Serafiina, Taavitsainen, Sinja, Högnäs, Gunilla, Lesluyes, Tom, Ansari-Pour, Naser, Tolonen, Teemu, Haase, Kerstin, Koskenalho, Antti, Kankainen, Matti, Jasu, Juho, Rauhala, Hanna, Kesäniemi, Jenni, Nikupaavola, Tiia, Kujala, Paula, Rinta-Kiikka, Irina, Riikonen, Jarno, Kaipia, Antti, Murtola, Teemu, Tammela, Teuvo L., Visakorpi, Tapio, Nykter, Matti, Wedge, David C., Van Loo, Peter, and Bova, G. Steven

Published
2023
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4. 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

5. 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

7. Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

Author

Shore, Neal D, Gratzke, Christian, Feyerabend, Susan, Werbrouck, Patrick, Carles, Joan, Vjaters, Egils, Tammela, Teuvo L J, Morris, David, Aragon-Ching, Jeanny B, Concepcion, Raoul S, Emmenegger, Urban, Fleshner, Neil, Grabbert, Markus, Lietuvietis, Vilnis, Mahammedi, Hakim, Cruz, Felipe M, Paula, Adriano, Pieczonka, Christopher, Rannikko, Antti, and Richardet, Martin

Subjects
THERAPEUTIC use of antineoplastic agents, CASTRATION-resistant prostate cancer, PATIENT safety, RESEARCH funding, DRUG side effects, DEATH, STATISTICAL sampling, BLIND experiment, TREATMENT effectiveness, RANDOMIZED controlled trials, METASTASIS, ANDROGEN receptors, DRUG tolerance, TIME, DISEASE incidence
Abstract

Background Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. Patients and Methods Patients with nmCRPC were randomized 2:1 to darolutamide (n  = 955) or placebo (n  = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval–specific new and cumulative event rates were determined during the first 24 months of the double-blind period. Results Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. Conclusion Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment–related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. Trial number ClinicalTrials.gov identifier NCT02200614 [ABSTRACT FROM AUTHOR]

Published
2024
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8. 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

9. 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

10. 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

14. Combined Longitudinal Clinical and Autopsy Phenomic Assessment in Lethal Metastatic Prostate Cancer: Recommendations for Advancing Precision Medicine

Author

Jasu, Juho, Tolonen, Teemu, Antonarakis, Emmanuel S., Beltran, Himisha, Halabi, Susan, Eisenberger, Mario A., Carducci, Michael A., Loriot, Yohann, Van der Eecken, Kim, Lolkema, Martijn, Ryan, Charles J., Taavitsainen, Sinja, Gillessen, Silke, Högnäs, Gunilla, Talvitie, Timo, Taylor, Robert J., Koskenalho, Antti, Ost, Piet, Murtola, Teemu J., Rinta-Kiikka, Irina, Tammela, Teuvo, Auvinen, Anssi, Kujala, Paula, Smith, Thomas J., Kellokumpu-Lehtinen, Pirkko-Liisa, Isaacs, William B., Nykter, Matti, Kesseli, Juha, and Bova, G. Steven

Published
2021
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15. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

Author

Urbanucci, Alfonso, Barfeld, Stefan J, Kytölä, Ville, Itkonen, Harri M, Coleman, Ilsa M, Vodák, Daniel, Sjöblom, Liisa, Sheng, Xia, Tolonen, Teemu, Minner, Sarah, Burdelski, Christoph, Kivinummi, Kati K, Kohvakka, Annika, Kregel, Steven, Takhar, Mandeep, Alshalalfa, Mohammed, Davicioni, Elai, Erho, Nicholas, Lloyd, Paul, Karnes, R Jeffrey, Ross, Ashley E, Schaeffer, Edward M, Griend, Donald J Vander, Knapp, Stefan, Corey, Eva, Feng, Felix Y, Nelson, Peter S, Saatcioglu, Fahri, Knudsen, Karen E, Tammela, Teuvo LJ, Sauter, Guido, Schlomm, Thorsten, Nykter, Matti, Visakorpi, Tapio, and Mills, Ian G

