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1. Prospective evaluation of NGS-based sequencing in epilepsy patients: results of seven NASGE-associated diagnostic laboratories

Author: Maximilian G. W. Witzel, Christian Gebhard, Sören Wenzel, Saskia Kleier, Birgit Eichhorn, Peter Lorenz, Laura von der Heyden, Marius Kuhn, Manuel Luedeke, Miriam Döcker, Jerome Jüngling, Björn Schulte, Konstanze Hörtnagel, Ralf Glaubitz, Sarah Knippenberger, Anna Teubert, Angela Abicht, and Teresa M. Neuhann
Subjects: epilepsy, pediatric, neurology, syndromic, genetics, next-generation sequencing, Neurology. Diseases of the nervous system, RC346-429
Abstract: BackgroundEpilepsy is one of the most common and disabling neurological disorders. It is highly prevalent in children with neurodevelopmental delay and syndromic diseases. However, epilepsy can also be the only disease-determining symptom. The exact molecular diagnosis is essential to determine prognosis, comorbidity, and probability of recurrence, and to inform therapeutic decisions.Methods and materialsHere, we describe a prospective cohort study of patients with epilepsy evaluated in seven diagnostic outpatient centers in Germany. Over a period of 2 months, 07/2022 through 08/2022, 304 patients (317 returned result) with seizure-related human phenotype ontology (HPO) were analyzed. Evaluated data included molecular results, phenotype (syndromic and non-syndromic), and sequencing methods.ResultsSingle exome sequencing (SE) was applied in half of all patients, followed by panel (P) testing (36%) and trio exome sequencing (TE) (14%). Overall, a pathogenic variant (PV) (ACMG cl. 4/5) was identified in 22%; furthermore, a significant number of patients (12%) carried a reported clinically meaningful variant of unknown significance (VUS). The average diagnostic yield in patients ≤ 12 y was higher compared to patients >12 y cf. Figure 2B vs. Figure 3B. This effect was more pronounced in cases, where TE was applied in patients ≤ 12 vs. >12 y [PV (PV + VUS): patients ≤ 12 y: 35% (47%), patients > 12 y: 20% (40%)]. The highest diagnostic yield was achieved by TE in syndromic patients within the age group ≤ 12 y (ACMG classes 4/5 40%). In addition, TE vs. SE had a tendency to result in less VUS in patients ≤ 12 y [SE: 19% (22/117) VUS; TE: 17% (6/36) VUS] but not in patients >12 y [SE: 19% (8/42) VUS; TE: 20% (2/10) VUS]. Finally, diagnostic findings in patients with syndromic vs. non-syndromic symptoms revealed a significant overlap of frequent causes of monogenic epilepsies, including SCN1A, CACNA1A, and SETD1B, confirming the heterogeneity of the associated conditions.ConclusionIn patients with seizures—regardless of the detailed phenotype—a monogenic cause can be frequently identified, often implying a possible change in therapeutic action (36.7% (37/109) of PV/VUS variants); this justifies early and broad application of genetic testing. Our data suggest that the diagnostic yield is highest in exome or trio-exome-based testing, resulting in a molecular diagnosis within 3 weeks, with profound implications for therapeutic strategies and for counseling families and patients regarding prognosis and recurrence risk.
Published: 2023
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2. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author: Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah Kerns, Harry Ostrer, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, and Zsofia Kote-Jarai
Subjects: Science
Abstract: Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.
Published: 2018
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3. Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

Author: Susanne Bens, Manuel Luedeke, Tanja Richter, Melanie Graf, Julia Kolarova, Gotthold Barbi, Krisztian Lato, Thomas F. Barth, and Reiner Siebert
Subjects: Genome-wide maternal uniparental disomy, Imprinting, Prenatal diagnostics, DNA methylation, Multilocus imprinting disturbances, Medicine, Genetics, QH426-470
Abstract: Abstract Background Uniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. However, the extreme form of uniparental disomy affecting the whole genome is usually not compatible with life, with the exception of very rare cases of patients with mosaic genome-wide uniparental disomy reported in the literature. Results We here report on a fetus with intrauterine growth retardation and malformations observed on prenatal ultrasound leading to invasive prenatal testing. By cytogenetic (conventional karyotyping), molecular cytogenetic (QF-PCR, FISH, array), and methylation (MS-MLPA) analyses of amniotic fluid, we detected mosaicism for one cell line with genome-wide maternal uniparental disomy and a second diploid cell line of biparental inheritance with trisomy X due to paternal isodisomy X. As expected for this constellation, we observed DNA methylation changes at all imprinted loci investigated. Conclusions This report adds new information on phenotypic outcome of mosaic genome-wide maternal uniparental disomy leading to an extreme form of multilocus imprinting disturbance. Moreover, the findings highlight the technical challenges of detecting these rare chromosome disorders prenatally.
Published: 2017
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4. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author: Alexander Gusev, Huwenbo Shi, Gleb Kichaev, Mark Pomerantz, Fugen Li, Henry W. Long, Sue A. Ingles, Rick A. Kittles, Sara S. Strom, Benjamin A. Rybicki, Barbara Nemesure, William B. Isaacs, Wei Zheng, Curtis A. Pettaway, Edward D. Yeboah, Yao Tettey, Richard B. Biritwum, Andrew A. Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Anand P. Chokkalingam, Esther M. John, Adam B. Murphy, Lisa B. Signorello, John Carpten, M. Cristina Leske, Suh-Yuh Wu, Anslem J. M. Hennis, Christine Neslund-Dudas, Ann W. Hsing, Lisa Chu, Phyllis J. Goodman, Eric A. Klein, John S. Witte, Graham Casey, Sam Kaggwa, Michael B. Cook, Daniel O. Stram, William J. Blot, Rosalind A. Eeles, Douglas Easton, ZSofia Kote-Jarai, Ali Amin Al Olama, Sara Benlloch, Kenneth Muir, Graham G. Giles, Melissa C. Southey, Liesel M. Fitzgerald, Henrik Gronberg, Fredrik Wiklund, Markus Aly, Brian E. Henderson, Johanna Schleutker, Tiina Wahlfors, Teuvo L. J. Tammela, Børge G. Nordestgaard, Tim J. Key, Ruth C. Travis, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Paul Pharoah, Nora Pashayan, Kay-Tee Khaw, Janet L. Stanford, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Christiane Maier, Walther Vogel, Manuel Luedeke, Kathleen Herkommer, Adam S. Kibel, Cezary Cybulski, Dominika Wokolorczyk, Wojciech Kluzniak, Lisa Cannon-Albright, Craig Teerlink, Hermann Brenner, Aida K. Dieffenbach, Volker Arndt, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Chavdar Slavov, Radka Kaneva, Vanio Mitev, Jyotsna Batra, Amanda Spurdle, Judith A. Clements, Manuel R. Teixeira, Hardev Pandha, Agnieszka Michael, Paula Paulo, Sofia Maia, Andrzej Kierzek, The PRACTICAL consortium, David V. Conti, Demetrius Albanes, Christine Berg, Sonja I. Berndt, Daniele Campa, E. David Crawford, W. Ryan Diver, Susan M. Gapstur, J. Michael Gaziano, Edward Giovannucci, Robert Hoover, David J. Hunter, Mattias Johansson, Peter Kraft, Loic Le Marchand, Sara Lindström, Carmen Navarro, Kim Overvad, Elio Riboli, Afshan Siddiq, Victoria L. Stevens, Dimitrios Trichopoulos, Paolo Vineis, Meredith Yeager, Gosia Trynka, Soumya Raychaudhuri, Frederick R. Schumacher, Alkes L. Price, Matthew L. Freedman, Christopher A. Haiman, and Bogdan Pasaniuc
Subjects: Science
Abstract: Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.
Published: 2016
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5. Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARΔLBD-signalling in human prostate cancer cells.

Author: Wolfgang Streicher, Manuel Luedeke, Anca Azoitei, Friedemann Zengerling, Alexander Herweg, Felicitas Genze, Mark G Schrader, Andres J Schrader, and Marcus V Cronauer
Subjects: Medicine, Science
Abstract: BACKGROUND: Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. METHODOLOGY: In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. RESULTS: The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. CONCLUSION: RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.
Published: 2014
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6. Prostate cancer risk is not altered by TP53AIP1 germline mutations in a German case-control series.

Author: Manuel Luedeke, Irina Coinac, Carmen M Linnert, Natalia Bogdanova, Antje E Rinckleb, Mark Schrader, Walther Vogel, Josef Hoegel, Andreas Meyer, Thilo Dörk, and Christiane Maier
Subjects: Medicine, Science
Abstract: Prostate cancer susceptibility has previously been associated with truncating germline variants in the gene TP53AIP1 (tumor protein p53 regulated apoptosis inducing protein 1). For two apparently recurrent mutations (p.Q22fs and p.S32X) a remarkable OR of 5.1 was reported for prostate cancer risk. Since these findings have not been validated so far, we genotyped p.Q22fs and p.S32X in two German series with a total of 1,207 prostate cancer cases and 1,495 controls. The truncating variants were not significantly associated with prostate cancer in none of the two cohorts, nor in the combined analysis [odds ratio (OR) = 1.16; 95% confidence interval (CI 95%) = 0.62-2.15; p = 0.66]. Carriers showed no significant differences in family history of prostate cancer, age at diagnosis, Gleason score or PSA at diagnosis when compared to non-carrier prostate cancer cases. The large sample size of the combined cohort rejects a high-risk effect greater than 2.2 and indicates a limited role of TP53AIP1 in prostate cancer predisposition.
Published: 2012
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7. Supplementary Grant Support from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Grant Support
Published: 2023

8. Supplementary Methods, Figures S1 - S3 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Figure S1. LocusZoom regional association plots for the seven new cross-cancer loci that were > 1 Mb from known index SNPs. Supplementary Figure S2A-B. Box plots showing eQTL associations between (A) rs9375701 and L3MBTL3 in normal breast and prostate tissues and (B) rs8037137 and RCCD1 in normal breast and ovarian tissues. Supplementary Figure S3. Interactions between BCL2L11 and the 32 Biocarta "Death Pathway" genes. Interactions were identified using the GeneMania server. Circles contain gene names, lines represent interactions, and the color of the line indicates a specific type of interaction as listed in the legend.
Published: 2023

9. Supplementary Tables S1 - S10 from Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Diether Lambrechts, Paul D.P. Pharoah, Rosalind Eeles, Georgia Chenevix-Trench, Douglas F. Easton, Simon A. Gayther, Per Hall, Fergus J. Couch, Stephen J. Chanock, Peter Kraft, Brian E. Henderson, David J. Hunter, Thomas A. Sellers, Amanda Spurdle, Christopher A. Haiman, Jacques Simard, Alison M. Dunning, Andrew Berchuck, Matthew L. Freedman, Fredrick Schumacher, Yu-Tang Gao, Xiao-Ou Shu, Wojciech Kluzniak, William J. Blot, Weiva Sieh, Wei Zheng, Walther Vogel, Volker Arndt, Vessela Kristensen, Veronica Wendy Setiawan, Veli-Matti Kosma, Vanio Mitev, Ute Hamann, Usha Menon, Todd L. Edwards, Tim J. Key, Tiina Wahlfors, Thomas Brüning, Thilo Dörk, Teuvo L.J. Tammela, Tanja Pejovic, Susanne Krüger Kjær, Susan M. Gapstur, Stig E. Bojesen, Stephen N. Thibodeau, Soo-Hwang Teo, Soo Chin Lee, Sonja Berndt, Sofia Maia, Shelley S. Tworoger, Shannon K. McDonnell, Sara H. Olson, Sara Benlloch, Ruth C. Travis, Roger L. Milne, Roberta Ness, Robert Winqvist, Robert N. Hoover, Robert J. MacInnis, Robert A. Stephenson, Rita K. Schmutzler, Reidun Kristin Kopperud, Ralf Butzow, Radka Kaneva, Qiyuan Li, Qiuyin Cai, Qin Wang, Peter Devilee, Peter A. Fasching, Per Broberg, Penelope M. Webb, Paula Paulo, Paul Brennan, Pascal Guénel, Paolo Peterlongo, Nora Pashayan, Nicolas Wentzensen, Nick Orr, Nhu D. Le, Nazneen Rahman, Natalia Bogdanova, Montserrat Garcia-Closas, Minouk J. Schoemaker, Ming-Feng Hou, Michelle A.T. Hildebrandt, Michael Lush, Michael Jones, Melissa C. Southey, Maureen Sanderson, Matthieu Moisse, Matthias W. Beckmann, Mary Anne Rossing, Markus Aly, Marjorie Riggan, Marjanka K. Schmidt, Marc T. Goodman, Manuel R. Teixeira, Manuel Luedeke, Manjeet K. Bolla, Malcolm C. Pike, Maartje J. Hooning, Lisa Cannon-Albright, Linda S. Cook, Liesel M. Fitzgerald, Leon F.A.G. Massuger, Lambertus A. Kiemeney, Kunle Odunsi, Kristiina Aittomäki, Kirsten B. Moysich, Kexin Chen, Kenneth Offitt, Kenneth Muir, Keitaro Matsuo, Kay-Tee Khaw, Kathleen Herkommer, Karen H. Lu, Kamila Czene, Jyotsna Batra, Julio Pow-Sang, Julie M. Cunningham, Julian Peto, Julia A. Knight, Judith A. Clements, Jonine Figueroa, Jong Y. Park, Jolanta Kupryjanczyk, John L. Hopper, Johanna Schleutker, Joellen M. Schildkraut, Joe Dennis, Jenny L. Donovan, Jenny Chang-Claude, Jennifer B. Permuth, Jennifer A. Doherty, Javier Benítez, Janet L. Stanford, Jan Lubiński, Jacek Gronwald, Ignace Vergote, Ian Campbell, Iain McNeish, Hui-Yi Lim, Honglin Song, Hoda Anton-Culver, Hiltrud Brauch, Hermann Brenner, Henrik Gronberg, Heli Nevanlinna, Helga B. Salvesen, Hatef Darabi, Harvey A. Risch, Hardev Pandha, Hans-Ulrich Ulmer, Hans Wildiers, Håkan Olsson, Graham G. Giles, Fredrik Wiklund, Freddie C. Hamdy, Francesmary Modugno, Florian Heitz, Fiona Bruinsma, Fengju Song, Estrid Høgdall, Elza Khusnutdinova, Ellen L. Goode, Elizabeth M. Poole, Elisa V. Bandera, Elinor J. Sawyer, Drakoulis Yannoukakos, Douglas A. Levine, Dominika Wokozorczyk, Digna R. Velez Edwards, Dieter Flesch-Janys, Diana Eccles, David E. Neal, Daniel W. Cramer, Daniel O. Stram, Daniel J. Schaid, Daniel C. Tessier, Daehee Kang, Craig C. Teerlink, Claus K. Høgdall, Christine B. Ambrosone, Christiane Maier, Christa Stegmaier, Chavdar Slavov, Cezary Cybulski, Celine Vachon, Celeste Leigh Pearce, Catriona McLean, Catherine Phelan, Carl Blomqvist, Børge G. Nordestgaard, Beth Y. Karlan, Barbara Burwinkel, Arif B. Ekici, Argyrios Ziogas, Anthony Swerdlow, Annika Lindblom, Anna H. Wu, Anna Gonzalez-Neira, Anja Rudolph, Angela Cox, Andrzej Kierzek, Ana Peixoto, Alvaro Monteiro, Alicja Wolk, Alice S. Whittemore, Aleksandra Gentry-Maharaj, Aida K. Dieffenbach, Agnieszka Michael, Agnieszka Dansonka-Mieszkowska, Adam S. Kibel, Deborah J. Thompson, Susan J. Ramus, Sara Lindstrom, Kate Lawrenson, ZSofia Kote-Jarai, Jonathan Tyrer, Kyriaki Michailidou, Ali Amin Al Olama, Jonathan Beesley, and Siddhartha P. Kar
Abstract: Supplementary Table S1. Known risk loci for each cancer. Supplementary Table S2. Regions where known index SNPs for at least two of the three cancers lie within 1 Mb of each other. Supplementary Table S3. Full results from the meta-analysis of breast, ovarian, and prostate cancer showing the 18 independent loci associated at P < 10-8 with the same direction of effect across all three cancers. Supplementary Table S4. Conditional analysis of the rs1469713 (breast-ovarian-prostate cancer) signal, conditioning on the rs4808801 (breast cancer-specific) signal that was < 1 Mb away using GCTA software. Supplementary Table S5. Most significantly-associated genotyped SNP at new loci where index SNPs were imputed. Supplementary Table S6. Expression QTL analysis results from the GTEx Portal for the new cross-cancer risk loci listed in main Table 2. Supplementary Table S7. SNPs with P < 10-8 at the new cross-cancer risk loci listed in main Table 2 that overlap predicted enhancers in at least two cell types. Supplementary Table S8. HaploReg and non-coding RNA annotation of variants with P < 10-8 at the new cross-cancer risk loci listed in main Table 2. Supplementary Table S9. Eight of the 32 genes involved in induction of apoptosis through DR3 and DR4/5 Death Receptors (MSigDB: Biocarta "Death Pathway") a that were < 1 Mb away from an independent P < 10-5 index SNP in the 3-cancer meta-analysis. Supplementary Table S10. INRICH pathway analysis results for pathways with empirical P < 0.05. Apoptosis-related pathways containing BCL2L11 are shaded.
Published: 2023

