42 results on '"Maren Weischer"'
Number of results to display per page
Search Results
2. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: evidence for synthetic association in prostate cancer.
- Author
-
Edward J Saunders, Tokhir Dadaev, Daniel A Leongamornlert, Sarah Jugurnauth-Little, Malgorzata Tymrakiewicz, Fredrik Wiklund, Ali Amin Al Olama, Sara Benlloch, David E Neal, Freddie C Hamdy, Jenny L Donovan, Graham G Giles, Gianluca Severi, Henrik Gronberg, Markus Aly, Christopher A Haiman, Fredrick Schumacher, Brian E Henderson, Sara Lindstrom, Peter Kraft, David J Hunter, Susan Gapstur, Stephen Chanock, Sonja I Berndt, Demetrius Albanes, Gerald Andriole, Johanna Schleutker, Maren Weischer, Børge G Nordestgaard, Federico Canzian, Daniele Campa, Elio Riboli, Tim J Key, Ruth C Travis, Sue A Ingles, Esther M John, Richard B Hayes, Paul Pharoah, Kay-Tee Khaw, Janet L Stanford, Elaine A Ostrander, Lisa B Signorello, Stephen N Thibodeau, Daniel Schaid, Christiane Maier, Adam S Kibel, Cezary Cybulski, Lisa Cannon-Albright, Hermann Brenner, Jong Y Park, Radka Kaneva, Jyotsna Batra, Judith A Clements, Manuel R Teixeira, Jianfeng Xu, Christos Mikropoulos, Chee Goh, Koveela Govindasami, Michelle Guy, Rosemary A Wilkinson, Emma J Sawyer, Angela Morgan, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, Douglas F Easton, Ken Muir, Rosalind A Eeles, and Zsofia Kote-Jarai
- Subjects
Genetics ,QH426-470 - Abstract
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.
- Published
- 2014
- Full Text
- View/download PDF
3. CHEK2∗1100delC Mutation and Risk of Prostate Cancer
- Author
-
Victoria Hale, Maren Weischer, and Jong Y. Park
- Subjects
Diseases of the genitourinary system. Urology ,RC870-923 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer. CHEK2 plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, of CHEK2 on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussed CHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating that CHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.
- Published
- 2014
- Full Text
- View/download PDF
4. Data from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
- Abstract
Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09).Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.
- Published
- 2023
- Full Text
- View/download PDF
5. Supplementary Figure 1 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
- Abstract
Supplementary Figure 1. Absolute Risk (With family history of prostate cancer)
- Published
- 2023
- Full Text
- View/download PDF
6. Supplementary Figure 3 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
- Abstract
Supplementary Figure 3. Absolute Risk (A model with only family history of prostate cancer)
- Published
- 2023
- Full Text
- View/download PDF
7. Supplementary Notes from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
- Abstract
Supplementary Notes. This document includes description of studies that they have been used for the analysis.
- Published
- 2023
- Full Text
- View/download PDF
8. Supplementary Tables 1-8 from Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Douglas F. Easton, Rosalind A. Eeles, Zsofia Kote-Jarai, Antje E. Rinckleb, Aritaya Lophatonanon, John L. Hopper, Kathleen Herkommer, Rosemary Wilkinson, Emma Sawyer, Koveela Govindasami, Sarah J. Little, Tokhir Dadaev, Michelle Guy, Malgorzata Tymrakiewicz, Edward Saunders, Daniel Leongamornlert, Liesel FitzGerald, Amanda B. Spurdle, Melissa C. Southey, Angela Cox, Robert Stephenson, Hong-Wei Zhang, Yong-Jie Lu, Maurice P. Zeegers, William D. Foulkes, Radka P. Kaneva, Pierre Hutter, Pierre O. Chappuis, Kathleen A. Cooney, Stephen N. Thibodeau, Tomonori Habuchi, Charnita Zeigler-Johnson, Timothy R. Rebbeck, Hermann Brenner, Lisa Cannon-Albright, Joanne L. Dickinson, Thilo Doerk, Christiane Maier, Cezary Cybulski, Jong Y. Park, Torben F. Orntoft, Karina D. Sorensen, Sue A. Ingles, Børge G. Nordestgaard, Maren Weischer, Suzanne K. Chambers, Judith A. Clements, Jyotsna Batra, Janet L. Stanford, Elaine A. Ostrander, Paul D.P. Pharoah, Nora Pashayan, Fredrick R. Schumacher, Christopher A. Haiman, Brian E. Henderson, Johanna Schleutker, Kenneth Muir, Jenny L. Donovan, Freddie C. Hamdy, David E. Neal, Gianluca Severi, Graham G. Giles, Antonis C. Antoniou, Sara Benlloch, and Ali Amin Al Olama