Subjects
Biological Sciences, Urologic Diseases, Prostate Cancer, Aging, Genetics, Cancer, 2.1 Biological and endogenous factors, Aetiology, ATPases Associated with Diverse Cellular Activities, Chromatin, Chromatin Assembly and Disassembly, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Male, Neoplasm Proteins, Prostatic Neoplasms, Castration-Resistant, Protein Serine-Threonine Kinases, Receptors, Androgen, Transcription Factors, ATAD2, BRD2, BRD4, BROMO-10, androgen receptor, bromodomain inhibitor, castration-resistant prostate cancer, chromatin, Biochemistry and Cell Biology, Medical Physiology, Biological sciences
Abstract

Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

Published
2017

16. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study

Author

Beer, Tomasz M, Armstrong, Andrew J, Rathkopf, Dana, Loriot, Yohann, Sternberg, Cora N, Higano, Celestia S, Iversen, Peter, Evans, Christopher P, Kim, Choung-Soo, Kimura, Go, Miller, Kurt, Saad, Fred, Bjartell, Anders S, Borre, Michael, Mulders, Peter, Tammela, Teuvo L, Parli, Teresa, Sari, Suha, van Os, Steve, Theeuwes, Ad, and Tombal, Bertrand

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Aging, Clinical Trials and Supportive Activities, Cancer, Prostate Cancer, Clinical Research, Urologic Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Antineoplastic Agents, Benzamides, Humans, Male, Nitriles, Phenylthiohydantoin, Prostatic Neoplasms, Castration-Resistant, Survival Analysis, Androgen receptor signaling inhibitor, Enzalutamide, Metastatic castration-resistant prostate cancer, Overall survival, Radiographic progression-free survival, Urology & Nephrology, Clinical sciences
Abstract

Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p

Published
2017

17. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Author

Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W, Ingles, Sue A, Kittles, Rick A, Strom, Sara S, Rybicki, Benjamin A, Nemesure, Barbara, Isaacs, William B, Zheng, Wei, Pettaway, Curtis A, Yeboah, Edward D, Tettey, Yao, Biritwum, Richard B, Adjei, Andrew A, Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P, John, Esther M, Murphy, Adam B, Signorello, Lisa B, Carpten, John, Leske, M Cristina, Wu, Suh-Yuh, Hennis, Anslem JM, Neslund-Dudas, Christine, Hsing, Ann W, Chu, Lisa, Goodman, Phyllis J, Klein, Eric A, Witte, John S, Casey, Graham, Kaggwa, Sam, Cook, Michael B, Stram, Daniel O, Blot, William J, Eeles, Rosalind A, Easton, Douglas, Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G, Southey, Melissa C, Fitzgerald, Liesel M, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E, Schleutker, Johanna, Wahlfors, Tiina, 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, Stanford, Janet L, 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, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K, Arndt, Volker, Park, Jong Y, Sellers, Thomas A, Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A, Teixeira, Manuel R, Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, PRACTICAL consortium, Conti, David V, and Albanes, Demetrius

Subjects
PRACTICAL consortium, Cell Line, Tumor, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Histones, Epigenesis, Genetic, Acetylation, Inheritance Patterns, Linkage Disequilibrium, Polymorphism, Single Nucleotide, African Americans, European Continental Ancestry Group, Male, Atlases as Topic, Genome-Wide Association Study, Genetic Loci, Cell Line, Tumor, Epigenesis, Genetic, Polymorphism, Single Nucleotide
Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016

18. Overdiagnosis and Overtreatment of Prostate Cancer

Author

Loeb, Stacy, Bjurlin, Marc A, Nicholson, Joseph, Tammela, Teuvo L, Penson, David F, Carter, H Ballentine, Carroll, Peter, and Etzioni, Ruth

Subjects
Prevention, Urologic Diseases, Cancer, Aging, Prostate Cancer, Good Health and Well Being, Biomarkers, Tumor, Early Detection of Cancer, False Positive Reactions, Humans, Incidence, Male, Patient Selection, Prostate-Specific Antigen, Prostatic Neoplasms, Unnecessary Procedures, Prostate cancer, Overdiagnosis, Overtreatment, Screening, Prostate-specific antigen, Clinical Sciences, Urology & Nephrology
Abstract