10. Supplementary notes from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author: Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin
Abstract: Supplementary acknowledgments.
Published: 2023

11. Data from Genome-Wide Association Study of Prostate Cancer–Specific Survival

Author: Fredrik Wiklund, Sara Lindström, Johanna Schleutker, Lovise Maehle, David G. Cox, Anne Tjønneland, Bas H. Bueno-de-Mesquita, Antonia Trichopoulou, Stephanie J. Weinstein, Victoria L. Stevens, Meir J. Stampfer, Kathryn L. Penney, Alison M. Mondul, Jing Ma, Loic Le Marchand, Peter Kraft, David J. Hunter, Edward L. Giovannucci, Susan M. Gapstur, Stephen Chanock, Sonja I. Berndt, Gerald L. Andriole, Demetrius Albanes, Judith A. Clements, Jyotsna Batra, Andrzej Kierzek, Agnieszka Michael, Hardev Pandha, Sofia Maia, Paula Paulo, Manuel R. Teixeira, Amanda Spurdle, Vanio I. Mitev, Radka P. Kaneva, Chavdar Slavov, Hui-Yi Lim, Thomas A. Sellers, Jong Y. Park, Bernd Holleczek, Volker Herrmann, Hermann Brenner, Lisa Cannon-Albright, Wojciech Kluźniak, Jan Lubiński, Cezary Cybulski, Adam S. Kibel, Kathleen Herkommer, Manuel Luedeke, Walther Vogel, Christiane Maier, Daniel J. Schaid, Shannon K. McDonnell, Stephen N. Thibodeau, Janet L. Stanford, Kay-Tee Khaw, Nora Pashayan, Paul D.P. Pharoah, Freddie C. Hamdy, Jenny L. Donovan, David E. Neal, Ruth C. Travis, Timothy J. Key, Børge G. Nordestgaard, Teuvo L.J. Tammela, Csilla Sipeky, Christopher A. Haiman, Fredrick R. Schumacher, Brian E. Henderson, Liesel M. FitzGerald, Melissa C. Southey, Graham G. Giles, Kenneth Muir, Sara Benlloch, Ali Amin Al Olama, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind A. Eeles, Henrik Gronberg, Markus Aly, Thomas Whitington, Robert Karlsson, and Robert Szulkin
Abstract: Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical.Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR).Results: We observed no significant association between genetic variants and prostate cancer survival.Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study.Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.
Published: 2023

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

Author: Sara Benlloch, Roger L. Milne, Azad Hassan Abdul Razack, José Manuel Ruiz-Dominguez, Steven Joniau, Maria P. Silva, Martin Andreas Røder, Constance Turman, Anne-Maree Haynes, Jin Ling, Robert N. Hoover, Jong Y. Park, Johanna Schleutker, Brian E. Henderson, Amy Hutchinson, Stephanie J. Weinstein, Manolis Kogevinas, Melissa Papargiris, Monique J. Roobol, Gill Barnett, Wayne D. Tilley, Elio Riboli, Samantha E.T. Larkin, Melissa C. Southey, Michelle Guy, Jeanette T. Bensen, Henrik Grönberg, Fredrick R. Schumacher, Karina Dalsgaard Sørensen, Davor Lessel, Carin Cavalli-Bjoerkman, Tomislav Kuliš, Barry S. Rosenstein, Paula Kujala, Michael Davis, Andrzej M. Kierzek, Antonio Finelli, Gerald L. Andriole, Leire Moya, Antonio Gómez-Caamaño, Demetrius Albanes, Jianming Guo, Lisa F. Newcomb, Koveela Govindasami, Ji Lin, Gert De Meerleer, Manuel Luedeke, Richard M. Martin, Zeljko Kastelan, Kay-Tee Khaw, Ruth C. Travis, Rebecca Elliott, Alexandre R. Zlotta, Xin Guo, Kirsi Talala, Yangling Zhang, Lorelei A. Mucci, Marie Sanchez, Paul D.P. Pharoah, Mariona Bustamante, Peter Klarskov, Aleksandrina Vlahova, Srilakshmi Srinivasan, Aik T. Ong, David E. Neal, Sylvie Cénée, Esther M. John, Sonja I. Berndt, Kan Wang, Peter Iversen, Harry Ostrer, Michael Borre, Freddie C. Hamdy, Christopher A. Haiman, Ji Wu, Florence Menegaux, Jacek Marzec, Sara S. Strom, David P. Dearnaley, Jyotsna Batra, Piet Ost, Mariana C. Stern, Kim De Ruyck, Hyun Soo Park, Trina Yeadon, Elenko Popov, Yudong Wu, Svetlana Christova, Thomas Van den Broeck, Loic Le Marchand, Daniel J. Schaid, Babu Zachariah, Sune F. Nielsen, Mary-Anne Kedda, Judith A. Clements, Olivier Cussenot, Robert Szulkin, Shiro Saito, Andrew Evans, Douglas F. Easton, Gemma Castaño-Vinyals, Steve Hazel, Thérèse Truong, Guomin Wang, Katarina Cuk, Ants Toi, Rosalind A. Eeles, Darina Kachakova, Lourdes Mengual, Lisa G. Horvath, Yuan Chun Ding, Catharine M L West, Ana Carballo, Suzanne K. Chambers, Aurelie Vogt, Angela Cox, Daniel W. Lin, Dominika Wokołorczyk, Manuela Gago-Dominguez, Stephen J. Chanock, Federico Canzian, Aleksandra Klim, Tokhir Dadaev, Kathleen Herkommer, Tihomir Dikov, Lovise Maehle, Jasmine Lim, Janet L. Stanford, Martin Eklund, Guido Jenster, Soo-Hwang Teo, Teemu J. Murtola, Torben F. Ørntoft, Stella Koutros, Christa Stegmaier, Sofia Maia, Mitchell J. Machiela, Lisa A. Cannon-Albright, Clare Berry, Pamela Saunders, Lluís Cecchini, Jeri Kim, Radka Kaneva, Brigitte Trétarre, Anne George, Meir J. Stampfer, Marija Gamulin, Meng H. Tan, Angela Morgan, Jenny L Donovan, Graham G. Giles, Geraldine Cancel-Tassin, Neil Fleshner, Shannon K. McDonnell, Hardeep Ranu, Naomi Livni, Kimmo Taari, Sarah L. Kerns, Csilla Sipeky, Alicja Wolk, Edward Giovannucci, Ninghan Feng, Marta Cardoso, Jan-Erik Johansson, Catherine M. Tangen, Guangwen Cao, Adam S. Kibel, Robert J. MacInnis, Bernd Holleczek, Sarah J Lewis, Bo Zhou, Michael Broms, Maria Elena Martinez, Renea A. Taylor, Børge G. Nordestgaard, Fritz H. Schröder, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jie Li, Lori S. Tillmans, Ana Vega, Patricia Calvo, Christopher J. Logothetis, David V. Conti, Miguel Aguado, Inés Gómez-Acebo, Tobias Nordström, Meiling Li, Elaine A. Ostrander, C.H. Bangma, Cyril Fisher, Joanne F. Aitken, Matthew Parliament, Gail P. Risbridger, John L. Hopper, Takashi Imai, Belynda Hicks, Victoria L. Stevens, Cezary Cybulski, G Marsden, Brian D. Carter, Vanessa M. Hayes, Nawaid Usmani, Vanio Mitev, Shan-Chao Zhao, Margaret Cook, Milan S. Geybels, Phyllis J. Goodman, Mark N. Brook, Nora Pashayan, Timothy J. Key, Yongwei Yu, Xavier Rebillard, David J. Hunter, Laura Fachal, Javier Llorca, Afshan Siddiq, Claire Aukim-Hastie, Trinidad Dierssen-Sotos, Walther Vogel, Angel Carracedo, Laura E. Beane Freeman, Julio M. Pow-Sang, Hardev Pandha, Robert A. Gardiner, Shaun M. Riska, Yong-Jie Lu, Zan Sun, Ramón Lobato-Busto, Ami Karlsson, Hongwei Zhang, Guoping Ren, Jing Ma, Huihai Wu, Søren M. Bentzen, John Pedersen, Claire Mulot, Girish S. Kulkarni, Jan Lubinski, Antonio Alcaraz, Jose E. Castelao, Athene Lane, Rasmus Bisbjerg, Thomas A. Sellers, Robert J. Hamilton, Jianfeng Xu, Sofie De Langhe, Artitaya Lophatananon, Maren Weisher, Agnieszka Michael, Yves Akoli Koudou, Niclas Håkansson, Alison M. Dunning, Hubert Thierens, Matthew L. Freedman, Kenneth Muir, Ian M. Thompson, Ian Whitmore, Susan L. Neuhausen, Chavdar Slavov, Wojciech Kluzniak, Laurence N. Kolonel, Lisa M. Butler, Teuvo L.J. Tammela, Alison Thwaites, Theodorus van der Kwast, Liesel M. FitzGerald, Thomas J. Schnoeller, Hermann Brenner, Christiane Maier, Amanda B. Spurdle, Jan Adolfsson, Atanaska Mitkova, Peter Kraft, Paula Peleteiro, Pär Stattin, Xin Sheng, Paul D. Brown, Ron H.N. van Schaik, Zsofia Kote-Jarai, Susan M. Gapstur, Paul A. Townsend, Edward J. Saunders, Bettina F. Drake, Stephen N. Thibodeau, Fredrik Wiklund, Paula Paulo, Esther Gracia-Lavedan, Xueying Mao, Marco Matejcic, Neil G. Burnet, A. L. Eckert, Manuel R. Teixeira, Sara Lindström, Weiyang He, Hui-Yi Lin, Suzanne Kolb, Linda Steele, Philipp Bohnert, Anssi Auvinen, Eli Marie Grindedal, Frank Claessens, and Kathryn L. Penney
Subjects: Urologic Diseases, 0301 basic medicine, Oncology, medicine.medical_specialty, Science, MEDLINE, General Physics and Astronomy, 02 engineering and technology, General Biochemistry, Genetics and Molecular Biology, Germline, 03 medical and health sciences, Internal medicine, medicine, PRACTICAL Consortium, lcsh:Science, Cancer, Prostate cancer risk, Multidisciplinary, business.industry, Prostate Cancer, Published Erratum, General Chemistry, 021001 nanoscience & nanotechnology, medicine.disease, Spelling, 3. Good health, 030104 developmental biology, Variation (linguistics), lcsh:Q, 0210 nano-technology, business
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

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

Author: Brian D. Carter, Gert De Meerleer, Michael B. Cook, Paul A. Townsend, Kim De Ruyck, Edward J. Saunders, Christopher A. Haiman, Atushi Takahashi, Sonja I. Berndt, Florence Menegaux, Cezary Cybulski, Barbara Nemesure, Loic Le Marchand, Sune F. Nielsen, Demetrius Albanes, Robert J. Hamilton, Ninghan Feng, Stella Koutros, Stephen J. Chanock, Wei Zheng, Thomas A. Sellers, Rick A. Kittles, Craig C. Teerlink, Stephen N. Thibodeau, Marija Gamulin, Artitaya Lophatananon, Niclas Håkansson, Fredrik Wiklund, Roberta McKean-Cowdin, Yuan Chun Ding, Nora Pashayan, Timothy J. Key, Børge G. Nordestgaard, Shannon K. McDonnell, Jong Y. Park, Laura Fachal, Martin Andreas Røder, Johanna Schleutker, Edward Giovannucci, Anssi Auvinen, Hardev Pandha, Maria Elena Martinez, Mitchell J. Machiela, Gill Barnett, Melissa C. Southey, Graham G. Giles, Barry S. Rosenstein, Stephen Watya, Bernd Holleczek, Pascal Blanchet, Agnieszka Michael, William J. Blot, James L. Mohler, Jack A. Taylor, Sarah L. Kerns, Adam S. Kibel, Piet Ost, Ana Vega, Richard M. Martin, Jennifer J. Hu, Nicholas Mancuso, Yukihide Momozawa, Robert J. MacInnis, Sue A. Ingles, Maureen Sanderson, Kai Uwe Saum, Markus Aly, Robert Szulkin, Davor Lessel, Hermann Brenner, Yves Akoli Koudou, Jan Lubinski, Mina Torres, Anselm Hennis, Eli Marie Grindedal, Csilla Sipeky, Susan L. Neuhausen, Alison M. Dunning, Alicja Wolk, Adam B. Murphy, Brandi Weaver, Mariana C. Stern, Paula Paulo, Stephanie J. Weinstein, Xueying Mao, Tobias Nordström, Neil Fleshner, Tokhir Dadaev, Teuvo L.J. Tammela, Jay H. Fowke, Tomislav Kuliš, Steven Joniau, Yudong Wu, Rosalind A. Eeles, Shan Chao Zhao, Kenneth Muir, Mark N. Brook, Hidewaki Nakagawa, Freddie C. Hamdy, Karina Dalsgaard Sørensen, Linda Steele, Alisha Chou, Dominika Wokołorczyk, Peggy Wan, Martin Eklund, Laurent Brureau, Lisa A. Cannon-Albright, Lilit C. Moss, Daniel J. Schaid, Luc Multigner, Benjamin A. Rybicki, Xin Sheng, Constance Turman, Ron H.N. van Schaik, Radka Kaneva, Zsofia Kote-Jarai, Frank Claessens, Katarina Cuk, Kay-Tee Khaw, Chad D. Huff, Henrik Grönberg, Kathryn L. Penney, Geraldine Cancel-Tassin, Eric A. Klein, Masashi Fujita, Jennifer Cullen, Michael Borre, Jenny L Donovan, Dana C. Crawford, Antonio Gómez-Caamaño, David V. Conti, Manuel Luedeke, Maya Ghoussaini, Janet L. Stanford, Peter Kraft, Ian M. Thompson, Koichi Matsuda, Soo-Hwang Teo, Christopher J. Logothetis, Robin J. Leach, Monique J. Roobol, Manuel R. Teixeira, Jose Esteban Castelao, Sara S. Strom, Vanio Mitev, Stig E. Bojesen, David J. Hunter, Wayne D. Tilley, Jyotsna Batra, Gerald L. Andriole, Christine Neslund-Dudas, Sara Lindström, Guido Jenster, Catherine M. Tangen, William S. Bush, Maren Weischer, Chavdar Slavov, Thomas J. Schnoeller, Javier Llorca, Claire Aukim-Hastie, Nawaid Usmani, Lisa G. Horvath, Daniel W. Lin, Esther M. John, Burcu F. Darst, Milan S. Geybels, Phyllis J. Goodman, Lynne R. Wilkens, Ali Amin Al Olama, Lorelei A. Mucci, Peter Iversen, Christiane Maier, Victoria L. Stevens, Andreia Brandão, Graham Casey, Neil G. Burnet, Ann W. Hsing, Hongwei Zhang, Laura E. Beane Freeman, Susan M. Gapstur, Sara Benlloch, James E. Mensah, Marie-Élise Parent, Jianfeng Xu, Bettina F. Drake, Jeannette T. Bensen, Azad Hassan Abdul Razack, Edward D. Yeboah, David E. Neal, John D. Carpten, Ruth C. Travis, Thomas J. Hoffmann, Thomas Van den Broeck, Jeri Kim, Ali Sahimi, Gemma Castaño-Vinyals, Alexander Lubwama, Leire Moya, Elio Riboli, Douglas F. Easton, Suzanne K. Chambers, Yong-Jie Lu, Melinda C. Aldrich, Manuela Gago-Dominguez, John S. Witte, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Lisa F. Newcomb, Fredrick R. Schumacher, Shiv Srivastava, Jasmine Lim, Meir J. Stampfer, Harry Ostrer, Judith A. Clements, Thérèse Truong, Catharine M L West, Zan Sun, Olivier Cussenot, Gyorgy Petrovics, Lovise Maehle, Elizabeth T. H. Fontham, William B. Isaacs, Hui Yi Lin, Rohit Varma, Elaine A. Ostrander, Manolis Kogevinas, Robert N. Hoover, Sandeep Singhal, Antonio Finelli, and Stephen K. Van Den Eeden
Subjects: 0303 health sciences, business.industry, Published Erratum, MEDLINE, Genome-wide association study, Computational biology, Biology, medicine.disease, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Meta-analysis, Genetics, medicine, Susceptibility locus, 06 Biological Sciences, 11 Medical and Health Sciences, Personalized medicine, Genetic risk, business, 030217 neurology & neurosurgery, 030304 developmental biology, Developmental Biology
Abstract: In the version of this article originally published, the names of the equally contributing authors and jointly supervising authors were switched. The correct affiliations are: “These authors contributed equally: David V. Conti, Burcu F. Darst. These authors jointly supervised this work: David V. Conti, Rosalind A. Eeles, Zsofia Kote-Jarai, Christopher A. Haiman.” The error has been corrected in the HTML and PDF versions of the article.
Published: 2021