- Abstract
Supplementary Tables 1-8. Supplementary table 1: Total number of cases and controls in PRACTICAL III and GWAS stage 3 by population and study. Supplementary Table 2: Data information for family history and age at diagnosis/observation. Supplementary Table 3: Grade-specific and family history-specific odds ratios. Supplementary Table 4: PSA levels by genotype in controls. Supplementary Table 5: Age-specific odds ratios. Supplementary Table 6: The results of 29 pair wise interaction of 25 SNPs significant at P
- Published
- 2023
- Full Text
- View/download PDF
9. 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
10. 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
- Full Text
- View/download PDF
11. 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
12. 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
- Full Text
- View/download PDF
13. 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
- Full Text
- View/download PDF
14. Increased Body Mass Index, Elevated C-reactive Protein, and Short Telomere Length
- Author
-
Line Rode, Maren Weischer, Stig E. Bojesen, and Børge G. Nordestgaard
- Subjects
Adult ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Clinical Biochemistry ,Context (language use) ,Biology ,Biochemistry ,Body Mass Index ,Young Adult ,Endocrinology ,Polymorphism (computer science) ,Internal medicine ,Mendelian randomization ,medicine ,Humans ,Obesity ,Aged ,Aged, 80 and over ,Inflammation ,Polymorphism, Genetic ,Biochemistry (medical) ,C-reactive protein ,nutritional and metabolic diseases ,Middle Aged ,Telomere ,medicine.disease ,C-Reactive Protein ,Multivariate Analysis ,biology.protein ,Population study ,Female ,Body mass index - Abstract
Obesity is associated with short telomere length. The cause of this association is unknown.We hypothesized that genetically increased body mass index (BMI) is associated with telomere length shortening and that low-grade inflammation might contribute through elevated C-reactive protein.We studied 45,069 individuals from the Copenhagen General Population Study with measurements of leukocyte telomere length, BMI, and C-reactive protein in a Mendelian randomization study. Using the three obesity-associated polymorphisms FTO rs9939609, MC4R rs17782313, and TMEM18 rs6548238, and the CRP promoter polymorphism rs3091244 in instrumental variable analyses, we estimated the associations between genetically increased BMI and telomere length and between genetically increased C-reactive protein and telomere length.In multivariable-adjusted observational analyses, telomere length decreased with seven base pairs (95% confidence interval, -9--5) per unit increase in BMI, and further adjustment for C-reactive protein attenuated this association to -5 base pairs (-8--3). In accordance, instrumental variable analysis showed a non-significant telomere length shortening of six base pairs (-37-25) per unit increase in genetically determined BMI. Furthermore, in observational analyses, telomere length decreased with nine base pairs (-16--2) for a doubling in C-reactive protein, supported by the instrumental variable analyses showing a corresponding genetically determined decrease of 66 base pairs (-124--7).High BMI is associated with short telomere length observationally. This might possibly be mediated through elevated C-reactive protein, given that genetically elevated C-reactive protein levels are associated with short telomere length.