ContextAlthough prostate cancer (PCa) screening reduces the incidence of advanced disease and mortality, trade-offs include overdiagnosis and resultant overtreatment.ObjectiveTo review primary data on PCa overdiagnosis and overtreatment.Evidence acquisitionElectronic searches were conducted in Cochrane Central Register of Controlled Trials, PubMed, and Embase from inception to July 2013 for original articles on PCa overdiagnosis and overtreatment. Supplemental articles were identified through hand searches.Evidence synthesisThe lead-time and excess-incidence approaches are the main ways used to estimate overdiagnosis in epidemiological studies, with estimates varying widely. The estimated number of PCa cases needed to be diagnosed to save a life has ranged from 48 down to 5 with increasing follow-up. In clinical studies, generally lower rates of overdiagnosis have been reported based on the frequency of low-grade minimal tumors at radical prostatectomy (1.7-46.8%). Autopsy studies have reported PCa in 18.5-38.5%, although not all are low grade or low volume. Factors influencing overdiagnosis include the study population, screening protocol, and background incidence, limiting generalizability between settings. Reported rates of overtreatment vary widely in the literature, although contemporary international studies suggest increasing use of conservative management.ConclusionsEpidemiological, clinical, and autopsy studies have been used to examine PCa overdiagnosis, with estimates ranging widely from 1.7% to 67%. Correspondingly, estimates of overtreatment vary widely based on patient features and may be declining internationally. Careful patient selection for screening and reducing overtreatment are important to preserve the benefits and reduce the downstream harms of prostate-specific antigen testing. Because all of these estimates are extremely population and context specific, this must be considered when using these data to inform policy.Patient summaryScreening reduces spread and death from prostate cancer (PCa) but overdiagnoses some low-risk tumors that may not have caused harm. Because treatment has potential side effects, it is critical that not all patients with PCa receive aggressive treatment.

Published
2014

25. Survivorship Data in Prostate Cancer: Where Are We and Where Do We Need To Be?

Author

Smith, Emma, N'Dow, James, Plass, Karin, Ribal, Maria, Mottet, Nicolas, Shepherd, Robert, Abbott, Tom, Mastris, Ken, Moris, Lisa, Lardas, Michael, Van den Broeck, Thomas, Willemse, Peter-Paul, Fossati, Nicola, Pang, Karl, Campi, Riccardo, Greco, Isabella, Gacci, Mauro, Serni, Sergio, Bjartell, Anders, Lonnerbro, Ragnar, Briganti, Alberto, Crosti, Daniele, Garzonio, Roberto, Gandaglia, Giorgio, Faticoni, Martina, Grant office, Bangma, Chris, Jongerden, Maria, Tilki, Derya, Auvinen, Anssi, Murtola, Teemu, Visakorpi, Tapio, Talala, Kirsi, Tammela, Teuvo, Siltari, Aino, Lejeune, Stephane, Colette, Laurence, Caputova, Simona, Poli, Delielena, Byrne, Sophie, Fialho, Luz, Rowland, Ashley, Tapela, Neo, Di Flora, Nicola, Apostolidis, Kathi, Lemair, Valerie, De Meulder, Bertrand, Auffray, Charles, Taibi, Nesrine, Hijazy, Ayman, Saporta, Albert, Sun, Kai, Power, Shaun, Zounemat Kermani, Nazanin, van Bochove, Kees, Tafreshiha, Azadeh, Bernini, Chiara, Horgan, Denis, Fullwood, Louise, Holtorf, Marc, Lancet, Doron, Bernstein, Gabi, Tripathee, Sheela, Wirth, Manfred, Froehner, Michael, Brenner, Beate, Borkowetz, Angelika, Thomas, Christian, Horn, Friedemann, Reiche, Kristin, Kreuz, Markus, Josefsson, Andreas, Gasi Tandefelt, Delila, Hugosson, Jonas, Schalken, Jack, Huisman, Henkjan, Hofmarcher, Thomas, Lindgren, Peter, Andersson, Emelie, Fridhammar, Adam, Tames Grijalva, Monica, Evans-Axelsson, Susan, Verholen, Frank, Zong, Jihong, Butler-Ransohoff, John-Edward, Williamson, Todd, Waldeck, Reg, Bruno, Amanda, Nevedomskaya, Ekaterina, Fatoba, Samuel, Constantinovici, Niculae, Steinbeisser, Carl, Maass, Monika, Torremante, Patrizia, Dochy, Emmanuelle, Pisa, Federica, Voss, Marc Dietrich, Papineni, Kishore, Wang-silvanto, Jing, Snijder, Robert, Wang, Xuewei, Lambrecht, Mark, Wolfinger, Russ, Eid, Sherinne, Palanisamy, Soundarya, Haque, Samiul, Antoni, Laurent, Servan, Angela, Pascoe, Katie, Robinson, Paul, Lencart, Joana, Jaton, Bertrand, Turunen, Heidi, Kilkku, Olavi, Pohjanjousi, Pasi, Voima, Olli, Nevalaita, Liina, Punakivi, Keijo, Seager, Sarah, Ratwani, Shilpa, Grzeslak, Katarzyna, Brash, James, Longden-Chapman, Elaine, Burke, Danny, Licour, Muriel, Payne, Sarah, Yong, Alan, Lujan, Flavia, Le Mare, Sophia, Hendrich, Jan, Bussmann, Michael, Juckeland, Kotik, Reich, Christian, Russell, Beth, Beyer, Katharina, Lawlor, Ailbhe, Roobol, Monique J., Venderbos, Lionne D.F., Remmers, Sebastiaan, Briers, Erik, MacLennan, Sara J., MacLennan, Steven, Omar, Muhammad Imran, and Van Hemelrijck, Mieke