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

Author: Paul A. Townsend, Edward J. Saunders, Hidewaki Nakagawa, Manuel R. Teixeira, Graham Casey, Demetrius Albanes, Christine Neslund-Dudas, Sara Lindström, William S. Bush, Maren Weischer, Lisa A. Cannon-Albright, Rick A. Kittles, Peggy Wan, Martin Eklund, Stephen N. Thibodeau, Burcu F. Darst, Fredrik Wiklund, Nicholas Mancuso, Jeri Kim, Jong Y. Park, Johanna Schleutker, Maureen Sanderson, Samantha E.T. Larkin, Radka Kaneva, Hongwei Zhang, Daniel J. Schaid, Luc Multigner, Marie-Élise Parent, Robert Szulkin, Fredrick R. Schumacher, Geraldine Cancel-Tassin, Jianfeng Xu, Gill Barnett, Melissa C. Southey, Yuan Chun Ding, Alexander Lubwama, Maria Elena Martinez, Manolis Kogevinas, Linda Steele, Laurent Brureau, Shiv Srivastava, Maya Ghoussaini, Alison M. Dunning, Adam B. Murphy, Kenneth Muir, Edward Giovannucci, Mitchell J. Machiela, James L. Mohler, Jack A. Taylor, Robert N. Hoover, Sandeep Singhal, Chavdar Slavov, Guido Jenster, Frank Claessens, Neil Fleshner, Sara Benlloch, Gert De Meerleer, Michael B. Cook, Zan Sun, Harry Ostrer, Pascal Blanchet, Lynne R. Wilkens, Ali Amin Al Olama, Sue A. Ingles, Markus Aly, Jay H. Fowke, Agnieszka Michael, Yves Akoli Koudou, Victoria L. Stevens, Kathryn L. Penney, Ana Vega, Xin Sheng, Ron H.N. van Schaik, Zsofia Kote-Jarai, Kim De Ruyck, Christopher A. Haiman, Atushi Takahashi, Florence Menegaux, Judith A. Clements, Stephen K. Van Den Eeden, Brian D. Carter, Wayne D. Tilley, Antonio Finelli, Jennifer J. Hu, Hermann Brenner, Thomas Van den Broeck, Shan Chao Zhao, Azad Hassan Abdul Razack, Edward D. Yeboah, Sonja I. Berndt, Barbara Nemesure, Mark N. Brook, David V. Conti, Katarina Cuk, Teuvo L.J. Tammela, Ali Sahimi, Stephen J. Chanock, Loic Le Marchand, Gemma Castaño-Vinyals, Sune F. Nielsen, Sara S. Strom, Ann W. Hsing, Roberta McKean-Cowdin, David J. Hunter, Ian M. Thompson, Børge G. Nordestgaard, Jyotsna Batra, Paula Paulo, Masashi Fujita, Jennifer Cullen, Susan M. Gapstur, Sarah L. Kerns, Lorelei A. Mucci, Neil G. Burnet, Xueying Mao, Hui Yi Lin, Rohit Varma, Marija Gamulin, Wei Zheng, Thomas A. Sellers, Adam S. Kibel, Robert J. Hamilton, Leire Moya, Ninghan Feng, Laura E. Beane Freeman, James E. Mensah, Catherine M. Tangen, Shannon K. McDonnell, Matthew Parliament, Davor Lessel, Gail P. Risbridger, Mina Torres, Janet L. Stanford, Bettina F. Drake, Soo-Hwang Teo, Robert J. MacInnis, Stig E. Bojesen, Jeannette T. Bensen, William J. Blot, Stella Koutros, Robin J. Leach, Graham G. Giles, Piet Ost, Artitaya Lophatananon, Laura Fachal, Tomislav Kuliš, Peter Kraft, Monique J. Roobol, Elaine A. Ostrander, Niclas Håkansson, Anselm Hennis, Yukihide Momozawa, Anssi Auvinen, Koichi Matsuda, Steven Joniau, Lisa G. Horvath, Javier Llorca, Claire Aukim-Hastie, Bernd Holleczek, Daniel W. Lin, Gerald L. Andriole, John D. Carpten, Eli Marie Grindedal, Rosalind A. Eeles, Elio Riboli, Constance Turman, Martin Andreas Røder, Yong-Jie Lu, Tobias Nordström, Kai Uwe Saum, Esther M. John, Melinda C. Aldrich, Peter Iversen, Henrik Grönberg, John S. Witte, Andreia Brandão, Eric A. Klein, Olivier Cussenot, Barry S. Rosenstein, Stephen Watya, Jan Lubinski, Douglas F. Easton, Dana C. Crawford, Gyorgy Petrovics, Thomas J. Schnoeller, Richard M. Martin, Stephanie J. Weinstein, Jose Esteban Castelao, Suzanne K. Chambers, Tokhir Dadaev, Karina Dalsgaard Sørensen, Antonio Gómez-Caamaño, Lisa F. Newcomb, Csilla Sipeky, Lovise Maehle, Brandi Weaver, Susan L. Neuhausen, Christiane Maier, Alicja Wolk, Vanio Mitev, Thérèse Truong, Manuel Luedeke, Jenny L Donovan, Mariana C. Stern, Catharine M L West, Manuela Gago-Dominguez, Elizabeth T. H. Fontham, William B. Isaacs, David E. Neal, Christopher J. Logothetis, Alisha Chou, Jasmine Lim, Benjamin A. Rybicki, Kay-Tee Khaw, Meir J. Stampfer, Chad D. Huff, Thomas J. Hoffmann, Michael Borre, Freddie C. Hamdy, Nawaid Usmani, Cezary Cybulski, Craig C. Teerlink, Milan S. Geybels, Nora Pashayan, Timothy J. Key, Phyllis J. Goodman, Hardev Pandha, Ruth C. Travis, Yudong Wu, Dominika Wokołorczyk, Lilit C. Moss, University of Southern California (USC), Keck School of Medicine [Los Angeles], CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pointe-à-Pitre/Abymes [Guadeloupe], The institute of cancer research [London], U01CA194393, National Institutes of Health, NA, Achievement Rewards for College Scientists Foundation, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Urology, Clinical Chemistry, Darst, Burcu F [0000-0002-6205-4632], Chou, Alisha [0000-0001-7521-6373], Schumacher, Fredrick R [0000-0002-3073-7463], Dadaev, Tokhir [0000-0002-8268-0438], Brook, Mark N [0000-0002-8969-2378], Hoffmann, Thomas J [0000-0001-6893-4449], Takahashi, Atushi [0000-0001-7099-8767], Matsuda, Koichi [0000-0001-7292-2686], Fujita, Masashi [0000-0002-1457-6233], Muir, Kenneth [0000-0001-6429-988X], Stevens, Victoria L [0000-0003-0259-4407], Schleutker, Johanna [0000-0002-1863-0305], Sipeky, Csilla [0000-0002-8853-4722], Auvinen, Anssi [0000-0003-1125-4818], Giles, Graham G [0000-0003-4946-9099], Martin, Richard M [0000-0002-7992-7719], Nordestgaard, Børge G [0000-0002-1954-7220], Bojesen, Stig E [0000-0002-4061-4133], Røder, Martin Andreas [0000-0002-0019-5333], Batra, Jyotsna [0000-0003-4646-6247], Tilley, Wayne [0000-0003-1893-2626], Risbridger, Gail P [0000-0003-3089-4028], Gronberg, Henrik [0000-0002-1073-2753], Eklund, Martin [0000-0001-5032-5266], Nordström, Tobias [0000-0003-4915-7546], Pashayan, Nora [0000-0003-0843-2468], Dunning, Alison M [0000-0001-6651-7166], Travis, Ruth C [0000-0002-9571-0763], Riboli, Elio [0000-0001-6795-6080], Park, Jong Y [0000-0002-6384-6447], Weinstein, Stephanie J [0000-0002-3834-1535], Kraft, Peter [0000-0002-4472-8103], Ostrander, Elaine A [0000-0001-6075-9738], Wolk, Alicja [0000-0001-7387-6845], Håkansson, Niclas [0000-0001-7673-5554], Machiela, Mitchell J [0000-0001-6538-9705], Sørensen, Karina Dalsgaard [0000-0002-4902-5490], Zheng, Wei [0000-0003-1226-070X], Mensah, James E [0000-0003-4133-1722], Lu, Yong-Jie [0000-0001-6174-6621], West, Catharine ML [0000-0002-0839-3449], Cancel-Tassin, Géraldine [0000-0002-9583-6382], Truong, Thérèse [0000-0002-2943-6786], Vega, Ana [0000-0002-7416-5137], Gómez-Caamaño, Antonio [0000-0002-9773-4590], Fachal, Laura [0000-0002-7256-9752], Kerns, Sarah L [0000-0002-6503-0011], Ostrer, Harry [0000-0002-2209-5376], Teixeira, Manuel R [0000-0002-4896-5982], Brandão, Andreia [0000-0003-0938-1543], Cannon-Albright, Lisa [0000-0003-2602-3668], Multigner, Luc [0000-0003-3205-8568], Klein, Eric A [0000-0002-1783-0698], Murphy, Adam B [0000-0001-9977-3473], Michael, Agnieszka [0000-0002-7262-6227], Ost, Piet [0000-0002-2203-4848], Xu, Jianfeng [0000-0002-1343-8752], Teo, Soo-Hwang [0000-0002-0444-590X], Lessel, Davor [0000-0003-4496-244X], Kulis, Tomislav [0000-0002-0895-5691], Joniau, Steven [0000-0003-3195-9890], Bush, William S [0000-0002-9729-6519], Crawford, Dana C [0000-0002-6437-6248], Roobol, Monique J [0000-0001-6967-1708], Jenster, Guido [0000-0002-8658-2552], Van Den Eeden, Stephen K [0000-0002-5599-8387], Easton, Douglas F [0000-0003-2444-3247], Chanock, Stephen J [0000-0002-2324-3393], Wiklund, Fredrik [0000-0002-4623-0544], Eeles, Rosalind A [0000-0002-3698-6241], Haiman, Christopher A [0000-0002-0097-9971], and Apollo - University of Cambridge Repository
Subjects: Male, 8Q24, Genome-wide association study, Continental Population Groups/genetics, VARIANTS, Prostate cancer, 0302 clinical medicine, Risk Factors, Epidemiology, IMPUTATION, Odds Ratio, Prostatic Neoplasms/diagnosis, 0303 health sciences, education.field_of_study, Continental Population Groups, Manchester Cancer Research Centre, Middle Aged, Càncer--Aspectes genètics, 3. Good health, ODDS RATIOS, 06 Biological Sciences, 11 Medical and Health Sciences, medicine.medical_specialty, Population, Biology, prostate cancer, meta-analysis, SEQUENCE, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetics, medicine, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Neoplasm Invasiveness, education, 030304 developmental biology, Genetic association, [SDV.GEN]Life Sciences [q-bio]/Genetics, MUTATIONS, ResearchInstitutes_Networks_Beacons/mcrc, Racial Groups, Prostatic Neoplasms, Molecular Sequence Annotation, Odds ratio, medicine.disease, BRCA2, Pròstata--Càncer, Genetic Loci, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Demography, Developmental Biology, Genome-Wide Association Study
Abstract: International audience; Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.
Published: 2021

15. A genetic risk score to personalize prostate cancer screening, applied to population data

Author: Douglas F. Easton, Shannon K. McDonnell, Bernd Holleczek, J. Kellogg Parsons, Rosalind A. Eeles, Jyotsna Batra, J. Athene Lane, Emma L Turner, Freddie C. Hamdy, Wojciech Kluzniak, Daniel J. Schaid, Chun Chieh Fan, Cezary Cybulski, Sofia Maia, Jenny L Donovan, Csilla Sipeky, Christiane Maier, C. Slavov, Teuvo L.J. Tammela, Sara Benlloch Garcia, Tyler M. Seibert, Radka Kaneva, Zsofia Kote-Jarai, Roshan Karunamuni, Paula Paulo, Hermann Brenner, Nora Pashayan, Markus Aly, Hui Yi Lin, Timothy J. Key, Ali Amin Al Olama, Judith A. Clements, Hardev Pandha, Adam S. Kibel, Anders M. Dale, Thomas A. Sellers, Ole A. Andreassen, Lisa A. Cannon-Albright, Ian G. Mills, Manuel R. Teixeira, Amanda B. Spurdle, Kathleen Herkommer, Eleanor I Walsh, Richard M. Martin, Vanio Mitev, Ruth C. Travis, Dominika Wokołorczyk, Kenneth Muir, Kay-Tee Khaw, Minh-Phuong Huynh-Le, Stephen N. Thibodeau, Fredrik Wiklund, Walther Vogel, Børge G. Nordestgaard, Agnieszka Michael, Ben Schöttker, David E. Neal, Jong Y. Park, Johanna Schleutker, Henrik Grönberg, Paul D.P. Pharoah, Manuel Luedeke, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, inorganic chemicals, Male, medicine.medical_specialty, Percentile, Epidemiology, Population, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, fluids and secretions, Internal medicine, Genotype, medicine, SNP, Humans, Cluster randomised controlled trial, Stage (cooking), education, Early Detection of Cancer, Aged, education.field_of_study, business.industry, Prostatic Neoplasms, Middle Aged, medicine.disease, equipment and supplies, 030104 developmental biology, Prostate cancer screening, 030220 oncology & carcinogenesis, bacteria, Population Control, Neoplasm Grading, business
Abstract: Background: A 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. Methods: United 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. Results: The 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. Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS. Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
Published: 2020
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16. A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (<60 years) and is associated with reduced DNA repair capacity

Author: Christiane Maier, Josef Hoegel, Maximilian Klar, Manuel Luedeke, Meta Volcic, Annette Hasenburg, Antje E. Rinckleb, Lisa Wiesmüller, Barbara Burwinkel, Walther Vogel, Helmut Deissler, Harald Surowy, Frederik Marmé, Christof Sohn, and Dominic Varga
Subjects: 0301 basic medicine, Genetics, Cancer Research, Candidate gene, Haplotype, Locus (genetics), Single-nucleotide polymorphism, Biology, Penetrance, 03 medical and health sciences, 030104 developmental biology, Oncology, Allele, Allele frequency, Imputation (genetics)
Abstract: Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed >60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R2 > 0.9), and a pattern of association very similar for both phenotypes (cases 0.9). Our findings propose a risk variant with high penetrance on the haplotype spanning SLX4/FANCP to be functionally associated to BC predisposition via decreased repair capacity and suggest this variant is carried by a fraction of these haplotypes that is enriched in early onset BC cases.
Published: 2017