- Published
- 2014
- Full Text
- View/download PDF
15. High tobacco consumption is causally associated with increased all-cause mortality in a general population sample of 55 568 individuals, but not with short telomeres: a Mendelian randomization study
- Author
-
Line Rode, Maren Weischer, Stig E. Bojesen, and Børge G. Nordestgaard
- Subjects
education.field_of_study ,Multivariate analysis ,Epidemiology ,business.industry ,Incidence (epidemiology) ,Population ,Hazard ratio ,Mendelian Randomization Analysis ,General Medicine ,Confidence interval ,Mendelian randomization ,Medicine ,Allele ,business ,education ,Demography - Abstract
BACKGROUND High cumulative tobacco consumption is associated with short telomeres and with increased all-cause mortality. We tested the hypothesis that high tobacco consumption is causally associated with short telomeres and with increased all-cause mortality. METHODS We studied 55,568 individuals including 32,823 ever smokers from the Danish general population, of whom 3430 died during 10 years of follow-up. All had telomere length measured, detailed information on smoking history, and CHRNA3 rs1051730 genotype, which is associated with tobacco consumption, determined. In a Mendelian randomization study, we conducted observational, genetic, and mediation analyses. RESULTS First, tobacco consumption was 21.1 pack-years in non-carriers, 22.8 in heterozygotes and 24.8 in homozygotes (P-trend
- Published
- 2014
- Full Text
- View/download PDF
16. 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
17. 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
- Full Text
- View/download PDF
18. Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array
- Author
-
Artitaya Lophatananon, W. Ryan Diver, Stig E. Bojesen, Roman Corral, Fredrick R. Schumacher, Stephen J. Chanock, Shannon K. McDonnell, Graham G. Giles, Craig C. Teerlink, Douglas F. Easton, Cezary Cybulski, Brian E. Henderson, Judith A. Clements, Ali Amin Al Olama, Francois Bacot, David P. Dearnaley, Elio Riboli, Peter Klarskov, Daniel Vincent, Rosemary A. Wilkinson, Danielle M. Karyadi, Michelle Guy, Vincent Khoo, Christopher A. Haiman, Afshan Siddiq, M. Andreas Røder, Amit Joshi, Jong Y. Park, Walther Vogel, Henrik Grönberg, Angela Cox, Rudolf Kaaks, Nora Pashayan, Timothy J. Key, C. R. J. Woodhouse, Jarmo Virtamo, Meredith Yeager, Malgorzata Tymrakiewicz, Sune F. Nielsen, Richard B. Hayes, Johanna Schleutker, Gianluca Severi, Robert Huddart, Wei Zheng, Thomas A. Sellers, Melanie Maranian, Shahana Ahmed, David E. Neal, Daniel Leongamornlert, Zsofia Kote-Jarai, Tiina Wahlfors, Loic Le Marchand, Kay-Tee Khaw, Tokhir Dadaev, Lisa A. Cannon-Albright, Janet L. Stanford, William J. Blot, Andy C. H. Lee, Freddie C. Hamdy, Siqun L. Zheng, Rosalind A. Eeles, Alison M. Dunning, Mariana C. Stern, Melissa C. Southey, Don M. Conroy, Kenneth Muir, Ahva Shahabi, Alan Horwich, Gerald L. Andriole, Antje E. Rinckleb, Srilakshmi Srinivasan, Tim Dudderidge, Joe Dennis, Radka Kaneva, Vanio Mitev, Angela Morgan, Sue A. Ingles, Adam S. Kibel, Markus Aly, Koveela Govindasami, Maya Ghoussaini, Jenny L Donovan, Manuel R. Teixeira, Emma J. Sawyer, Sara Lindström, Jiangfeng Xu, Maren Weischer, Ed Dicks, Jyotsna Batra, S Jugurnauth-Little, Hui-Yi Lin, Suzanne Kolb, Lisa B. Signorello, Dallas R. English, Antonis C. Antoniou, Federico Canzian, Anssi Auvinen, Mia M. Gaudet, Paula Paulo, Paul D.P. Pharoah, Heiko Müller, Qiuyin Cai, Børge G. Nordestgaard, Esther M. John, Sonja I. Berndt, D J Schaid, Daniele Campa, Chris Ogden, Colin Cooper, Craig