Published
2024
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26. Identification of long noncoding RNAs with aberrant expression in prostate cancer metastases

Author

Sattari, Mina, primary, Kohvakka, Annika, additional, Moradi, Elaheh, additional, Rauhala, Hanna, additional, Urhonen, Henna, additional, Isaacs, William B, additional, Nykter, Matti, additional, Murtola, Teemu J, additional, Tammela, Teuvo L. J., additional, Latonen, Leena, additional, Bova, G. Steven, additional, Kesseli, Juha, additional, and Visakorpi, Tapio, additional

Published
2023
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29. Abstract 5644: Spatially resolved transcriptomics points to distinct malignant cell populations within primary and castration resistant prostate cancer

Author

Kiviaho, Antti, primary, Kallio, Heini M., additional, Eerola, Sini K., additional, Vuorinen, Elisa M., additional, Häkkinen, Tomi, additional, Taavitsainen, Sinja, additional, Afyounian, Ebrahim, additional, Tolonen, Teemu, additional, Kesseli, Juha, additional, Urbanucci, Alfonso, additional, Rautajoki, Kirsi J., additional, Tammela, Teuvo L., additional, Visakorpi, Tapio, additional, and Nykter, Matti, additional

Published
2023
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32. Relationship Between Baseline Prostate-specific Antigen on Cancer Detection and Prostate Cancer Death: Long-term Follow-up from the European Randomized Study of Screening for Prostate Cancer

Author

Remmers, Sebastiaan, Bangma, Chris H., Godtman, Rebecka A., Carlsson, Sigrid V., Auvinen, Anssi, Tammela, Teuvo L.J., Denis, Louis J., Nelen, Vera, Villers, Arnauld, Rebillard, Xavier, Kwiatkowski, Maciej, Recker, Franz, Wyler, Stephen, Zappa, Marco, Puliti, Donella, Gorini, Giuseppe, Paez, Alvaro, Lujan, Marcos, Nieboer, Daan, Schröder, Fritz H., Roobol, Monique J., Urology, and Public Health