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

Author: Jong Y. Park, Johanna Schleutker, Douglas F. Easton, Stephen N. Thibodeau, Fredrik Wiklund, Paul D.P. Pharoah, David E. Neal, Amanda B. Spurdle, Shannon K. McDonnell, Christiane Maier, Rosalind A. Eeles, Manuel R. Teixeira, Anders M. Dale, Wojciech Kluzniak, Daniel J. Schaid, Thomas A. Sellers, Sara Benlloch Garcia, Bernd Holleczek, Minh-Phuong Huynh-Le, Radka Kaneva, Ben Schöttker, Jenny L Donovan, C. Slavov, Teuvo L.J. Tammela, Cezary Cybulski, Sofia Maia, Chun Chieh Fan, Vanio Mitev, Tyler M. Seibert, Judith A. Clements, Ole A. Andreassen, Roshan Karunamuni, Jyotsna Batra, Csilla Sipeky, Hermann Brenner, Ruth C. Travis, Agnieszka Michael, Hui Yi Lin, Dominika Wokołorczyk, Paula Paulo, Kay-Tee Khaw, Ian G. Mills, Kathleen Herkommer, Zsofia Kote-Jarai, Ali Amin Al Olama, Kenneth Muir, Lisa A. Cannon-Albright, Markus Aly, Børge G. Nordestgaard, Freddie C. Hamdy, Walther Vogel, Henrik Grönberg, Nora Pashayan, Timothy J. Key, Manuel Luedeke, Hardev Pandha, and Adam S. Kibel
Subjects: Hazard (logic), Male, Multifactorial Inheritance, Context (language use), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Article, Prostate cancer, SDG 3 - Good Health and Well-being, Statistics, Genetics research, Genetics, medicine, Humans, Genetics (clinical), Genetic association, Mathematics, Proportional Hazards Models, Clinical Trials as Topic, Models, Genetic, Proportional hazards model, Hazard ratio, Prostatic Neoplasms, Stepwise regression, medicine.disease, Risk factors, Sample size determination, Test set, Sample Size, Population study, Age of onset, Genome-Wide Association Study
Abstract: We aimed to determine the effect of sample size on performance of polygenic hazard score (PHS) models in predicting the age at onset of 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 (34,444 samples) and testing (6,417 samples) sets. Two PHS model-building strategies were investigated. Established-SNP model considered 65 SNPs that had been associated with prostate cancer in the literature. A stepwise SNP selection was used to develop Discovery-SNP models. The performance of each PHS model was calculated for random sizes of the training set (1 to 30 thousand). The performance of a representative Established-SNP model was estimated for random sizes of the testing set (0.5 to 6 thousand). Mean HR98/50 (hazard ratio of top 2% to the average in the 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 to 30 thousand. The 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 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 to 30 thousand men is required to develop Discovery-SNP PHS models for prostate cancer. The required sample size could be reduced to 10 thousand samples, if a set of SNPs associated with the disease has already been established.Author summaryPolygenic hazard scores represent a recent advancement in polygenic prediction to model the age of onset of various diseases, such as Alzheimer’s disease or prostate cancer. These scores accumulate small effect sizes from several tens of genetic variants and can be used to establish an individual’s risk of experiencing an event relative to a control population across time. The largest barrier to the development of polygenic hazard scores is the large number of study subjects needed to develop the underlying models. We sought to understand the effect of varying the total number of samples on the performance of a polygenic hazard score in the context of prostate cancer. We found that the performance of the score did not appreciably change beyond 20 to 30 thousand observations when developing the model from scratch. However, when the discovery of the genetic variants can be borrowed from those already identified in the literature to be associated with the disease, the required number of samples is reduced to 10 thousand with no appreciable detriment in performance. We hope that these results can guide the design of future studies of polygenic scores in other diseases and demonstrate the importance of genome-wide association studies.
Published: 2019

18. A genetic hazard score to personalize prostate cancer screening, applied to population data

Author: Keith W. Muir, Amanda B. Spurdle, Anders M. Dale, J K Parsons, Ian G. Mills, D J Schaid, Rosalind A. Eeles, Wojciech Kluzniak, Jenny L Donovan, Andrzej M. Kierzek, C. Slavov, Csilla Sipeky, P Pharoah, Henrik Grönberg, Chun Chieh Fan, Jyotsna Batra, B.G. Nordestgaard, Emma L Turner, F. Wiklund, Jong Y. Park, Johanna Schleutker, Manuel Luedeke, Eleanor I Walsh, Tyler M. Seibert, Zsofia Kote-Jarai, Manuel R. Teixeira, Tammela Tlj., T A Sellers, Freddie C. Hamdy, W. Vogel, Judith A. Clements, Cezary Cybulski, Shannon K. McDonnell, Richard M. Martin, Kathleen Herkommer, Lin H-Y., Olama Aaa., Bernd Holleczek, Huynh-Le M-P., Nora Pashayan, Timothy J. Key, H Brenner, Lisa A. Cannon-Albright, Hardev Pandha, Ruth C. Travis, Dominika Wokołorczyk, Adam S. Kibel, Markus Aly, Doug Easton, Paula Paulo, Ole A. Andreassen, David E. Neal, J A Lane, S. N. Thibodeau, Khaw K-T., Roshan Karunamuni, Ben Schöttker, Vanio Mitev, Sara Benlloch Garcia, Radka Kaneva, Sofia Maia, Christiane Maier, and Agnieszka Michael
Subjects: medicine.medical_specialty, Percentile, Psa screening, business.industry, Incidence (epidemiology), Hazard ratio, urologic and male genital diseases, medicine.disease, Prostate cancer, Prostate cancer screening, Internal medicine, Population data, Medicine, Age of onset, business
Abstract: BackgroundGenetic risk stratification may inform decisions of whether—and when—a man should undergo prostate cancer (PCa) screening. We previously validated a polygenic hazard score (PHS), a weighted sum of 54 single-nucleotide polymorphism genotypes, for accurate prediction of age of onset of aggressive PCa and improved screening performance. We now assess the potential impact of PHS-informed screening.MethodsUnited Kingdom population data were fit to a continuous model of age-specific PCa incidence. Using hazard ratios estimated from ProtecT trial data, age-specific incidence rates were calculated for percentiles of genetic risk. Incidence of higher-grade PCa (Gleason≥7) was estimated from age-specific data from the linked CAP trial. PHS and incidence data were combined to give a risk-equivalent age, when a man with a given PHS percentile will have risk of higher-grade PCa equivalent to that of a typical man at age 50 (50-years standard). Positive predictive value (PPV) of PSA testing was calculated using PHS-adjusted (PCa-risk-equivalent age) groups identified from ProtecT.ResultsExpected age of onset of higher-grade PCa is modulated by 19 years between the 1st and 99th PHS percentiles. A man with PHS in the 99th percentile reaches 50-years-standard risk at age 41; conversely, a man in the 1st percentile reaches this risk at age 60. PPV of PSA was higher for men with higher PHS-adjusted age.ConclusionsPHS informs PCa screening strategies with individualized estimates of risk-equivalent age for higher-grade PCa. Screening initiation could be adjusted according to a man’s genetic hazard score, improving PPV of PSA screening.
Published: 2019

19. Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci

Author: Robert J. Hamilton, Douglas F. Easton, Suzanne K. Chambers, Edward Giovannucci, Henrik Grönberg, Artitaya Lophatananon, Niclas Håkansson, Sue A. Ingles, Markus Aly, Antonio Gómez-Caamaño, B. E. Henderson, Samantha E.T. Larkin, Manuel Luedeke, Fredrick R. Schumacher, Zan Sun, Karina Dalsgaard Sørensen, Jasmine Lim, Marija Gamulin, Lu Y-J., Meir J. Stampfer, Shannon K. McDonnell, Maria Elena Martinez, Harry Ostrer, Piet Ost, Michael Borre, Monique J. Roobol, F Canzian, D J Schaid, Lin H-Y., Rasmus Bisbjerg, Judith A. Clements, Ezequiel Anokian, Martin Andreas Røder, Ed Saunders, Agnieszka Michael, G Jenster, Bernd Holleczek, Guomin Wang, Jakub Lubiński, Jeri Kim, Genetic Associations, Rosalind A. Eeles, Yves Akoli Koudou, Gemma Castaño-Vinyals, Jing Ma, Leire Moya, Sonja I. Berndt, Thérèse Truong, Maren Weischer, Robert Szulkin, T. Van Den Broeck, Davor Lessel, Børge G. Nordestgaard, Chee Goh, Torben F. Ørntoft, Manolis Kogevinas, Catherine M. Tangen, Gerald L. Andriole, Robert N. Hoover, Ana Vega, Stephanie J. Weinstein, West Cml., Tomislav Kuliš, Neil Fleshner, Graham G. Giles, Barry S. Rosenstein, Z Cui, Marta Cardoso, Tokhir Dadaev, Jenny L Donovan, David E. Neal, Richard M. Martin, Tyrer Jp, Thomas J. Schnoeller, Sandeep Singhal, Clara Cieza-Borrella, Ian M. Thompson, Lisa A. Cannon-Albright, Jong Y. Park, Johanna Schleutker, Brian D. Carter, Esther M. John, Christiane Maier, Matthew Parliament, Antonio Finelli, Mark N. Brook, Gail P. Risbridger, Xin Guo, Lisa G. Horvath, Daniel W. Lin, Mariana C. Stern, Tobias Nordström, Demetrius Albanes, Melissa C. Southey, Zhang H-W., Liesel M. FitzGerald, Christopher I. Amos, Freddie C. Hamdy, P Pharoah, Wayne D. Tilley, Susan M. Gapstur, Teo S-H., Claire Aukim-Hastie, Christopher J. Logothetis, Elio Riboli, Bettina F. Drake, Csilla Sipeky, Alicja Wolk, Cezary Cybulski, Joe Dennis, Olama Aaa., Hermann Brenner, Lorelei A. Mucci, Yuan Chun Ding, L E Beane Freeman, Stella Koutros, G De Meerleer, A. Siddiq, Lisa F. Newcomb, Mitchell J. Machiela, Munaza Ahmed, Jyotsna Batra, Susan L. Neuhausen, Christopher A. Haiman, Stephen J. Chanock, T A Sellers, Florence Menegaux, David V. Conti, Lovise Maehle, O. Cussenot, Neil G. Burnet, Nora Pashayan, Timothy J. Key, P Iversen, Hardev Pandha, Katarina Cuk, David J. Hunter, Khaw K-T., Janet L. Stanford, Loic Le Marchand, Javier Llorca, Steven Joniau, Elaine A. Ostrander, Sarah L. Kerns, van Schaik Rhn., Adam S. Kibel, Robert J. MacInnis, Tammela Tlj., Sune F. Nielsen, Constance Turman, Peter Kraft, Laurence N. Kolonel, Nawaid Usmani, K. De Ruyck, Sara Benlloch, C. Slavov, Azad Hassan Abdul Razack, Milan S. Geybels, Jianfeng Xu, Phyllis J. Goodman, Martin Eklund, Alison M. Dunning, Radka Kaneva, Paul A. Townsend, Kenneth Muir, Manuel R. Teixeira, Sara Lindström, Geraldine Cancel-Tassin, Mechanisms in Oncology, Anssi Auvinen, Victoria L. Stevens, Laura Fachal, Stephen N. Thibodeau, Linda Steele, Manuela Gago-Dominguez, Frank Claessens, Kathryn L. Penney, Fredrik Wiklund, Eli Marie Grindedal, Xin Sheng, Ruth C. Travis, Zsofia Kote-Jarai, Dominika Wokołorczyk, D. Leongamornlert, Paula Paulo, Xueying Mao, Vanio Mitev, Jose Esteban Castelao, and Ninghan Feng
Subjects: Oncology, 0303 health sciences, medicine.medical_specialty, Published Erratum, MEDLINE, Impact study, PROSTATE CANCER SUSCEPTIBILITY, Biology, urologic and male genital diseases, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genetics, medicine, Association (psychology), Biological sciences, 030217 neurology & neurosurgery, 030304 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 (PC, 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 PrCa(1).
Published: 2019

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

Author: Rosalind A. Eeles, Karina Dalsgaard Sørensen, Torben F. Ørntoft, Jeri Kim, Wayne D. Tilley, Ruth C. Travis, Lorelei A. Mucci, Jenny L Donovan, Kay-Tee Khaw, Edward Giovannucci, Christopher I. Amos, Soo Hwang Teo, Claire Aukim-Hastie, Gerald L. Andriole, Linda Steele, Martin Eklund, Guomin Wang, Michael Borre, Antonio Finelli, Liesel M. FitzGerald, Thérèse Truong, Robert N. Hoover, Sandeep Singhal, Radka Kaneva, Frank Claessens, Robert Szulkin, Javier Llorca, Dominika Wokołorczyk, Esther M. John, Daniel J. Schaid, Jyotsna Batra, Kathryn L. Penney, Børge G. Nordestgaard, Catharine M L West, Hermann Brenner, Sue A. Ingles, Markus Aly, Jonathan Tyrer, Thomas J. Schnoeller, Xin Guo, Peter Iversen, Olivier Cussenot, Laurence N. Kolonel, Henrik Grönberg, Ninghan Feng, Geraldine Cancel-Tassin, Christiane Maier, David E. Neal, Marija Gamulin, Ezequiel Anokian, Christopher J. Logothetis, Shannon K. McDonnell, Lovise Maehle, Anssi Auvinen, Antonio Gómez-Caamaño, Tomislav Kuliš, Manuel Luedeke, Teuvo L.J. Tammela, Brian D. Carter, Zan Sun, Jong Y. Park, Nawaid Usmani, Ian M. Thompson, Zuxi Cui, Johanna Schleutker, Bernd Holleczek, Davor Lessel, Katarina Cuk, Eli Marie Grindedal, Milan S. Geybels, Yuan Chun Ding, Phyllis J. Goodman, Jing Ma, Paul A. Townsend, Edward J. Saunders, Melissa C. Southey, Graham G. Giles, Robert J. Hamilton, Laura Fachal, Mitchell J. Machiela, Demetrius Albanes, Gert De Meerleer, Paula Paulo, Agnieszka Michael, Yves Akoli Koudou, Janet L. Stanford, Kim De Ruyck, Thomas Van den Broeck, Tokhir Dadaev, Clara Cieza-Borrella, Sonja I. Berndt, Artitaya Lophatananon, Brian E. Henderson, Niclas Håkansson, Christopher A. Haiman, Florence Menegaux, Xueying Mao, Jan Lubinski, Elio Riboli, Paul D.P. Pharoah, David J. Hunter, Loic Le Marchand, Stephen N. Thibodeau, Fredrik Wiklund, Tobias Nordström, Thomas A. Sellers, Chee Goh, Elaine A. Ostrander, Sune F. Nielsen, Neil E. Fleshner, Neil G. Burnet, Rasmus Bisbjerg, Manuela Gago Dominguez, Csilla Sipeky, Maria Elena Martinez, Susan L. Neuhausen, Stephen J. Chanock, Hui Yi Lin, Laura E. Beane Freeman, A. Siddiq, Alicja Wolk, Gemma Castaño-Vinyals, Lisa F. Newcomb, Catherine M. Tangen, Ana Vega, Peter Kraft, Chavdar Slavov, Daniel Leongamornlert, Lisa A. Cannon-Albright, Stella Koutros, Manuel R. Teixeira, Susan M. Gapstur, Federico Canzian, Sara Lindström, Maren Weischer, Bettina F. Drake, Lisa G. Horvath, Daniel W. Lin, Jose Esteban Castelao, Yong-Jie Lu, Xin Sheng, Vanio Mitev, Ron H.N. van Schaik, Monique J. Roobol, Zsofia Kote-Jarai, Leire Moya, Alison M. Dunning, Mahbubl Ahmed, Kenneth Muir, Douglas F. Easton, Suzanne K. Chambers, Hongwei Zhang, Jianfeng Xu, Jasmine Lim, Meir J. Stampfer, Guido Jenster, Ali Amin Al Olama, Victoria L. Stevens, Sara Benlloch, Mark N. Brook, Azad Hassan Abdul Razack, Marta Cardoso, Matthew Parliament, Gail P. Risbridger, Samantha E.T. Larkin, Fredrick R. Schumacher, Martin Andreas Røder, Harry Ostrer, Judith A. Clements, Manolis Kogevinas, Barry S. Rosenstein, Steven Joniau, Richard M. Martin, Constance Turman, Mariana C. Stern, Joe Dennis, David V. Conti, Sarah L. Kerns, Adam S. Kibel, Robert J. MacInnis, Stephanie J. Weinstein, Freddie C. Hamdy, Cezary Cybulski, Nora Pashayan, Timothy J. Key, Hardev Pandha, Piet Ost, Urology, Clinical Chemistry, Imperial College Trust, Schumacher, Fredrick R [0000-0002-3073-7463], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Male, PREDICTION, Cancer of the Prostate in Sweden (CAPS), Genome-wide association study, PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, VARIANTS, Australian Prostate Cancer BioResource (APCB), urologic and male genital diseases, DISEASE, FAMILY-HISTORY, PATHWAY, Prostate cancer, Prostate Cancer Genome-wide Association Study of Uncommon Susceptibility Loci (PEGASUS), 11 Medical and Health Sciences, Genetics & Heredity, RISK, education.field_of_study, Profile Study, IMPACT Study, 3. Good health, prostate cancer (PrCa)-susceptibility loci, Centre for Surgical Research, BIOLOGICAL PATHWAYS, ICEP, Life Sciences & Biomedicine, Medical Genetics, Risk, medicine.medical_specialty, Genotype, Population, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, MULTIPLE LOCI, Breast and Prostate Cancer Cohort Consortium (BPC3), SDG 3 - Good Health and Well-being, Internal medicine, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, education, Genotyping, METAANALYSIS, Medicinsk genetik, Genetic association, Canary PASS Investigators, Science & Technology, IDENTIFICATION, CONSORTIUM, Case-control study, Prostatic Neoplasms, 06 Biological Sciences, medicine.disease, GENE, Genetic Associations and Mechanisms in Oncology (GAME-ON)/Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium, 030104 developmental biology, Genetic Loci, Relative risk, Case-Control Studies, genotype, humans, male, Developmental Biology, Genome-Wide Association Study
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 < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>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 PrCa 1 .
Published: 2018