Luccarini, Jan Lubinski, Elaine A. Ostrander, Ruth C. Travis, Dominika Wokołorczyk, John L. Hopper, Sofia Maia, Sara Benlloch, Chris Parker, Erika M. Kwon, Nicholas van As, Caroline Baynes, C. Slavov, Teuvo L.J. Tammela, Ethan M. Lange, Daniel C. Tessier, David J. Hunter, Dietrich Rothenbacher, Robert A. Stephenson, Liesel M. FitzGerald, Christiane Maier, Hermann Brenner, Kathleen A. Cooney, Graham A. Colditz, Felicity Lose, Edward J. Saunders, Demetrius Albanes, Stephen N. Thibodeau, Fredrik Wiklund, Amanda B. Spurdle, Jan Adolfsson, Susan M. Gapstur, Peter Kraft, Bettina F. Drake, and Alan Thompson
- Subjects
Male ,genetic association ,genotype ,Genome-wide association study ,Bioinformatics ,genetic risk ,developed country ,Prostate cancer ,0302 clinical medicine ,Risk Factors ,Genotype ,Cooperative Behavior ,breast cancer ,cancer prognosis ,cancer susceptibility ,cell adhesion ,cell cycle arrest ,chromosome 14 ,chromosome 2 ,double stranded DNA break ,embryo development ,extracellular matrix ,gene frequency ,gene linkage disequilibrium ,genetic predisposition ,Gleason score ,heterozygote ,human ,intron ,priority journal ,promoter region ,prostate cancer ,quality control ,regulator gene ,Oligonucleotide Array Sequence Analysis ,0303 health sciences ,education.field_of_study ,3. Good health ,030220 oncology & carcinogenesis ,Population ,Single-nucleotide polymorphism ,Biology ,ta3111 ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Meta-Analysis as Topic ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,education ,Genotyping ,030304 developmental biology ,Case-control study ,Cancer ,Prostatic Neoplasms ,medicine.disease ,ta3122 ,Genetic Loci ,Case-Control Studies ,Genome-Wide Association Study - Abstract
Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.
- Published
- 2016
- Full Text
- View/download PDF
19. No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- Author
-
Agnieszka Dansonka-Mieszkowska, Angela Brooks-Wilson, Ingo B. Runnebaum, Kenneth Offit, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Christine Maugard, Marco Montagna, Annette Fontaine, Janusz Menkiszak, Robert Winqvist, Pascal Guénel, Rosalind Glasspool, Usha Menon, Daniel Barrowdale, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Martha J. Shrubsole, Lambertus A. Kiemeney, Camilla Krakstad, Dong Liang, Minouk J. Schoemaker, Judith S. Brand, Joseph Vijai, Marc T. Goodman, Thomas A. Sellers, David Van Den Berg, Celeste Leigh Pearce, Alice S. Whittemore, Irene L. Andrulis, Radka Platte, Kunle Odunsi, Orland Diez, Estrid Høgdall, Brooke L. Fridley, C. J. van Asperen, Mary Anne Rossing, Vessela N. Kristensen, Jonathan Tyrer, Tara M. Friebel, Douglas F. Easton, Per Hall, Mads Thomassen, Christine Walsh, Thilo Dörk, Louise A. Brinton, Keith Humphreys, Douglas A. Levine, Allison F. Vitonis, Anna H. Wu, Hermann Brenner, Maria Bisogna, Joellen M. Schildkraut, Maria A. Caligo, Jonine D. Figueroa, Lynne R. Wilkens, Grace Friel, Michael G. Schrauder, Evgeny N. Imyanitov, Sune F. Nielsen, Sylvie Mazoyer, Diana Eccles, Andrew Berchuck, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, Gad Rennert, Arif B. Ekici, Elisa Alducci, Bjarni A. Agnarsson, Linda S. Cook, Javier Benitez, Paolo Peterlongo, Natalia Antonenkova, Annika Lindblom, Patrick Neven, Julia A. Knight, Alan Ashworth, Matti A. Rookus, Frans B. L. Hogervorst, Daniela Zaffaroni, Banu Arun, Sue Healey, Robert P. Edwards, Susanne K. Kjaer, Laura J. van't Veer, John W.M. Martens, Christa Stegmaier, Claudine Isaacs, Daniel W. Cramer, Lars