Subjects
SDG 3 - Good Health and Well-being, Urology
Abstract

Background: The European Association of Urology guidelines recommend a risk-based strategy for prostate cancer screening based on the first prostate-specific antigen (PSA) level and age. Objective: To analyze the impact of the first PSA level on prostate cancer (PCa) detection and PCa-specific mortality (PCSM) in a population-based screening trial (repeat screening every 2–4 yr). Design, setting, and participants: We evaluated 25 589 men aged 55–59 yr, 16 898 men aged 60–64 yr, and 12 936 men aged 65–69 yr who attended at least one screening visit in the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial (screening arm: repeat PSA testing every 2–4 yr and biopsy in cases with elevated PSA; control arm: no active screening offered) during 16-yr follow-up (FU). Outcome measurements and statistical analysis: We assessed the actuarial probability for any PCa and for clinically significant (cs)PCa (Gleason ≥7). Cox proportional-hazards regression was performed to assess whether the association between baseline PSA and PCSM was comparable for all age groups. A Lorenz curve was computed to assess the association between baseline PSA and PCSM for men aged 60–61 yr. Results and limitations: The overall actuarial probability at 16 yr ranged from 12% to 16% for any PCa and from 3.7% to 5.7% for csPCa across the age groups. The actuarial probability of csPCa at 16 yr ranged from 1.2–1.5% for men with PSA

Published
2023

37. Genome-wide association of familial prostate cancer cases identifies evidence for a rare segregating haplotype at 8q24.21

Author

Teerlink, Craig C., Leongamornlert, Daniel, Dadaev, Tokhir, Thomas, Alun, Farnham, James, Stephenson, Robert A., Riska, Shaun, McDonnell, Shannon K., Schaid, Daniel J., Catalona, William J., Zheng, S. Lilly, Cooney, Kathleen A., Ray, Anna M., Zuhlke, Kimberly A., Lange, Ethan M., Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel M., Rinckleb, Antje, Luedeke, Manuel, Maier, Christiane, Stanford, Janet L., Ostrander, Elaine A., Kaikkonen, Elina M., Sipeky, Csilla, Tammela, Teuvo, Schleutker, Johanna, Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Xu, Jianfeng, Cancel-Tassin, Geraldine, Cussenot, Olivier, Mandal, Diptasri, Laurie, Cecelia, Laurie, Cathy, Thibodeau, Stephen N., Eeles, Rosalind A., Kote-Jarai, Zsofia, Cannon-Albright, Lisa, The PRACTICAL consortium, and International Consortium for Prostate Cancer Genetics

Published
2016
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39. Abstract 401: Single-cell transcriptome and chromatin sequencing uncover gene expression and gene regulatory patterns associated with enzalutamide resistance

Author

Taavitsainen, Sinja, primary, Engedal, Nikolai, additional, Cao, Shaolong, additional, Handle, Florian, additional, Erickson, Andrew, additional, Prekovic, Stefan, additional, Wetterskog, Daniel, additional, Tolonen, Teemu, additional, Vuorinen, Elisa M., additional, Kiviaho, Antti, additional, Nätkin, Reetta, additional, Häkkinen, Tomi, additional, Devlies, Wout, additional, Henttinen, Sallamari, additional, Kaarijärvi, Roosa, additional, Lahnalampi, Mari, additional, Kaljunen, Heidi, additional, Nowakowska, Karolina, additional, Syvälä, Heimo, additional, Bläuer, Merja, additional, Cremaschi, Paolo, additional, Claessens, Frank, additional, Visakorpi, Tapio, additional, Tammela, Teuvo L., additional, Murtola, Teemu, additional, Granberg, Kirsi J., additional, Lamb, Alastair D., additional, Ketola, Kirsi, additional, Mills, Ian G., additional, Attard, Gerhardt, additional, Wang, Wenyi, additional, Nykter, Matti, additional, and Urbanucci, Alfonso, additional

Published
2022
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41. Randomised double-blind phase 3 clinical study testing impact of atorvastatin on prostate cancer progression after initiation of androgen deprivation therapy: study protocol

Author

Siltari, Aino, primary, Riikonen, Jarno, additional, Koskimäki, Juha, additional, Pakarainen, Tomi, additional, Ettala, Otto, additional, Boström, Peter, additional, Seikkula, Heikki, additional, Kotsar, Andres, additional, Tammela, Teuvo, additional, Helminen, Mika, additional, Raittinen, Paavo V, additional, Lehtimäki, Terho, additional, Fode, Mikkel, additional, Østergren, Peter, additional, Borre, Michael, additional, Rannikko, Antti, additional, Marttila, Timo, additional, Salonen, Arto, additional, Ronkainen, Hanna, additional, Löffeler, Sven, additional, and Murtola, Teemu J, additional