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

Author: Ruth C. Travis, Markus Aly, Chun Chieh Fan, Dominika Wokołorczyk, Fredrik Wiklund, Ole A. Andreassen, Børge G. Nordestgaard, Adam S. Kibel, Amanda B. Spurdle, Verena Zuber, Douglas F. Easton, J. Kellogg Parsons, Agnieszka Michael, Lisa A. Cannon-Albright, Judith A. Clements, Cezary Cybulski, Roshan Karunamuni, M. Andreas Røder, Kathleen Herkommer, Vanio Mitev, Zsofia Kote-Jarai, Walther Vogel, Jong Y. Park, Johanna Schleutker, Tyler M. Seibert, Paul D.P. Pharoah, Hermann Brenner, Ian G. Mills, Kai Uwe Saum, Manuel R. Teixeira, Nora Pashayan, Timothy J. Key, Henrik Grönberg, Maren Weischer, Hardev Pandha, Andrzej M. Kierzek, Manuel Luedeke, Rasmus Bisbjerg, Christiane Maier, Freddie C. Hamdy, Katarina Cuk, Sofia Maia, Paula Paulo, Kay-Tee Khaw, Anders M. Dale, Thomas A. Sellers, Csilla Sipeky, Rosalind A. Eeles, Jenny L Donovan, Wojciech Kluzniak, David E. Neal, Yunpeng Wang, David S. Karow, Teuvo L.J. Tammela, Peter Iversen, Chavdar Slavov, Jyotsna Batra, Sune F. Nielsen, Kenneth Muir, Sara Benlloch Garcia, Radka Kaneva, and Ali Amin Al Olama
Subjects: 0301 basic medicine, Oncology, Male, Percentile, IMPACT, urologic and male genital diseases, Cohort Studies, Prostate cancer, PSA, 0302 clinical medicine, Outcome Assessment, Health Care, Overdiagnosis, Age of Onset, European Continental Ancestry Group/genetics, Early Detection of Cancer, risk, OUTCOMES, OVERDIAGNOSIS, Hazard ratio, Prostatic Neoplasms/blood, General Medicine, Middle Aged, Polymorphism, Single Nucleotide/genetics, STATISTICS, ddc, Prostate-specific antigen, Editorial, Centre for Surgical Research, 030220 oncology & carcinogenesis, TRIAL, Kallikreins, Risk assessment, Life Sciences & Biomedicine, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Genotype, European Continental Ancestry Group, Prostate-Specific Antigen/analysis, Polymorphism, Single Nucleotide, Risk Assessment, White People, Disease-Free Survival, 03 medical and health sciences, Outcome Assessment (Health Care), Medicine, General & Internal, AGE, Predictive Value of Tests, Internal medicine, General & Internal Medicine, medicine, Journal Article, BREAST-CANCER, Humans, Kallikreins/analysis, Survival analysis, Aged, Science & Technology, RISK PREDICTION, business.industry, screening, Prostatic Neoplasms, prediction, Prostate-Specific Antigen, medicine.disease, ta3122, PREVENTION, PRACTICAL Consortium, Survival Analysis, 030104 developmental biology, age, Age of onset, genetic, Early Detection of Cancer/methods, business
Abstract: Objectives To 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. Design Analysis 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. Setting Multiple institutions that were members of international PRACTICAL consortium. Participants All 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 Measure Prediction with hazard score of age of onset of aggressive cancer in validation set. Results In 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. Conclusions Polygenic hazard scores can be used for personalised genetic risk estimates that can predict for age at onset of aggressive PCa.
Published: 2018

22. Prediction of individual genetic risk to prostate cancer using a polygenic score

Author: Cezary Cybulski, Rosalind A. Eeles, Douglas F. Easton, Robert Szulkin, Nora Pashayan, Timothy J. Key, B. E. Henderson, G.G. Giles, Hardev Pandha, Jenny L Donovan, Zsofia Kote-Jarai, Henrik Grönberg, Jong Y. Park, Johanna Schleutker, Kenneth Muir, Melissa C. Southey, Fredrick R. Schumacher, Manuel Luedeke, Markus Aly, David E. Neal, Paul D.P. Pharoah, Ruth C. Travis, Børge G. Nordestgaard, Jyotsna Batra, D J Schaid, Fredrik Wiklund, Judith A. Clements, Amanda B. Spurdle, Katja Butterbach, Lisa A. Cannon-Albright, Janet L. Stanford, Kathleen Herkommer, Adam S. Kibel, W. Vogel, Wojciech Kluźniak, Vanio Mitev, Paula Paulo, Liesel M. FitzGerald, Hermann Brenner, T A Sellers, Shannon K. McDonnell, Tammela Tlj., Lin H-Y., Freddie C. Hamdy, Ali Amin Al Olama, Jan Lubinski, Manuel R. Teixeira, C. Slavov, S. N. Thibodeau, Tom Whitington, C. Stegmaier, Andrzej M. Kierzek, Agnieszka Michael, Christiane Maier, Christopher A. Haiman, Sofia Maia, Khaw K-T., Tiina Wahlfors, Martin Eklund, Radka Kaneva, and Sara Benlloch
Subjects: Linkage disequilibrium, education.field_of_study, business.industry, Urology, Population, Area under the curve, Disease, Bioinformatics, medicine.disease, Prostate cancer, Oncology, Genetic marker, Cohort, Genetic variation, Medicine, business, education
Abstract: BACKGROUND: Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS: We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS: The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS: Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
Published: 2015

23. Obesity and Prostate Cancer Risk According to Tumor TMPRSS2:ERG Gene Fusion Status

Author: Antje E. Rinckleb, Suzanne Kolb, Manuel Luedeke, Marian L. Neuhouser, Christiane Maier, Lieke Egbers, Jonathan L. Wright, and Janet L. Stanford
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Epidemiology, Original Contributions, medicine.medical_treatment, Population, TMPRSS2, Body Mass Index, Prostate cancer, Transcriptional Regulator ERG, Internal medicine, medicine, Humans, Oncogene Fusion, Obesity, education, Aged, Gynecology, education.field_of_study, Prostatectomy, business.industry, Serine Endopeptidases, Case-control study, Prostatic Neoplasms, Odds ratio, Middle Aged, medicine.disease, Confidence interval, Case-Control Studies, Trans-Activators, business, Body mass index
Abstract: The T2E gene fusion, formed by fusion of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific (ETS)-related gene (ERG), is found in approximately 50% of prostate cancers and may characterize distinct molecular subtypes of prostate cancer with different etiologies. We investigated the relationship between body mass index (BMI; weight (kg)/height (m)(2)) and prostate cancer risk by T2E status. Study participants were residents of King County, Washington, recruited for 2 population-based case-control studies conducted in 1993-1996 and 2002-2005. Tumor T2E status was determined for 563 prostate cancer patients who underwent radical prostatectomy. Information on weight, height, and covariables was obtained through in-person interviews. We performed polytomous logistic regression to calculate odds ratios and 95% confidence intervals for T2E-positive and -negative prostate cancer. Comparing the highest BMI quartile with the lowest, inverse associations were observed between recent (≥29.7 vs.
Published: 2015

24. Mosaic genome-wide maternal isodiploidy: an extreme form of imprinting disorder presenting as prenatal diagnostic challenge

Author: Melanie Graf, Krisztian Lato, Manuel Luedeke, Thomas F. E. Barth, Julia Kolarova, Gotthold Barbi, Reiner Siebert, Susanne Bens, and Tanja Richter
Subjects: Adult, 0301 basic medicine, Genome-wide maternal uniparental disomy, lcsh:QH426-470, Multilocus imprinting disturbances, lcsh:Medicine, Biology, Ultrasonography, Prenatal, Prenatal diagnostics, Genomic Imprinting, 03 medical and health sciences, Pregnancy, Genetics, medicine, Humans, Imprinting (psychology), Molecular Biology, Genetics (clinical), DNA methylation, Mosaicism, Research, lcsh:R, Chromosome, Imprinting, Karyotype, Uniparental Disomy, medicine.disease, Human genetics, Uniparental disomy, lcsh:Genetics, 030104 developmental biology, Female, Trisomy, Genomic imprinting, Genome-Wide Association Study, Developmental Biology
Abstract: Background Uniparental disomy of certain chromosomes are associated with a group of well-known genetic syndromes referred to as imprinting disorders. However, the extreme form of uniparental disomy affecting the whole genome is usually not compatible with life, with the exception of very rare cases of patients with mosaic genome-wide uniparental disomy reported in the literature. Results We here report on a fetus with intrauterine growth retardation and malformations observed on prenatal ultrasound leading to invasive prenatal testing. By cytogenetic (conventional karyotyping), molecular cytogenetic (QF-PCR, FISH, array), and methylation (MS-MLPA) analyses of amniotic fluid, we detected mosaicism for one cell line with genome-wide maternal uniparental disomy and a second diploid cell line of biparental inheritance with trisomy X due to paternal isodisomy X. As expected for this constellation, we observed DNA methylation changes at all imprinted loci investigated. Conclusions This report adds new information on phenotypic outcome of mosaic genome-wide maternal uniparental disomy leading to an extreme form of multilocus imprinting disturbance. Moreover, the findings highlight the technical challenges of detecting these rare chromosome disorders prenatally. Electronic supplementary material The online version of this article (10.1186/s13148-017-0410-y) contains supplementary material, which is available to authorized users.
Published: 2017

25. A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (60 years) and is associated with reduced DNA repair capacity

Author: Harald, Surowy, Dominic, Varga, Barbara, Burwinkel, Frederik, Marmé, Christof, Sohn, Manuel, Luedeke, Antje, Rinckleb, Christiane, Maier, Helmut, Deissler, Meta, Volcic, Lisa, Wiesmüller, Annette, Hasenburg, Maximilian, Klar, Josef, Hoegel, and Walther, Vogel
Subjects: Adult, DNA Repair, Age Factors, Breast Neoplasms, Penetrance, Middle Aged, Recombinases, Gene Frequency, Haplotypes, Case-Control Studies, Germany, Humans, DNA Breaks, Double-Stranded, Female
Abstract: Only a fraction of breast cancer (BC) cases can be yet explained by mutations in genes or genomic variants discovered in linkage, genome-wide association and sequencing studies. The known genes entailing medium or high risk for BC are strongly enriched for a function in DNA double strand repair. Thus, aiming at identifying low frequency variants conferring an intermediate risk, we here investigated 17 variants (MAF: 0.01-0.1) in 10 candidate genes involved in DNA repair or cell cycle control. In an exploration cohort of 437 cases and 1189 controls, we show the variant rs3810813 in the SLX4/FANCP gene to be significantly associated with both BC (≤60 years; OR = 2.6(1.6-3.9), p = 1.6E-05) and decreased DNA repair capacity (≤60 years; beta = 37.8(17.9-57.8), p = 5.3E-4). BC association was confirmed in a verification cohort (N = 2441). Both associations were absent from cases diagnosed60 years and stronger the earlier the diagnosis. By imputation we show that rs3810813 tags a haplotype with 5 additional variants with the same allele frequency (R
Published: 2017

26. Subgroups of familial and aggressive prostate cancer with considerable frequencies ofBRCA2mutations

Author: Mark Schrader, Walther Vogel, Christiane Maier, Kathleen Herkommer, Antje E. Rinckleb, and Manuel Luedeke
Subjects: Oncology, medicine.medical_specialty, Urology, Biology, urologic and male genital diseases, medicine.disease, Prostate-specific antigen, Prostate cancer, Breast cancer, Germline mutation, medicine.anatomical_structure, Prostate, Internal medicine, Mutation (genetic algorithm), Cohort, medicine, Cancer research, Family history
Abstract: BACKGROUND One of the known risk factors for prostate cancer (PrCa) is germline mutations in the BRCA2 gene. Previous searches for clinical characteristics which could identify a subgroup of patients enriched for mutation carriers revealed early onset and aggressive PrCa as useful parameters, but they are rather unspecific. METHODS Identification of BRCA2 mutation carriers by sequencing all exons of BRCA2 in a German cohort of 382 familial PrCa cases and of 92 sporadic PrCa cases with early onset (≤60 years). To define a subgroup of PrCa patients enriched for BRCA2 mutation carriers, we used clinical parameters including a detailed family history (FH) for PrCa and breast cancer. RESULTS Five BRCA2 mutations and ten variants of unknown significance (VUS) were identified. While the VUS were evenly distributed among the groups, mutation carriers were lacking from the sporadic cases and over represented among familial cases with aggressive disease. High prostate specific antigen (PSA) at diagnosis (>20 ng/ml) was the only criterion with significant enrichment of mutation carriers (6.4%, P = 0.0005). In men with aggressive disease, death from PrCa (6.3% including FH of lethal PrCa; P = 0.05) and FH of both prostate and breast cancer (4.8%; P = 0.3) increased the frequency of mutation carriers. Larger studies and/or meta-analyses are needed to validate these parameters. CONCLUSIONS We have identified three potentially useful criteria, high PSA, death from PrCa (patient or FH), and aggressive PrCa in combination with FH of breast and prostate cancer. If confirmed, they may become useful for the decision which patients may benefit from BRCA2 testing. Prostate 74:1444–1451, 2014. © 2014 Wiley Periodicals, Inc.
Published: 2014