Beckmann, Liisa M. Pelttari, Dieter Flesch-Janys, Irene Orlow, Atocha Romero, Diana Torres, Marjanka K. Schmidt, Simon S. Cross, Alison M. Dunning, Rosemary L. Balleine, Sandra L. Halverson, Benoit Beuselinck, Melissa C. Larson, Senno Verhoef, Jirong Long, Angela Cox, Maartje J. Hooning, Bruce Poppe, Katarzyna Jaworska, Jolanta Kupryjanczyk, Nicolas Wentzensen, Gustavo C. Rodriguez, Tanja Pejovic, Roberta B. Ness, James Paul, Dominique Stoppa-Lyonnet, Nadine Tung, Gianluca Severi, Malcolm C. Pike, Hoda Anton-Culver, Ans M.W. van den Ouweland, Mark E. Robson, Roger L. Milne, Jan C. Oosterwijk, Laima Tihomirova, Helen Tsimiklis, Pierre Laurent-Puig, Florian Heitz, Beth Y. Karlan, Ian Tomlinson, Thérèse Truong, Bernardo Bonanni, Frederik Marmé, Qin Wang, Conxi Lázaro, Volker Arndt, Antoinette Hollestelle, Jacek Gronwald, M. Pilar Zamora, Barbara Wappenschmidt, Maren Weischer, Veli-Matti Kosma, Giulietta Scuvera, Jenny Lester, Andreas Berger, Stephen J. Chanock, Line Bjørge, Anthony J. Swerdlow, Andrew K. Godwin, Mervi Grip, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Paolo Radice, Bent Ejlertsen, Frederieke H. van der Baan, Lothar Haeberle, Valerie McGuire, Kamila Czene, Rob A. E. M. Tollenaar, Maria Soller, Katherine L. Nathanson, Sandrina Lambrechts, Susan J. Ramus, Anja Rudolph, Penny Soucy, Caroline Weltens, Hiltrud Brauch, Olivia Fletcher, Sara H. Olson, Yael Laitman, Marion Piedmonte, Arto Mannermaa, Agnieszka Budzilowska, Olga M. Sinilnikova, Christian F. Singer, Cezary Cybulski, Weiva Sieh, Ed Dicks, Elizabeth J. van Rensburg, Isabel dos Santos Silva, Hans Ehrencrona, Timothy R. Rebbeck, Jaana M. Hartikainen, Sandra Orsulic, Jingmei Li, Carmel Apicella, Anna deFazio, Ian G. Campbell, Ignace Vergote, Rita K. Schmutzler, Fredrick R. Schumacher, Julian Peto, Nadeem Siddiqui, Brian E. Henderson, Starr R. Guzman, Maria Kabisch, John L. Hopper, Arto Leminen, Jeffrey N. Weitzel, Honglin Song, J. Margriet Collée, Ingvild L. Tangen, Børge G. Nordestgaard, Antonis C. Antoniou, Lara Sucheston, Helena C. van Doorn, Lídia Feliubadaló, Leon F.A.G. Massuger, Iain A. McNeish, Nichola Johnson, Simon A. Gayther, Jennifer A. Doherty, Anders Bojesen, Gord Glendon, Yukie Bean, Celine M. Vachon, Barbara Burwinkel, Edith Olah, Shan Wang-Gohrke, Brita Arver, Marc Tischkowitz, Arja Jukkola-Vuorinen, Martin Gore, Vesa Kataja, Nicola Miller, Pamela J. Thompson, Malcolm W.R. Reed, Michelle A.T. Hildebrandt, Ritu Salani, Janet E. Olson, Catriona McLean, Cecilia M. Dorfling, Georgia Chenevix-Trench, Frederique Mariette, Laura Ottini, Fergus J. Couch, Linda E. Kelemen, Nhu D. Le, Michael J. Kerin, Claus Høgdall, Miguel de la Hoya, Jonathan Carter, Mercedes Durán, Inge Søkilde Pedersen, Julie M. Cunningham, Manjeet K. Bolla, Galina Lurie, Loic Le Marchand, Ute Hamann, Muy-Kheng Tea, Karoline Kuchenbaecker, Irene Konstantopoulou, Thomas Hansen, Francesca Damiola, Stefano Fortuzzi, Shelley S. Tworoger, Mikael Eriksson, Carl Blomqvist, Joan Brunet, Allan Jensen, Karen Lu, Elisa V. Bandera, Anne M. van Altena, Anne-Marie Gerdes, Lene Lundvall, Susan L. Neuhausen, Wei Zheng, Ana Osorio, Fiona Bruinsma, Hannah P. Yang, Graham G. Giles, Christoph Engel, Nick Orr, Harvey A. Risch, Jan Lubinski, Jacoba P. Knol-Bout, Phuong L. Mai, Martine Dumont, Xifeng Wu, Christof Sohn, Noah D. Kauff, Kristiina Aittomäki, Natalia Bogdanova, Alexander Hein, Francesmary Modugno, Heli Nevanlinna, Helga B. Salvesen, Adriana Lasa, Daphne Gschwantler Kaulich, Dominiek Smeets, Jenny Permuth-Wey, Josef Herzog, Catherine M. Phelan, Clareann