Published
2022
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42. Population-based randomized trial of screening for clinically significant prostate cancer ProScreen : a pilot study

Author

Rannikko, Antti, Leht, Mare, Mirtti, Tuomas, Kenttämies, Anu, Tolonen, Teemu, Rinta-Kiikka, Irina, Kilpeläinen, Tuomas P., Natunen, Kari, Lilja, Hans, Lehtimäki, Terho, Raitanen, Jani, Kujala, Paula, Ronkainen, Johanna, Matikainen, Mika, Petas, Anssi, Taari, Kimmo, Tammela, Teuvo, Auvinen, Anssi, Tampere University, Department of Pathology, Department of Radiology, Clinical Medicine, Health Sciences, Department of Clinical Chemistry, and Department of Surgery

Subjects
3122 Cancers, urologic and male genital diseases, 3126 Surgery, anesthesiology, intensive care, radiology, 3142 Public health care science, environmental and occupational health
Abstract

Objectives: To evaluate the feasibility of a population-based screening trial using prostate-specific antigen (PSA), a kallikrein panel and multiparametric magnetic resonance imaging (MRI) aimed at minimizing overdiagnosis, while retaining mortality benefit. Patients and Methods: Feasibility of the screening algorithm was evaluated in terms of participation, screening test results and cancer detection. A random sample of 400 men aged 65 years was identified from the population registry and invited for screening with three stepwise tests (PSA, kallikrein panel and MRI). Men with PSA levels ≥3 ng/mL were further tested with the kallikrein panel, and those with positive findings (risk >7.5%) were referred for prostate MRI. Men with positive MRI (Prostate Imaging Reporting and Data System [PI-RADS] score 3–5) had targeted biopsies only. Men with negative MRI, but PSA density ≥0.15 underwent systematic biopsies. Results: Of the 399 men invited, 158 (40%) participated and 27 had PSA levels ≥3 ng/mL (7% of the invited and 17% of the participants). Of these, 22 had a positive kallikrein panel (6% of the invited and 81% of the PSA-positive men). Finally, 10 men (3% of the invited and 45% of 4Kscore [kallikrein panel]-positive) had a suspicious MRI finding (PI-RADS score ≥3) and five were diagnosed with a clinically significant prostate cancer (Gleason Grade Group [GG] ≥2) at fusion biopsy (3% of the participants), with two GG 1 cases (1%). Additional testing (kallikrein panel and MRI) after PSA reduced biopsies by 56%. Conclusion: The findings constitute proof of principle for our screening protocol, as we achieved a substantial detection rate for clinically significant cancer with few clinically insignificant cases. Participation, however, was suboptimal. publishedVersion

Published
2022

43. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer

Author

Smith, Matthew R, Hussain, Maha, Saad, Fred, Fizazi, Karim, Sternberg, Cora N, Crawford, E David, Kopyltsov, Evgeny, Park, Chandler H, Alekseev, Boris, Montesa-Pino, Álvaro, Dingwei, Ye, Parnis, Francis, Cruz, Felipe, Tammela, Teuvo L J, Suzuki, Hiroyoshi, Utriainen, Tapio, Cheng, Fu, Uemura, Motohide, Méndez-Vidal, María J, Maughan, Benjamin L, Joensuu, Heikki, Thiele, Silke, Rui, Li, Kuss, Iris, Tombal, Bertrand, Arasens, Investigators, Milella, Michele, UCL - SSS/IREC/CHEX - Pôle de chirgurgie expérimentale et transplantation, and UCL - (SLuc) Service d'urologie

Subjects
Aged, 80 and over, Male, Neutropenia, Prostatic Neoplasms, Androgen Antagonists, Antineoplastic Agents, General Medicine, Docetaxel, Kaplan-Meier Estimate, Middle Aged, Castration-Resistant, Prostatic Neoplasms, Castration-Resistant, Drug Therapy, Combination, Medicine and Health Sciences, 80 and over, Androgen Receptor Antagonists, Humans, Pyrazoles, Drug Therapy, Combination, Neoplasm Metastasis, Aged, Proportional Hazards Models
Abstract

BACKGROUND Darolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown. METHODS In this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival. RESULTS The primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P= 10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively). CONCLUSIONS In this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, .) Darolutamide in Metastatic Prostate Cancer Standard therapy for metastatic, hormone-sensitive prostate cancer is androgen-deprivation therapy, usually with docetaxel. A large, multinational, phase 3 trial assessed the addition of the androgen-receptor blocker darolutamide to standard therapy. At 4 years, survival was higher with darolutamide than with placebo (62.7% vs. 50.4%), with no major differences in the frequency of adverse events.