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

Author: Laurie Burdette, Rick A. Kittles, Hidewaki Nakagawa, Janet L. Stanford, Wojciech Kluźniak, Karen Park, Sofia Maia, Lisa A. Cannon-Albright, Douglas F. Easton, Dennis J. Hazelett, Hermann Brenner, Paula Paulo, Peter Klarskov, Zhaoming Wang, Koveela Govindasami, Loic Le Marchand, David V. Conti, Phyllis J. Goodman, Chavdar Slavov, Manuel R. Teixeira, Sara Lindström, Maren Weischer, Suzanne Kolb, Lisa B. Signorello, Jianfeng Xu, W. Ryan Diver, Barbara Nemesure, Fredrick R. Schumacher, Michael B. Cook, Qiyuan Li, William J. Blot, Jyotsna Batra, Malgorzata Tymrakiewicz, Anand P. Chokkalingam, Esther M. John, Christopher A. Haiman, Merideth Yeager, David E. Neal, John D. Carpten, Daniel Leongamornlert, Cezary Cybulski, Kathryn L. Penney, Sara Benlloch, Peter Iversen, Judith A. Clements, Shannon K. McDonnell, Matthew L. Freedman, Adam B. Murphy, Mahbubl Ahmed, Kenneth Muir, Sonja I. Berndt, Aida Karina Dieffenbach, Cristina Leske, William B. Isaacs, Chee Goh, Edward D. Yeboah, Jong Y. Park, Ruth C. Travis, Atsushi Takahashi, Nora Pashayan, Timothy J. Key, Evelyn Tay, Lorelei A. Mucci, Edward Giovannucci, Stephen N. Thibodeau, Fredrik Wiklund, Amanda B. Spurdle, Teuvo L.J. Tammela, Peter Kraft, Johanna Schleutker, Melissa C. Southey, Elio Riboli, Afshan Siddiq, Sara S. Strom, Hardev Pandha, Curtis A. Pettaway, Sue A. Ingles, Demetrius Albanes, Brian E. Henderson, Rosalind A. Eeles, Meir J. Stampfer, Markus Aly, Suh-Yuh Wu, Constance Chen, Sune F. Nielsen, Federico Canzian, Christa Stegmaier, Hui-Yi Lin, Amy K. Hutchinson, John S. Witte, Andrzej M. Kierzek, Elizabeth M. Gillanders, Vanio Mitev, Dominika Wokołorczyk, Ali Amin Al Olama, Richard B. Biritwum, Andrew A. Adjei, Ann Truelove, Daniel J. Schaid, Mitchell J. Machiela, Graham Casey, Børge G. Nordestgaard, Wei Zheng, Tokhir Dadaev, Thomas A. Sellers, Lucy Xia, Antonio Hurtado Coll, Tiina Wahlfors, Paul D.P. Pharoah, Jenny L Donovan, Victoria L. Stevens, Kristin A. Rand, Kai Yu, Alex Stram, Anssi Auvinen, Lisa Chu, Adam S. Kibel, Yao Tettey, Gerhard A. Coetzee, Martin Andreas Røder, Gianluca Severi, Daniel O. Stram, Anselm Hennis, Charles C. Chung, Jing Ma, Stephen J. Chanock, Katri A. Leinonen, Stephanie J. Weinstein, Jonathan Tyrer, Freddie C. Hamdy, Shelley Niwa, Kathleen Herkommer, Beatrice S. Knudsen, Laurence N. Kolonel, David J. Hunter, Christine Neslund-Dudas, Loreall Pooler, Robert N. Hoover, Antje E. Rinckleb, Jarmo Virtamo, Henrik Grönberg, Peggy Wan, Eric A. Klein, Michelle Guy, Manuel Luedeke, Radka Kaneva, Xin Sheng, Zsofia Kote-Jarai, Daniella Seminara, Tapio Visakorpi, Christiane Maier, Ann W. Hsing, Susan M. Gapstur, Sara Jugurnauth-Little, Ying Han, Ed Saunders, Agnieszka Michael, Alan W. Partin, Graham G. Giles, S. Lilly Zheng, Michiaki Kubo, Benjamin A. Rybicki, Kay-Tee Khaw, and Sarah K. Holt
Subjects: Male, Genotype, Single-nucleotide polymorphism, Genome-wide association study, Disease, Biology, ta3111, Polymorphism, Single Nucleotide, Risk Assessment, Article, Prostate cancer, Risk Factors, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, ta113, ta112, ta1184, ta1182, Cancer, Prostatic Neoplasms, medicine.disease, ta3122, Genetic Loci, Meta-analysis, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.
Published: 2014

28. Whole Exome Sequencing Revealed a Candidate Gene for Finkelstein-Seidlmayer Disease

Author: Manuel Luedeke, Alessandra Ferrarini, Saskia Biskup, Gabriel Bronz, Heinz Gabriel, Carlo Mainetti, Gian Paolo Ramelli, and Sebastiano A. G. Lava
Subjects: medicine.medical_specialty, Mutation, Candidate gene, business.industry, General Medicine, Disease, medicine.disease_cause, Genetic analysis, Dermatology, Penetrance, medicine, business, Gene, Exome sequencing, Aunt
Abstract: Background: Finkelstein-Seidlmayer disease (FSD) is a benign cutaneous small-vessel leukocytoclastic vasculitis syndrome, which normally affects children between 2-60 months in a male-to-female ratio of 2:1. Skin lesions may appear as papules, erythematous macules, or urticaria. They are symmetric, sharp-edged and favouring the face, ears and extremities. Frequently they are targetoid, annular, medallion-like, or cockade. Fever and extracutaneous involvement are rare and spontaneous resolution occurs in 1-3 weeks. Case Information: In 2015, we reported a familial occurrence of FSD. Patients described in that article were the mother and all her three sons. All of them had a history of recurrent and relapsing non-thrombocytopenic, red-to-purpuric skin lesions, with a neonatal-onset. There was no systemic involvement. Anamnestic data revealed that maternal aunt, cousin and grandmother had also a positive history of neonatal onset of an acute cockade purpura and oedema. At that time, we suspected a genetic form of FSD with an autosomal dominant transmission or X-linked inheritance and incomplete penetrance. Method and Results: Blood samples were obtained from all available family members and a whole exome sequencing (WES) was performed on various affected and non-affected members of this family. The genetic analysis identified a common new mutation in the HCK gene. Conclusion: Up now, FSD is considered a sporadic disease and no genetic researches have been published on affected patients. We performed WES on a previously reported familiar case of FSD and the result was a common mutation in HCK gene. We found out the mutation on all the analysed affected and obligate-carrier members of the family. HCK gene encodes for a hematopoietic cell kinase protein, which is a member of the SRC family of cytoplasmic tyrosine kinases (SFK). We propose that HCK gene could be a candidate gene in the pathophysiology of some types of FSD. We also discuss the autosomal dominant transmission and incomplete penetrance of these specific types of disease.
Published: 2019

29. HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Author: Nicola J. Camp, Ros Eeles, Graham G. Giles, Kathleen E. Wiley, Kimberly A. Zuhlke, Gianluca Severi, Johanna Schleutker, Henrik Grönberg, Doug Easton, Stephen N. Thibodeau, Sarah D. Isaacs, William J. Catalona, Fredrik Wiklund, Melissa S. DeRycke, Craig C. Teerlink, Walther Vogel, Lisa A. Cannon-Albright, Manuel Luedeke, Siqun L. Zheng, Alice S. Whittemore, Teuvo L.J. Tammela, Olivier Cussenot, Joan E. Bailey-Wilson, Chih-Lin Hsieh, Isaac J. Powell, William B. Isaacs, Pål Møller, Shannon K. McDonnell, Elaine A. Ostrander, Ethan M. Lange, Nancy Hamel, Anna Johnson, Patrick C. Walsh, Tiina Wahlfors, Lovise Mahle, John L. Hopper, Diptasri Mandal, William D. Foulkes, Zsofia Kote-Jarai, Elisa M. Ledet, Christiane Maier, Daniel J. Schaid, Geraldine Cancel-Tassin, Lingyi Lu, Janet L. Stanford, John D. Carpten, Kathleen A. Cooney, Jianfeng Xu, Daniela Seminara, and Zhong Wang
Subjects: Male, Heterozygote, Mutation, Missense, Single-nucleotide polymorphism, Biology, Bioinformatics, Polymorphism, Single Nucleotide, White People, Cohort Studies, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Germline mutation, Gene Frequency, Mutation Carrier, Genetics, medicine, Missense mutation, Humans, Genetics(clinical), Genetic Predisposition to Disease, Allele frequency, Genetic Association Studies, Germ-Line Mutation, Genetics (clinical), 030304 developmental biology, Original Investigation, Homeodomain Proteins, 0303 health sciences, Haplotype, International Agencies, Prostatic Neoplasms, Odds ratio, medicine.disease, 3. Good health, Amino Acid Substitution, 030220 oncology & carcinogenesis
Abstract: Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10−8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10−6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer. Electronic supplementary material The online version of this article (doi:10.1007/s00439-012-1229-4) contains supplementary material, which is available to authorized users.
Published: 2013
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30. A genetic risk score to guide age-specific, personalized prostate cancer screening

Author: Tyler M. Seibert, Ian G. Mills, Hermann Brenner, Jyotsna Batra, Chavdar Slavov, Kay-Tee Khaw, Adam S. Kibel, Sofia Maia, Rosalind A. Eeles, Agnieszka Michael, Kenneth Muir, Kai-Uwe Saum, David E. Neal, Wojciech Kluzniak, Markus Aly, Anders M. Dale, Zsofia Kote-Jarai, Thomas A. Sellers, Jenny L Donovan, Teuvo L.J. Tammela, Freddie C. Hamdy, Jong Y. Park, Judith A. Clements, David S. Karow, Johanna Schleutker, Fredrik Wiklund, Maren Weischer, Kathleen Herkommer, Cezary Cybulski, Amanda B. Spurdle, Christiane Maier, Ruth C. Travis, Chun Chieh Fan, Vanio Mitev, Andrzej M. Kierzek, Henrik Grönberg, Lisa A. Cannon-Albright, Ole A. Andreassen, J. Kellogg Parsons, M. Andreas Røder, Paul D.P. Pharoah, Manuel Luedeke, Nora Pashayan, Timothy J. Key, Dominika Wokołorczyk, Hardev Pandha, Walther Vogel, Ali Amin Al Olama, Douglas F. Easton, Manuel R. Teixeira, Rasmus Bisbjerg, Paula Paulo, Roshan Karunamuni, Børge G. Nordestgaard, Katarina Cuk, Sara Benlloch Garcia, Csilla Sipeky, Radka Kaneva, Yunpeng Wang, Peter Iversen, Sune F. Nielsen, and Verena Zuber
Subjects: Oncology, medicine.medical_specialty, Percentile, education.field_of_study, business.industry, Population, Single-nucleotide polymorphism, medicine.disease, Bioinformatics, urologic and male genital diseases, Clinical trial, Prostate cancer, Prostate cancer screening, Internal medicine, Genotype, medicine, business, education, Survival analysis
Abstract: BackgroundProstate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to a high false-positive rate, among other concerns, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient’s risk. Genetic risk may provide key information to guide the decisions of whether and at what age to screen an individual man for PCa.MethodsGenotype, PCa status, and age from 34,444 men of European ancestry from the PRACTICAL consortium database were analyzed to select single-nucleotide polymorphisms (SNPs) associated with prostate cancer diagnosis. These SNPs were then incorporated into a survival analysis to estimate their effects on age at PCa diagnosis. The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was validated in an independent dataset comprised of 6,417 men with screening PSA and genotype data. PHS was calculated for these men to test for prediction of PCa-free survival. PHS was also combined with age-specific PCa incidence data from the U.S. population to generate a PCa-Risk (PCaR) age that relates a given man’s risk to that of the population average. PHS and PCaR age were evaluated for prediction of positive predictive value (PPV) of PSA screening.FindingsPHS calculated from 54 SNPs was very highly predictive of age at PCa diagnosis for men in the validation set (p =10−53). PPV of PSA screening varied from 0.18 to 0.52 for men with low and high genetic risk, respectively. PHS modulates PCa-free survival curves by an estimated 20 years between men in the 1st or 99th percentiles of genetic risk.InterpretationPolygenic hazard scores give personalized genetic risk estimates and can inform the decisions of whether and at what age to screen a man for PCa.FundingDepartment of Defense #W81XWH-13-1-0391
Published: 2016
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31. Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

Author: Agnieszka Dansonka-Mieszkowska, Usha Menon, Melissa C. Southey, Diana Eccles, Robert Winqvist, Keitaro Matsuo, Matthias W. Beckmann, Robert A. Stephenson, Paul D.P. Pharoah, Lambertus A. Kiemeney, Elizabeth M. Poole, Paul Brennan, Wojciech Kluzniak, Liesel M. FitzGerald, Alice S. Whittemore, Kunle Odunsi, Mary Anne Rossing, Craig C. Teerlink, Javier Benitez, Arif B. Ekici, Thilo Dörk, Per Hall, C. Slavov, Matthieu Moisse, Jennifer B. Permuth, Hermann Brenner, Apcb BioResource, Julia A. Knight, Teuvo L.J. Tammela, Douglas A. Levine, Alicja Wolk, Sofia Maia, Kamila Czene, Vessela N. Kristensen, Radka Kaneva, Hoda Anton-Culver, Jonathan Tyrer, Manjeet K. Bolla, Maureen Sanderson, Fengju Song, Veli-Matti Kosma, Dieter Flesch-Janys, Douglas F. Easton, John L. Hopper, Marjanka K. Schmidt, Jolanta Kupryjanczyk, Amanda B. Spurdle, Nicolas Wentzensen, kConFab Investigators, Peter A. Fasching, Leon F.A.G. Massuger, Jonathan Beesley, Qin Wang, Pascal Guénel, Penelope M. Webb, Paolo Peterlongo, Daniel C. Tessier, Peter Kraft, Jennifer A. Doherty, Daehee Kang, Christine B. Ambrosone, Weiva Sieh, Anja Rudolph, Ignace Vergote, Hiltrud Brauch, Celeste Leigh Pearce, Robert N. Hoover, Paula Paulo, Nbcs Investigators, Rosalind A. Eeles, Honglin Song, Fergus J. Couch, Brian E. Henderson, Lisa A. Cannon-Albright, William J. Blot, Soo-Chin Lee, Abctb Investigators, Ute Hamann, Angela Cox, Peter Devilee, Andrzej M. Kierzek, Qiuyin Cai, Elinor J. Sawyer, Jacek Gronwald, Janet L. Stanford, Soo-Hwang Teo, Fredrick R. Schumacher, Montserrat Garcia-Closas, Susanne K. Kjaer, Christa Stegmaier, Thomas Brüning, Graham G. Giles, Catriona McLean, Thomas A. Sellers, Georgia Chenevix-Trench, Ellen L. Goode, Maartje J. Hooning, Kathleen Herkommer, Jenny L Donovan, Fiona Bruinsma, Minouk J. Schoemaker, Marc T. Goodman, Volker Arndt, Estrid Høgdall, Yu-Tang Gao, Ruth C. Travis, Claus Høgdall, Celine M. Vachon, Jan Lubinski, Qiyuan Li, Vanio Mitev, Argyrios Ziogas, Julie M. Cunningham, Ming-Feng Hou, Marjorie J. Riggan, David J. Hunter, T. Wahlfors, Michael Jones, Diether Lambrechts, Hui-Yi Lim, Stephen N. Thibodeau, Kenneth Offitt, Stig E. Bojesen, Kexin Chen, Harvey A. Risch, Fredrik Wiklund, Hans-Ulrich Ulmer, Natalia Bogdanova, Joellen M. Schildkraut, Kristiina Aittomäki, Helga B. Salvesen, Markus Aly, Hatef Darabi, Christopher A. Haiman, Shelley S. Tworoger, Zsofia Kote-Jarai, Judith A. Clements, Andrew Berchuck, Francesmary Modugno, Drakoulis Yannoukakos, Catherine M. Phelan, Julian Peto, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Nazneen Rahman, Todd L. Edwards, Wei Zheng, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Anna H. Wu, Stephen J. Chanock, Kirsten B. Moysich, Per Broberg, Ana Peixoto, Sara Lindström, Daniel J. Schaid, Sonja I. Berndt, Dominika Wokozorczyk, Jonine D. Figueroa, Aida Karina Dieffenbach, Anna González-Neira, Reidun K. Kopperud, Jacques Simard, Alvaro N.A. Monteiro, David E. Neal, Tanja Pejovic, Florian Heitz, Beth Y. Karlan, Elza Khusnutdinova, Anthony J. Swerdlow, Joe Dennis, Veronica Wendy Setiawan, Heli Nevanlinna, Christiane Maier, Walther Vogel, Henrik Grönberg, Aleksandra Gentry-Maharaj, Kay-Tee Khaw, Jenny Chang-Claude, Carl Blomqvist, Susan M. Gapstur, Adam S. Kibel, Daniel W. Cramer, Manuel Luedeke, Robert J. MacInnis, Agnieszka Michael, Daniel O. Stram, Michelle A.T. Hildebrandt, Xiao-Ou Shu, Roberta B. Ness, Ian G. Campbell, Nora Pashayan, Timothy J. Key, Julio M. Pow-Sang, Hardev Pandha, Karen Lu, Elisa V. Bandera, Freddie C. Hamdy, Håkan Olsson, Sara H. Olson, Ali Amin Al Olama, Iain A. McNeish, Alison M. Dunning, Matthew L. Freedman, Kenneth Muir, Nhu D. Le, Linda S. Cook, Annika Lindblom, Sara Benlloch, Roger L. Milne, Kate Lawrenson, Digna R. Velez Edwards, Michael Lush, Hans Wildiers, Deborah J. Thompson, Susan J. Ramus, Kyriaki Michailidou, Rita K. Schmutzler, Nick Orr, Jyotsna Batra, Malcolm C. Pike, Cezary Cybulski, Shannon K. McDonnell, Jong Y. Park, Johanna Schleutker, Medical Oncology, Clinical Genetics, Amin Al Olama, Ali [0000-0002-7178-3431], Tyrer, Jonathan [0000-0003-3724-4757], Thompson, Deborah [0000-0003-1465-5799], Song, Honglin [0000-0001-5076-7371], Dennis, Joe [0000-0003-4591-1214], Khaw, Kay-Tee [0000-0002-8802-2903], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, Datasets as Topic, Genome-wide association study, Prostate cancer, Gene Regulatory Networks, Ovarian Neoplasms, Genetics, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Chromosome Mapping, prostate cancer, 3. Good health, Enhancer Elements, Genetic, ovarian cancer, Oncology, Organ Specificity, Centre for Surgical Research, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Signal Transduction, Quantitative Trait Loci, Population, Breast Neoplasms, Quantitative trait locus, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Breast cancer, breast cancer, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, pleiotropy, medicine, Humans, Genetic Predisposition to Disease, education, Genetic association, Prostatic Neoplasms, Cancer, medicine.disease, 030104 developmental biology, Genetic Loci, Case-Control Studies, Expression quantitative trait loci, genome-wide association studies, Genome-Wide Association Study
Abstract: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10−8 seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type–specific expression quantitative trait locus and enhancer–gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10−5 in the three-cancer meta-analysis. Significance: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052–67. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 932
Published: 2016

32. Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors

Author: Joshi J. Alumkal, Piet A. van den Brandt, Manuel Luedeke, Jian-Bing Fan, Irene M. Shui, Marina Bibikova, Janet L. Stanford, Brandy Klotzle, Ziding Feng, Milan S. Geybels, Christiane Maier, Elaine A. Ostrander, Antje E. Rinckleb, Shanshan Zhao, Epidemiologie, RS: CAPHRI School for Public Health and Primary Care, RS: CAPHRI - R3 - Functioning, Participating and Rehabilitation, RS: CAPHRI - R5 - Optimising Patient Care, RS: GROW - Oncology, and RS: GROW - R1 - Prevention
Subjects: BODY METHYLATION, RAB40C, PDE4D, Tumor tissue, Fusion gene, Prostate cancer, 0302 clinical medicine, DNA METHYLATION, Genetics (clinical), Epigenomics, Genetics, 0303 health sciences, TRIB2, REARRANGEMENTS, GREM1, ASSOCIATION, CpG site, 3. Good health, CACNA1D, TARGET, 030220 oncology & carcinogenesis, ERG, DNA methylation, Epigenetics, Unsupervised clustering, ERG-EXPRESSION, Gene fusion, KLK10, Biology, NT5C, TMPRSS2, 03 medical and health sciences, Epigenomic profiling, ST ARRAYS, medicine, SEPT9, Molecular Biology, 030304 developmental biology, C3orf14, Research, mRNA expression, TCGA, IN-SITU HYBRIDIZATION, medicine.disease, HYPERMETHYLATION, TISSUE, Cancer research, Developmental Biology
Abstract: Background About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status. Results The study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) “break-apart” assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value
Published: 2015

33. Heritability of baseline and induced micronucleus frequencies

Author: Madeleine Stuber, Harald Surowy, Josef Hoegel, Christiane Maier, Anna Wecker, Antje E. Rinckleb, Walther Vogel, Dominic Varga, and Manuel Luedeke
Subjects: Adult, Male, Adolescent, Intraclass correlation, DNA repair, Health, Toxicology and Mutagenesis, Biology, Toxicology, Radiation Tolerance, Young Adult, Twins, Dizygotic, Genetics, Humans, Genetic Predisposition to Disease, Micronuclei, Chromosome-Defective, Genetics (clinical), Micronucleus Tests, Twins, Monozygotic, Heritability, Twin study, Phenotype, Micronucleus test, Female, Micronucleus, Estimation methods, Mutagens
Abstract: The scoring of micronuclei (MN) is widely used in biomonitoring and mutagenicity testing as a surrogate marker of chromosomal damage inflicted by clastogenic agents or by aneugens. Individual differences in the response to a mutagenic challenge are known from studies on cancer patients and carriers of mutations in DNA repair genes. However, it has not been studied to which extent genetic factors contribute to the observed variability of individual MN frequencies. Our aim was to quantify this heritable genetic component of both baseline and radiation-induced MN frequencies. We performed a twin study comprising 39 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs. Due to the small number of DZ pairs, we had to recruit controls from which 38 age- and gender-matched random control pairs (CPs) were generated. For heritability estimates, we used biometrical modelling of additive genetic, common environmental, and unique environmental components (ACE model) of variance and direct comparison of variance between the sample groups. While heritability estimates from MZ to DZ comparisons produced inconclusive results, both estimation methods revealed a high degree of heritability (h(2)) for baseline MN frequency (h(2) = 0.68 and h(2) = 0.72) as well as for the induced frequency (h(2) = 0.68 and h(2) = 0.57) when MZ were compared to CP. The result was supported by the different intraclass correlation coefficients of MZ, DZ and CP for baseline (r = 0.63, r = 0.31 and r = 0.0, respectively) as well as for induced MN frequencies (r = 0.79, r = 0.74 and r = 0.0, respectively). This study clearly demonstrates that MN frequencies are determined by genetic factors to a major part. The strong reflection of the genetic background supports the idea that MN frequencies represent an intermediate phenotype between molecular DNA repair mechanisms and the cancer phenotype and affirms the approaches that are made to utilise them as predictors of, for example, cancer risk.
Published: 2010

34. Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

Author: Jo Fen Liu, Timothy R. Rebbeck, Brian E. Henderson, Vincent Khoo, Lynne T. O'Brien, Anna M. Ray, Klara Stefflova, Ethan M. Lange, Joanne L. Dickinson, Shannon K. McDonnell, Sarah J Lewis, Amit Joshi, Thilo Dörk, Jyotsna Batra, Yong-Jie Lu, Manuel Luedeke, Rosemary A. Wilkinson, Michelle Guy, C. R. J. Woodhouse, David E. Neal, Christopher A. Haiman, Gianluca Severi, Liesel M. FitzGerald, Audrey Ardern-Jones, Douglas F. Easton, Erika M. Kwon, Colin Cooper, Dallas R. English, Kathleen A. Cooney, Daniel Leongamornlert, Graham G. Giles, Loic Le Marchand, Laurence N. Kolonel, C. Slavov, Daniel J. Schaid, Ahva Shahabi, Suzanne K. Chambers, Teuvo L.J. Tammela, Jong Y. Park, Johanna Schleutker, Robert Huddart, Melissa C. Southey, Sue A. Ingles, Tim Christmas, Judith A. Clements, Mary-Anne Kedda, Malgorzata Tymrakiewicz, David P. Dearnaley, Radka Kaneva, Edward J. Saunders, Thomas A. Sellers, Janet L. Stanford, Anssi Auvinen, Alan Thompson, Jonathan J. Morrison, Guangwen Cao, Amanda L. Hall, Humera Khan, Pierre Hutter, Stephen M. Edwards, Esther M. John, Emma J. Sawyer, Angela Cox, Lisa A. Cannon-Albright, Tiina Wahlfors, Pierre O. Chappuis, Stephen N. Thibodeau, Freddie C. Hamdy, Elaine A. Ostrander, Hong Wei Zhang, Nicholas Van As, John L. Hopper, Walther Vogel, Amanda B. Spurdle, Jürgen Serth, Joanne F. Aitken, Chris Ogden, Atanaska Mitkova, Felicity Lose, Zsofia Kote-Jarai, Elizabeth Page, Christiane Maier, Joseph S. Koopmeiners, William D. Foulkes, Kenneth Muir, Alan Horwich, Danielle M. Karyadi, Chris Parker, Briony Patterson, Julio M. Pow-Sang, Robert A. Gardiner, Ali Amin Al Olama, Mariana C. Stern, Roman Corral, Maurice P. Zeegers, Andrea M. Polanowski, Artitaya Lophatananon, Rosalind A. Eeles, Andreas Meyer, J. M. Farnham, Jenny L Donovan, Complexe Genetica, Populatie Genetica, and RS: NUTRIM - R4 - Gene-environment interaction
Subjects: Genetics, Male, Genotype, Genome, Human, Cancer, Prostatic Neoplasms, Genome-wide association study, Single-nucleotide polymorphism, Locus (genetics), Biology, medicine.disease, urologic and male genital diseases, Polymorphism, Single Nucleotide, Article, Prostate cancer, medicine.anatomical_structure, Prostate, medicine, Chromosomes, Human, Humans, Disease Susceptibility, Allele, Genome-Wide Association Study
Abstract: Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in developed countries. To identify common PrCa susceptibility alleles, we previously conducted a genome-wide association study in which 541,129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and in 1,894 controls. We have now extended the study to evaluate promising associations in a second stage in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls and in a third stage involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to replicating previous associations, we identified seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11 and 22 (with P = 1.6 x 10(-8) to P = 2.7 x 10(-33)).
Published: 2009

35. Expression changes of CAV1 and EZH2, located on 7q31∼q36, are rarely related to genomic alterations in primary prostate carcinoma

Author: Guenter Assum, Natascha Bachmann, Thomas Paiss, Rainer Kuefer, Christiane Maier, Manuel Luedeke, Walther Vogel, Juergen Haeusler, Sven Perner, and Josef Hoegel
Subjects: Male, Cancer Research, Tumor suppressor gene, Caveolin 1, Bisulfite sequencing, Gene Dosage, macromolecular substances, Biology, Gene dosage, Genetics, Humans, Gene silencing, Enhancer of Zeste Homolog 2 Protein, RNA, Messenger, Molecular Biology, In Situ Hybridization, Fluorescence, DNA Primers, Regulation of gene expression, Reverse Transcriptase Polymerase Chain Reaction, Polycomb Repressive Complex 2, Prostatic Neoplasms, DNA Methylation, Middle Aged, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Tumor progression, Chromosomal region, DNA methylation, Cancer research, CpG Islands, Chromosomes, Human, Pair 7, Transcription Factors
Abstract: The chromosomal region 7q was repeatedly found to be rearranged in prostate carcinoma. It harbors several well described candidate tumor suppressor and oncogenes. We addressed two genes with opposite roles in cancer; CAV1, a putative tumor suppressor gene at 7q31, and EZH2 at 7q36, which is believed to promote tumor progression. Our primary aim was to assess their expression changes in primary tumors, and then to elucidate the underlying mechanism, assuming that genomic alterations of either locus could affect the other gene as well. In 35 prostate tumor samples, compared with adjacent tissues, CAV1 was overall downregulated (P < 10(-06)), whereas EZH2 was significantly overexpressed (P < 10(-06)). The observed dysregulations were coincident in nearly 70% of the cases. Copy number changes occurred in few tumors. Loss of CAV1 DNA was only marginally associated with reduced expression (P = 0.07), however, and genomic amplification of EZH2 could not explain its upregulation. Through bisulfite sequencing of four tumor samples, CpG-hypermethylation was verified as an alternative mechanism for CAV1 silencing, as reported previously. Moreover, it could also be involved in the reactivation of EZH2.
Published: 2008

36. Prediction of Individual Genetic Risk to Prostate Cancer Using a Polygenic Score

Author: Robert, Szulkin, Thomas, Whitington, Martin, Eklund, Markus, Aly, Rosalind A, Eeles, Douglas, Easton, Z Sofia, Kote-Jarai, Ali, Amin Al Olama, Sara, Benlloch, Kenneth, Muir, Graham G, Giles, Melissa C, Southey, Liesel M, Fitzgerald, Brian E, Henderson, Fredrick, Schumacher, Christopher A, Haiman, Johanna, Schleutker, Tiina, Wahlfors, Teuvo L J, Tammela, Børge G, Nordestgaard, Tim J, Key, Ruth C, Travis, David E, Neal, Jenny L, Donovan, Freddie C, Hamdy, Paul, Pharoah, Nora, Pashayan, Kay-Tee, Khaw, Janet L, Stanford, Stephen N, Thibodeau, Shannon K, McDonnell, Daniel J, Schaid, Christiane, Maier, Walther, Vogel, Manuel, Luedeke, Kathleen, Herkommer, Adam S, Kibel, Cezary, Cybulski, Jan, Lubiński, Wojciech, Kluźniak, Lisa, Cannon-Albright, Hermann, Brenner, Katja, Butterbach, Christa, Stegmaier, Jong Y, Park, Thomas, Sellers, Hui-Yi, Lin, Hui-Yi, Lim, Chavdar, Slavov, Radka, Kaneva, Vanio, Mitev, Jyotsna, Batra, Judith A, Clements, Amanda, Spurdle, Manuel R, Teixeira, Paula, Paulo, Sofia, Maia, Hardev, Pandha, Agnieszka, Michael, Andrzej, Kierzek, Henrik, Gronberg, and Danielle M, Karyadi
Subjects: Genetic Markers, Male, Risk Factors, Genetic Variation, Humans, Prostatic Neoplasms, Genetic Predisposition to Disease, Linkage Disequilibrium, Article
Abstract: BACKGROUND. Polygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction. METHODS. We built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls. RESULTS. The polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5 E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk. CONCLUSIONS. Inclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
Published: 2015

37. Genome-wide association study of prostate cancer-specific survival

Author: David E. Neal, Jing Ma, Kenneth Muir, Sara Benlloch, David J. Hunter, Graham G. Giles, Fredrick R. Schumacher, Judith A. Clements, Douglas F. Easton, Andrzej M. Kierzek, Cezary Cybulski, Demetrius Albanes, Ruth C. Travis, Jong Y. Park, Stephen N. Thibodeau, Fredrik Wiklund, Johanna Schleutker, Brian E. Henderson, Gerald L. Andriole, Christiane Maier, David G. Cox, Daniel J. Schaid, Melissa C. Southey, Amanda B. Spurdle, Thomas A. Sellers, Nora Pashayan, Timothy J. Key, Peter Kraft, Rosalind A. Eeles, Volker Herrmann, Hardev Pandha, Sofia Maia, Wojciech Kluźniak, Børge G. Nordestgaard, Stephen J. Chanock, Paul D.P. Pharoah, Meir J. Stampfer, Sonja I. Berndt, Agnieszka Michael, Adam S. Kibel, Robert Szulkin, Jyotsna Batra, Liesel M. FitzGerald, Kay-Tee Khaw, Janet L. Stanford, Alison M. Mondul, Stephanie J. Weinstein, Hermann Brenner, C. Slavov, Csilla Sipeky, Teuvo L.J. Tammela, Paula Paulo, Freddie C. Hamdy, Susan M. Gapstur, Kathleen Herkommer, Jenny L Donovan, Vanio Mitev, Edward Giovannucci, Walther Vogel, Anne Tjønneland, Bas Bueno-de-Mesquita, Henrik Grönberg, Markus Aly, Manuel Luedeke, Kathryn L. Penney, Antonia Trichopoulou, Robert Karlsson, Hui-Yi Lim, Manuel R. Teixeira, Shannon K. McDonnell, Sara Lindström, Zsofia Kote-Jarai, Bernd Holleczek, Lisa A. Cannon-Albright, Lovise Maehle, Christopher A. Haiman, Loic Le Marchand, Tom Whitington, Radka Kaneva, Jan Lubinski, Ali Amin Al Olama, and Victoria L. Stevens
Subjects: Oncology, Male, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Cancer, Prostatic Neoplasms, Genome-wide association study, Disease, medicine.disease, Polymorphism, Single Nucleotide, Survival Analysis, Article, Management of prostate cancer, Prostate cancer, Polymorphism (computer science), Internal medicine, Cohort, medicine, Humans, business, Survival analysis, Genome-Wide Association Study
Abstract: Background: Unnecessary intervention and overtreatment of indolent disease are common challenges in clinical management of prostate cancer. Improved tools to distinguish lethal from indolent disease are critical. Methods: We performed a genome-wide survival analysis of cause-specific death in 24,023 prostate cancer patients (3,513 disease-specific deaths) from the PRACTICAL and BPC3 consortia. Top findings were assessed for replication in a Norwegian cohort (CONOR). Results: We observed no significant association between genetic variants and prostate cancer survival. Conclusions: Common genetic variants with large impact on prostate cancer survival were not observed in this study. Impact: Future studies should be designed for identification of rare variants with large effect sizes or common variants with small effect sizes. Cancer Epidemiol Biomarkers Prev; 24(11); 1796–800. ©2015 AACR.
Published: 2015

38. Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status

Author: Sarah K. Holt, Jonathan L. Wright, Antje E. Rinckleb, Daniel W. Lin, Christiane Maier, Manuel Luedeke, Janet L. Stanford, and Lisly Chéry
Subjects: 0301 basic medicine, Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Pathology, genetic structures, Oncogene Proteins, Fusion, Urology, Prostatitis, urologic and male genital diseases, TMPRSS2, Article, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, In Situ Hybridization, Fluorescence, Aged, Prostatectomy, Aspirin, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Prostatic Neoplasms, Middle Aged, medicine.disease, eye diseases, digestive system diseases, Prostate-specific antigen, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Androgens, sense organs, Benign prostatic hyperplasia (BPH), business, Erg, medicine.drug
Abstract: The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status.Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use.T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (P0.01). Current aspirin use was associated with a 37% risk reduction of T2E-positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43-0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen.Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted.
Published: 2015