H. Bunker, Steve Ellis, Christopher A. Haiman, Jolanta Lissowska, Judy Garber, Joanna Plisiecka-Halasa, Robert A. Vierkant, Steven A. Narod, Mark H. Greene, Florence Menegaux, Norbert Arnold, Primitiva Menéndez, Robert L. Nussbaum, Katja K.H. Aben, Andreas Schneeweiss, Katri Pylkäs, Els Van Nieuwenhuysen, Tomasz Huzarski, Joe Dennis, Susan M. Domchek, Andreas du Bois, Aleksandra Gentry-Maharaj, Florentia Fostira, Mary Beth Terry, Jenny Chang-Claude, Eitan Friedman, Argyrios Ziogas, Hatef Darabi, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Stig E. Bojesen, Jo Perkins, Raanan Berger, Sharon E. Johnatty, Taru A. Muranen, Montserrat Garcia-Closas, Uffe Birk Jensen, Thomas Brüning, Heiko Müller, Debra Frost, Peter A. Fasching, Lesley McGuffog, Diether Lambrechts, Kelly-Anne Phillips, Caroline M. Seynaeve, Kathryn L. Terry, Ira Schwaab, Ralf Bützow, Manuel R. Teixeira, Joseph H. Rothstein, Bernard Peissel, Anna von Wachenfeldt, Saundra S. Buys, Peter Devilee, Alfons Meindl, Laura Baglietto, Kirsten B. Moysich, Arjen R. Mensenkamp, Philipp Harter, Jacques Simard, Generalitat de Catalunya, Ministerio de Ciencia e Innovación (España), Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, National Institutes of Health (US), Wellcome Trust, European Commission, National Cancer Institute (US), Medical Oncology, Clinical Genetics, Erasmus MC other, Pediatric Surgery, Pathology, and Neurology
- Subjects
0301 basic medicine ,Oncology ,endocrine system diseases ,Endometriosis ,Breast cancer ,Clinical outcome ,Genetic association ,KRAS variant ,Ovarian cancer ,Genome-wide association study ,Carcinoma, Ovarian Epithelial ,medicine.disease_cause ,Prostate ,Brjóstakrabbamein ,Clinical outcomes ,Genotype ,Obstetrics and Gynaecology ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,PROSTATE ,Neoplasms, Glandular and Epithelial ,skin and connective tissue diseases ,RISK ,Ovarian Neoplasms ,Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17] ,Obstetrics and Gynecology ,WOMEN ,female genital diseases and pregnancy complications ,3. Good health ,medicine.anatomical_structure ,Treatment Outcome ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Female ,KRAS ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Breast Neoplasms ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Internal medicine ,medicine ,Carcinoma ,Humans ,GENOME-WIDE ASSOCIATION ,Genetic Association Studies ,POLYMORPHISMS ,Krabbamein ,MICRORNA-BINDING-SITE ,IDENTIFICATION ,business.industry ,ENDOMETRIOSIS ,Arfgengi ,medicine.disease ,030104 developmental biology ,PTT12 ,Eggjastokkar ,business - Abstract
Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, and Consortium of Modifiers of BRCA1 and BRCA2: et al., [Objective]: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. [Methods]: Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). [Results]: We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. [Conclusions]: rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers., The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 — HEALTH-F2-2009-223175). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). Funding for the project was provided by the Wellcome Trust under award 076113. This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrileña Foundation (FMMA) and SAF2010-20493. Was supported by a grant RD12/00369/0006 and 12/00539 from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Contract grant sponsor: Asociación Española Contra el Cáncer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285 and 2009SGR290.