Published
2022

46. Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate cancer associated SNPs for familial disease

Author

Teerlink, Craig C., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Rinckleb, Antje, Maier, Christiane, Vogel, Walther, Cancel-Tassin, Geraldine, Egrot, Christophe, Cussenot, Olivier, Foulkes, William D., Giles, Graham G., Hopper, John L., Severi, Gianluca, Eeles, Ros, Easton, Douglas, Kote-Jarai, Zsofia, Guy, Michelle, Cooney, Kathleen A., Ray, Anna M., Zuhlke, Kimberly A., Lange, Ethan M., FitzGerald, Liesel M., Stanford, Janet L., Ostrander, Elaine A., Wiley, Kathleen E., Isaacs, Sarah D., Walsh, Patrick C., Isaacs, William B., Wahlfors, Tiina, Tammela, Teuvo, Schleutker, Johanna, Wiklund, Fredrik, Grönberg, Henrik, Emanuelsson, Monica, Carpten, John, Bailey-Wilson, Joan, Whittemore, Alice S., Oakley-Girvan, Ingrid, Hsieh, Chih-Lin, Catalona, William J., Zheng, S. Lilly, Jin, Guangfu, Lu, Lingyi, Xu, Jianfeng, Camp, Nicola J., Cannon-Albright, Lisa A., and International Consortium for Prostate Cancer Genetics

Published
2014
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47. Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Author

Amin Al Olama, Ali, Dadaev, Tokhir, Hazelett, Dennis J., Li, Qiuyan, Leongamornlert, Daniel, Saunders, Edward J., Stephens, Sarah, Cieza-Borrella, Clara, Whitmore, Ian, Benlloch Garcia, Sara, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel, Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schumacher, Fredrick, Haiman, Christopher A., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L., 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, Stanford, Janet L., Thibodeau, Stephen N., Mcdonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokołorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Brenner, Hermann, Butterbach, Katja, Arndt, Volker, Park, Jong Y., Sellers, Thomas, 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, Kierzek, Andrzej, Govindasami, Koveela, Guy, Michelle, Lophatonanon, Artitaya, Muir, Kenneth, Viñuela, Ana, Brown, Andrew A., Freedman, Mathew, Conti, David V., Easton, Douglas, Coetzee, Gerhard A., Eeles, Rosalind A., Kote-Jarai, Zsofia, Easton, Douglas F., Pharoah, Paul, Michailidou, Kyriaki, Bolla, Manjeet K., Wang, Qin, Berchuck, Andrew, Eeles, Rosalind A., Easton, Douglas F., Kote-Jarai, Zsofia, Al Olama, Ali Amin, Benlloch, Sara, Chenevix-Trench, Georgia, Antoniou, Antonis, McGuffog, Lesley, Couch, Fergus, Offit, Ken, Dennis, Joe, Dunning, Alison M., Lee, Andrew, Dicks, Ed, Luccarini, Craig, Benitez, Javier, Gonzalez-Neira, Anna, Simard, Jacques, Tessier, Daniel C., Bacot, Francois, Vincent, Daniel, LaBoissière, Sylvie, Robidoux, Frederic, Bojesen, Stig E., Nielsen, Sune F., Nordestgaard, Borge G., Cunningham, Julie M., Windebank, Sharon A., Hilker, Christopher A., and Meyer, Jeffrey

Published
2015
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48. Atorvastatin induces adrenal androgen downshift in men with prostate cancer: A post Hoc analysis of a pilot adaptive Randomised clinical trial

Author

Raittinen, Paavo V.H., Syvälä, Heimo, Tammela, Teuvo L.J., Häkkinen, Merja R., Ilmonen, Pauliina, Auriola, Seppo, Murtola, Teemu J., Department of Mathematics and Systems Analysis, Tampere University, University of Eastern Finland, Aalto-yliopisto, Aalto University, BioMediTech, TAYS Cancer Centre, Department of Surgery, and Clinical Medicine