39. Stilbene induced inhibition of androgen receptor dimerization: implications for AR and ARΔLBD-signalling in human prostate cancer cells

Author: Anca Azoitei, Felicitas Genze, Marcus V. Cronauer, Andres Jan Schrader, Friedemann Zengerling, Alexander Herweg, Wolfgang Streicher, Mark Schrader, and Manuel Luedeke
Subjects: Male, Urology, lcsh:Medicine, Biology, Prostate cancer, Endocrinology, In vivo, Cell Line, Tumor, Stilbenes, Medicine and Health Sciences, medicine, Humans, Receptor, lcsh:Science, Reporter gene, Multidisciplinary, lcsh:R, Prostatic Neoplasms, Biological activity, medicine.disease, Androgen receptor, Oncology, Biochemistry, Receptors, Androgen, Cancer cell, Cancer research, lcsh:Q, Signal transduction, Dimerization, Signal Transduction, Research Article
Abstract: Background Advanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens. Methodology In this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay. Results The stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo. Conclusion RSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.
Published: 2014

40. 2139 ASPIRIN USE REDUCES RISK OF TMPRSS2:ERG FUSION POSITIVE PROSTATE CANCER

Author: Lisly Chery, Janet L. Stanford, Sarah K. Holt, Jonathan L. Wright, Christiane Maier, Daniel W. Lin, Manuel Luedeke, and Antje E. Rinckleb
Subjects: Oncology, Aspirin, medicine.medical_specialty, Prostate cancer, business.industry, Urology, Internal medicine, medicine, medicine.disease, business, Erg, TMPRSS2, medicine.drug
Published: 2013

41. A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease

Author: Cao G-W., Joanne L. Dickinson, Gianluca Severi, Tokhir Dadaev, Alan Horwich, S. Lindstrom, Sonja I. Berndt, Jong Y. Park, Shannon K. McDonnell, Lin H-Y., Amit Joshi, Daniel Leongamornlert, Johanna Schleutker, Robert Huddart, Zhang H-W., Ruth Frikke-Schmidt, Melissa C. Southey, Amanda B. Spurdle, Jan Adolfsson, Michael Gaziano, David G. Cox, Elio Riboli, Erika M. Kwon, Jyotsna Batra, K. Govindasami, Amanda L. Hall, Karina Dalsgaard Sørensen, S. Benlloch, E. Saunders, Vanio Mitev, Paula Kujala, Chris Ogden, Peter Kraft, Anssi Auvinen, S. J. Chanock, Vincent Khoo, Kathleen Herkommer, Michael Borre, C. Slavov, Rosalind A. Eeles, Heiko Müller, Lisa A. Cannon-Albright, D J Schaid, David E. Neal, Doug Easton, Tammela Tlj., W. R. Diver, E J Sawyer, Martin Andreas Røder, Afshan Siddiq, Jianfeng Xu, Michelle Guy, Andreas Meyer, Joanne F. Aitken, Shintaro Narita, Michael J. Thun, Malgorzata Tymrakiewicz, James R. Marthick, Torben F. Ørntoft, Lynne T. O'Brien, Edward Giovannucci, R A Wilkinson, Fredrick R. Schumacher, Mariana C. Stern, Zsofia Kote-Jarai, Antje E. Rinckleb, Ahva Shahabi, Jarmo Virtamo, T A Sellers, Christiane Maier, C.R.J. Woodhouse, Pedro Vaz Pinto, Sue A. Ingles, Cezary Cybulski, Jenny L Donovan, Anna M. Ray, Henrik Grönberg, Markus Aly, Kenneth Muir, Suzanne K. Chambers, Tim Dudderidge, Danielle M. Karyadi, Judith A. Clements, Briony Patterson, Susan M. Gapstur, Manuel Luedeke, Demetrius Albanes, Federico Canzian, B. E. Henderson, Elaine A. Ostrander, Thilo Dörk, John L. Hopper, Fredrik Wiklund, Lu Y-J., Timothy J. Key, Meredith Yeager, Robert A. Stephenson, Liesel M. FitzGerald, Robert A. Gardiner, Ali Amin Al Olama, Manuel R. Teixeira, Rudolph Kaaks, David P. Dearnaley, Hermann Brenner, Kathleen A. Cooney, Maren Weischer, Jan Lubinski, Angela Cox, Aritaya Lophatonanon, Ruth C. Travis, Jürgen Serth, Suzanne Kolb, David J. Hunter, Stig E. Bojesen, Felicity Lose, Jonathan J. Morrison, Dominika Wokołorczyk, W. Vogel, W. Isaacs, Freddie C. Hamdy, Siqun L. Zheng, N. van As, A. Thompson, N. Mahmud, Dallas R. English, S. N. Thibodeau, Roman Corral, Janet L. Stanford, Colin Cooper, Norihiko Tsuchiya, Gerald L. Andriole, T. Wahlfors, D Campa, Craig C. Teerlink, Kimmo Taari, Tomonori Habuchi, Esther M. John, Chris Parker, Richard B. Hayes, Dietrich Rothenbacher, João Vasco Santos, Børge G. Nordestgaard, Radka Kaneva, Peter Klarskov, Christopher A. Haiman, Loic Le Marchand, and Graham G. Giles
Subjects: Oncology, Male, genetic association, genotype, Genome-wide association study, urologic and male genital diseases, 0302 clinical medicine, single nucleotide polymorphism, genetic variability, Odds Ratio, Genetics (clinical), Genetics, family history, 0303 health sciences, Association Studies Articles, chromosome 19, General Medicine, cancer susceptibility, prostate cancer, 3. Good health, priority journal, cancer prognosis, cancer staging, gene frequency, gene locus, gene replication, human, meta analysis, 030220 oncology & carcinogenesis, Disease Progression, Medical genetics, medicine.medical_specialty, Quantitative Trait Loci, Single-nucleotide polymorphism, Biology, ta3111, Polymorphism, Single Nucleotide, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Genotyping, 030304 developmental biology, Genetic association, Case-control study, Prostatic Neoplasms, Reproducibility of Results, Odds ratio, ta3122, Case-Control Studies, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified multiple common genetic variants associated with an increased risk of prostate cancer (PrCa), but these explain less than one-third of the heritability. To identify further susceptibility alleles, we conducted a meta-analysis of four GWAS including 5953 cases of aggressive PrCa and 11 463 controls (men without PrCa). We computed association tests for approximately 2.6 million SNPs and followed up the most significant SNPs by genotyping 49 121 samples in 29 studies through the international PRACTICAL and BPC3 consortia. We not only confirmed the association of a PrCa susceptibility locus, rs11672691 on chromosome 19, but also showed an association with aggressive PrCa [odds ratio = 1.12 (95% confidence interval 1.03-1.21), P = 1.4 × 10(-8)]. This report describes a genetic variant which is associated with aggressive PrCa, which is a type of PrCa associated with a poorer prognosis.
Published: 2013

42. The prostate cancer risk locus at 10q11 is associated with DNA repair capacity

Author: Manuel Luedeke, Harald Surowy, Antje E. Rinckleb, Walther Vogel, Mark Schrader, Josef Hoegel, Christiane Maier, and Dominic Varga
Subjects: Adult, Male, Candidate gene, Adolescent, DNA Repair, DNA repair, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Biochemistry, Polymorphism, Single Nucleotide, Prostate cancer, Young Adult, Genotype, medicine, Mitotic Index, Humans, MSMB, DNA Breaks, Double-Stranded, Genetic Predisposition to Disease, Lymphocytes, Molecular Biology, Genetics, Micronucleus Tests, Chromosomes, Human, Pair 10, Prostatic Neoplasms, Cell Biology, medicine.disease, Gamma Rays, Genetic Loci, Female, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) that mildly predict prostate cancer risk. These SNPs are local tagging markers for causal gene alterations. Consideration of candidate genes in the tagged regions would be facilitated by additional information on the particular pathomechanisms which contribute to the observed risk increase. In this study we test for an association of prostate cancer tagging SNPs with alterations in DNA repair capacity, a phenotype that is frequently involved in cancer predisposition. DNA repair capacity was assessed on blood lymphocytes from 128 healthy probands after ionizing irradiation. We used the micronucleus (MN) assay to determine the cellular DNA double-strand break repair capacity and flow cytometry to measure damage induced mitotic delay (MD). Probands were genotyped for a panel of 14 SNPs, each representing an independent prostate cancer risk locus previously identified by GWAS. Associations between germline variants and DNA repair capacity were found for the SNPs rs1512268 (8p21), rs6983267 (8q24) and rs10993994 (10q11). The most significant finding was an association of homozygous rs10993994 T-allele carriers with a lower MN frequency (p = 0.0003) and also a decreased MD index (p = 0.0353). Cells with prostate cancer risk alleles at rs10993994 seem to cope more efficiently with DNA double strand breaks (less MN) in a shorter time (decreased MD index). This intriguing finding imposes concern about the accuracy of repair, with respect to the cancer risk that is mediated by T genotypes. To date, MSMB (microseminoprotein β) is favored as the causal gene at the 10q11 risk locus, since it was the first candidate gene known to be expressionally altered by rs10993994. Based on the present observation, candidate genes from the contexts of DNA repair and apoptosis may be more promising targets for expression studies with respect to the rs10993994 genotype.
Published: 2012

43. Predisposition for TMPRSS2-ERG fusion in prostate cancer by variants in DNA repair genes

Author: Walther Vogel, Harald Surowy, Matthias D. Hofer, Antje E. Rinckleb, Josef Hoegel, Manuel Luedeke, Carmen M. Linnert, Christiane Maier, Rainer Kuefer, and Mark A. Rubin
Subjects: Adult, Male, Candidate gene, Oncogene Proteins, Fusion, Epidemiology, DNA repair, Biology, urologic and male genital diseases, Genetic analysis, TMPRSS2, Genetic linkage, Genotype, Humans, Genetic Predisposition to Disease, Allele, Aged, Neoplasm Staging, Genetics, Aged, 80 and over, Prostatic Neoplasms, Middle Aged, Prognosis, Minor allele frequency, Survival Rate, DNA Repair Enzymes, Oncology, Case-Control Studies, Mutation
Abstract: The somatic fusion of TMPRSS2 to ETS oncogenes is a common event in prostate cancer (PCa). We hypothesized that defects in DNA repair may lead to an increase of chromosomal rearrangements and thus to the occurrence of ETS oncogene fusion. We have previously conducted a genome-wide linkage analysis in TMPRSS2-ERG fusion-positive PCa families, revealing potential susceptibility loci on chromosomes 5q14, 9q21, 10q26, 11q24, 12q15, 13q12, 18q, and Xq27. In the present study, nine candidate genes from these regions were selected from the context of DNA repair and screened for mutations in TMPRSS2-ERG fusion-positive families. Thirteen nonsynonymous variants, 5 of which had a minor allele frequency of
Published: 2009

44. POU5F1P1, a putative cancer susceptibility gene, is overexpressed in prostatic carcinoma

Author: Guenter Assum, Lisa Honold, Silvia Kastler, Peter Möller, Josef Hoegel, Walther Vogel, Rainer Kuefer, Christiane Maier, and Manuel Luedeke
Subjects: Male, Pathology, medicine.medical_specialty, Urology, Pseudogene, Adenocarcinoma, Biology, Gene product, Prostate cancer, Prostate, Cell Line, Tumor, medicine, Carcinoma, Humans, Genetic Predisposition to Disease, Promoter Regions, Genetic, Gene, Aged, Prostatic Neoplasms, Cancer, Epithelial Cells, Middle Aged, medicine.disease, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, Cancer research, Immunohistochemistry, Octamer Transcription Factor-3, Chromosomes, Human, Pair 8
Abstract: BACKGROUND Association between genetic variants located on human chromosome 8q24.21 with an increased risk for prostatic carcinoma has been well established. POU5F1P1, a processed pseudogene homologous to the pluripotency factor OCT4, is the only sequence with coding capacity in this region. The objective of this study was to investigate the POU5F1P1 expression in prostatic carcinoma and carcinoma surrounding prostatic tissue. METHODS RT-PCR and real-time PCR was used to measure the expression of POU5F1P1 relative to the expression of HPRT1 in cell lines, prostatic carcinoma and carcinoma surrounding prostatic tissue. The structure of the POU5F1P1 mRNA and the promoter sequence were elucidated by 5′-RACE experiments. The POU5F1P1 protein was shown with immunohistochemistry on prostate tissue. RESULTS POU5F1P1 was found to be the only member of the POU5F1 family to be expressed in prostate with over-expression in prostatic carcinoma compared to surrounding prostatic tissue probably because of an increased density of expressing cells. The POU5F1P1 expression is driven by a variety of promoter structures scattered over a genomic region of 860 kB. CONCLUSIONS The over-expression of POU5F1P1 in prostatic carcinoma in addition to its genomic location and the putative function of its gene product render POU5F1P1 a good candidate to harbour functional genetic variants which modulate prostatic cancer susceptibility. Prostate 70: 666–674, 2010. © 2009 Wiley-Liss, Inc.
Published: 2009

45. Association of the prostate cancer risk mutation G84E in HOXB13 with the subtype of ETS fusion negative adenocarcinoma with early age of diagnosis

Author: Johanna Schleutker, Kathleen Herkommer, Tiina Wahlfors, Zsofia Kote-Jarai, Josef Hoegel, Thomas J. Schnoeller, Christiane Maier, Antje E. Rinckleb, Liesel M. FitzGerald, Hans Krause, Manuel Luedeke, Steffen Weikert, Janet L. Stanford, and Ros Eeles
Subjects: Oncology, Prostate cancer risk, Cancer Research, medicine.medical_specialty, business.industry, Susceptibility gene, urologic and male genital diseases, medicine.disease, Bioinformatics, European descent, Prostate cancer, Germline mutation, Internal medicine, Mutation (genetic algorithm), medicine, Adenocarcinoma, business
Abstract: 5021 Background: HOXB13 was discovered as the first prostate cancer (PrCa) specific high-risk susceptibility gene. The most prevalent HOXB13 germline mutation in PrCa patients of European descent i...
Published: 2015

46. Detecting predictive androgen receptor modifications in circulating prostate cancer cells

Author: Jochen K. Lennerz, Konrad Steinestel, Julie Steinestel, Thomas J. Schnoeller, Christiane Maier, Annette Arndt, Marcus V. Cronauer, Andres J. Schrader, Carina Wurm, and Manuel Luedeke
Subjects: Cancer Research, medicine.medical_treatment, circulating tumor cells, medicine.disease_cause, urologic and male genital diseases, Androgen deprivation therapy, Prostate cancer, Circulating tumor cell, castration-resistant prostate cancer, Medicine, splice, androgen receptor modification, Mutation, Chemotherapy, splice variants, business.industry, Point mutation, food and beverages, medicine.disease, Clinical trial, Androgen receptor, Oncology, Immunology, Cancer research, business, Research Paper
Abstract: Molecular modifications of the androgen receptor (AR) can cause resistance to androgen deprivation therapy (ADT) in prostate cancer patients. Since lack of representative tumor samples hinders therapy adjustments according to emerging AR-modifications, we evaluated simultaneous detection of the two most common AR modifications (AR-V7 splice variant and AR point mutations) in circulating tumor cells (CTCs). We devised a single-tube assay to detect AR-V7 splice variants and AR point mutations in CTCs using immunomagnetic cell isolation, followed by quantitative real-time PCR and DNA pyrosequencing. We prospectively investigated 47 patients with PSA progression awaiting therapy switch. Comparison of response to newly administered therapy and CTC-AR-status allowed effect size estimation. Nineteen (51%) of 37 patients with detectable CTCs carried AR-modifications. Seventeen patients carried the AR-V7 splice variant, one harbored a p.T878A point mutation and one harbored both AR-V7 and a p.H875Y mutation. We estimated a positive predictive value for response and non-response to therapy by AR status in CTCs of ~94%. Based on a conservative calculation, we estimated the effect size for molecularly-informed therapy switches for prospective clinical trial planning to ~27%. In summary, the ability to determine key resistance-mediating AR modifications in CTCs has the potential to considerably improve prostate cancer treatment.
Published: 2015

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