- Published
- 2016
- Full Text
- View/download PDF
20. Short Telomere Length, Myocardial Infarction, Ischemic Heart Disease, and Early Death
- Author
-
Maren Weischer, Jacob J. Freiberg, Stig E. Bojesen, Børge G. Nordestgaard, Richard M. Cawthon, and Anne Tybjærg-Hansen
- Subjects
Adult ,Male ,Aging ,medicine.medical_specialty ,Time Factors ,Denmark ,Population ,Myocardial Infarction ,Myocardial Ischemia ,Early death ,Disease ,Real-Time Polymerase Chain Reaction ,Risk Assessment ,Risk Factors ,Internal medicine ,Humans ,Medicine ,Genetic Predisposition to Disease ,Prospective Studies ,Myocardial infarction ,education ,Prospective cohort study ,Telomere Shortening ,Aged ,Proportional Hazards Models ,education.field_of_study ,business.industry ,Hazard ratio ,Age Factors ,Middle Aged ,medicine.disease ,Telomere ,Phenotype ,Cardiology ,Population study ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Objective— We tested the hypothesis that short telomere length is associated with increased risk of myocardial infarction, ischemic heart disease, and early death. Methods and Results— We measured leukocyte telomere length in 2 prospective studies of 19 838 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 19 years for incident myocardial infarction (n=929), ischemic heart disease (n=2038), and death (n=4342). Follow-up was 100% complete. Telomere length decreased linearly with increasing age in women and men in both studies ( P =7×10 −74 to P =3×10 −125 ). Multifactorially adjusted hazard ratios were 1.10 (95% CI 1.01–1.19) for myocardial infarction, 1.06 (1.00–1.11) for ischemic heart disease, and 1.09 (1.05–1.13) for early death per 1000–base pair decrease in telomere length. The multifactorially adjusted hazard ratios for the shortest versus the longest decile of telomere length were 1.49 (1.07–2.07) for myocardial infarction, 1.24 (1.01–1.53) for ischemic heart disease, and 1.25 (1.07–1.46) for early death. Conclusion— Short telomere length is associated with only modestly increased risk of myocardial infarction, ischemic heart disease, and early death.
- Published
- 2012
- Full Text
- View/download PDF
21. Prothrombin and risk of venous thromboembolism, ischemic heart disease and ischemic cerebrovascular disease in the general population
- Author
-
Maren Weischer, Rolf Steffensen, Børge G. Nordestgaard, Gorm B. Jensen, Torben V. Schroeder, Anne Tybjærg-Hansen, Jeppe Zacho, and Klaus Juul
- Subjects
Risk ,Heterozygote ,medicine.medical_specialty ,Denmark ,Population ,Myocardial Infarction ,Myocardial Ischemia ,Thrombophilia ,Ischemia ,Internal medicine ,Odds Ratio ,medicine ,Factor V Leiden ,Humans ,cardiovascular diseases ,Risk factor ,education ,Stroke ,Proportional Hazards Models ,education.field_of_study ,business.industry ,Venous Thromboembolism ,Odds ratio ,medicine.disease ,Surgery ,Cerebrovascular Disorders ,Venous thrombosis ,Case-Control Studies ,Cardiology ,Prothrombin G20210A ,Prothrombin ,Pulmonary Embolism ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective We tested the hypotheses that Prothrombin G20210A heterozygosity associate with increased risk of venous thromboembolism (VTE), ischemic heart disease (IHD), and ischemic cerebrovascular disease (ICVD) in the general population and re-tested risk of IHD and ICVD in two case-control studies. Methods 9231 individuals from the Danish general population were followed for VTE (VTE=DVT+PE), deep venous thrombosis (DVT), pulmonary embolism (PE), IHD, myocardial infarction (MI), ICVD, and ischemic stroke (IS) for a median of 24 years. Case-control studies included 2461 IHD cases and 867 ICVD cases. Results In the general population, Prothrombin G20210A heterozygotes had1.3 (95% CI:0.6–2.9) fold risk for VTE, 0.6 (0.2–2.0) for DVT, 1.7(0.6–4.8) for PE, 1.5(1.1–2.1) for IHD, 1.7(1.1–2.7) for MI, 1.1(0.6–1.9) for ICVD, and 1.1(0.5–2.1) for IS compared to non-carriers. Double heterozygotes for Prothrombin G20210A and Factor V Leiden versus double non-carriers had a multifactorially adjusted hazard ratio for IHD of 6.0(2.0–19). In case-control studies, multifactorially adjusted odds ratios for Prothrombin G20210A heterozygotes versus non-carriers were 2.0(1.1–3.4) for IHD, 2.0(1.0–3.8) for MI, 1.4(0.7–3.1) for ICVD, and 2.1(0.8–5.4) for IS. Conclusion Prothrombin G20210A heterozygosity alone and in combination with Factor V Leiden R506Q heterozygosity predicts 1.5 and 6.0 fold risk of IHD compared to non-carriers.