Subjects
Male, Medicine (General), Prostatic tissue adrenal androgens, 3122 Cancers, Pilot Projects, Mass Spectrometry, R5-920, Double-Blind Method, Atorvastatin, Humans, Testosterone, Prospective Studies, Finland, Aged, Prostate cancer, Statins, Prostatic Neoplasms, Middle Aged, 3126 Surgery, anesthesiology, intensive care, radiology, Clinical trial, Treatment Outcome, Serum adrenal androgens, Medicine, lipids (amino acids, peptides, and proteins), Research Paper, Chromatography, Liquid
Abstract

Background: Prostate cancer (PCa) progression depends on androgen receptor activity. Cholesterol is required for biosynthesis of all steroid hormones, including androgens. Impact of cholesterol-lowering statins on androgens is unknown. We explored atorvastatin influence on serum and prostatic tissue steroidomic profiles (SP) to expose novel pathways for limiting androgen concentration in men with PCa. Methods: This is a pre-planned post hoc analysis of ESTO-1 pilot randomised, double-blinded, clinical trial. Statin naïve men, scheduled for radical prostatectomy due to localised PCa, were randomised 1:1 to use daily 80 mg of atorvastatin or placebo before the surgery for a median of 28 days. Participants were recruited and treated at the Pirkanmaa Hospital District, Tampere, Finland. 108 of the 158 recruited men were included in the analysis based on sample availability for hormone profiling. Serum and prostatic tissue steroid profiles were determined using liquid chromatography mass spectrometry. Wilcoxon rank sum test and bootstrap confidence intervals (CI) were used to analyse the difference between placebo and atorvastatin arms. Findings: Most serum and prostatic steroids, including testosterone and dihydrotestosterone, were not associated with atorvastatin use. However, atorvastatin use induced serum SP changes in 11-ketoandrostenedione (placebo 960pM, atorvastatin 617.5pM, p-value

Published
2021

50. Rare Germline Variants in ATM Predispose to Prostate Cancer : A PRACTICAL Consortium Study

Author

PRACTICAL Consortium, Karlsson, Questa, Brook, Mark N, Dadaev, Tokhir, Wakerell, Sarah, Saunders, Edward J, Muir, Kenneth, Neal, David E, Giles, Graham G, MacInnis, Robert J, Thibodeau, Stephen N, McDonnell, Shannon K, Cannon-Albright, Lisa, Teixeira, Manuel R, Paulo, Paula, Cardoso, Marta, Huff, Chad, Li, Donghui, Yao, Yu, Scheet, Paul, Permuth, Jennifer B, Stanford, Janet L, Dai, James Y, Ostrander, Elaine A, Cussenot, Olivier, Cancel-Tassin, Géraldine, Hoegel, Josef, Herkommer, Kathleen, Schleutker, Johanna, Tammela, Teuvo L J, Rathinakannan, Venkat, Sipeky, Csilla, Wiklund, Fredrik, Grönberg, Henrik, Aly, Markus, Isaacs, William B, Dickinson, Jo L, FitzGerald, Liesel M, Chua, Melvin L K, Nguyen-Dumont, Tu, Schaid, Daniel J, Southey, Melissa C, Eeles, Rosalind A, Kote-Jarai, Zsofia, Tampere University, Department of Surgery, and Clinical Medicine

Subjects
Oncology, Male, medicine.medical_specialty, Urology, 030232 urology & nephrology, Disease, Ataxia Telangiectasia Mutated Proteins, urologic and male genital diseases, Targeted screening and therapy, Germline, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Internal medicine, Genetic predisposition, medicine, SNP, Humans, Radiology, Nuclear Medicine and imaging, Genetic Predisposition to Disease, Germ-Line Mutation, Variant Call Format, business.industry, Prostatic Neoplasms, Odds ratio, Priority Article, medicine.disease, 3126 Surgery, anesthesiology, intensive care, radiology, Confidence interval, ddc, 030220 oncology & carcinogenesis, Surgery, ATM gene mutations, business
Abstract

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (

Published
2021

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