- Published
- 2010
- Full Text
- View/download PDF
22. Genotyping for NOD2 Genetic Variants and Crohn Disease: a Metaanalysis
- Author
-
Børge G. Nordestgaard, Maren Weischer, and Shiva Yazdanyar
- Subjects
Genetics ,medicine.medical_specialty ,Crohn's disease ,Genotype ,Biochemistry (medical) ,Clinical Biochemistry ,Nod2 Signaling Adaptor Protein ,Genetic Variation ,Odds ratio ,Biology ,Compound heterozygosity ,medicine.disease ,Gastroenterology ,Crohn Disease ,Internal medicine ,NOD2 ,Meta-analysis ,medicine ,Humans ,Genetic Predisposition to Disease ,Allele ,Genotyping ,Alleles - Abstract
Background: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. Methods: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. Results: The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0–2.5) for Arg702Trp, 2.6 (2.2–2.9) for Gly908Arg, and 3.8 (3.4–4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0–2.8) for simple heterozygotes, 9.0 (6.0–13.5) for compound heterozygotes, and 6.7 (4.1–10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). Conclusions: The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.
- Published
- 2009
- Full Text
- View/download PDF
23. Missense Polymorphisms inBRCA1andBRCA2and Risk of Breast and Ovarian Cancer
- Author
-
Maren Weischer, Anne Tybjærg-Hansen, Børge G. Nordestgaard, Jacob J. Freiberg, Stig E. Bojesen, and Sarah Louise Dombernowsky
- Subjects
Oncology ,medicine.medical_specialty ,endocrine system diseases ,Epidemiology ,Genetic counseling ,Genes, BRCA2 ,Population ,Genes, BRCA1 ,Breast Neoplasms ,Single-nucleotide polymorphism ,Biology ,Polymerase Chain Reaction ,Loss of heterozygosity ,Breast cancer ,Risk Factors ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,education ,Ovarian Neoplasms ,education.field_of_study ,Polymorphism, Genetic ,Incidence ,Cancer ,medicine.disease ,Cancer research ,Female ,Breast disease ,Ovarian cancer - Abstract
Purpose: BRCA1 and BRCA2 are key tumor suppressors with a role in cellular DNA repair, genomic stability, and checkpoint control. Mutations in BRCA1 and BRCA2 often cause hereditary breast and ovarian cancer; however, missense polymorphisms in these genes pose a problem in genetic counseling, as their impact on risk of breast and ovarian cancer is unclear.Experimental Design: We resequenced BRCA1 and BRCA2 in 194 women with a familial history of breast and/or ovarian cancer and identified nine possibly biologically relevant polymorphisms (BRCA1 Gln356Arg, Pro871Leu, Glu1038Gly, Ser1613Gly, and Met1652Ile. BRCA2 Asn289His, Asn372His, Asp1420Tyr, and Tyr1915Met). We evaluated risk of breast and/or ovarian cancer by these polymorphisms in a prospective study of 5,743 women from the general population followed for 39 years and in a case-control study of 1,201 breast cancer cases and 4,120 controls.Results: We found no association between heterozygosity or homozygosity for any of the nine polymorphisms and risk of breast and/or ovarian cancer in either study. We had 80% power to exclude hazard/odds ratios for heterozygotes and/or homozygotes for all nine missense polymorphisms above 1.3 to 3.3 in the prospective study, and above 1.2 to 3.2 in the case-control study.Conclusions: Heterozygosity and homozygosity of any of the examined nine BRCA1 and BRCA2 missense polymorphisms cannot explain the increased risk of breast and/or ovarian cancer observed in families with hereditary breast and/or ovarian cancer. Therefore, genetic counseling of such families safely can disregard findings of these missense polymorphisms. (Cancer Epidemiol Biomarkers Prev 2009;18(8):2339–42)
- Published
- 2009
- Full Text
- View/download PDF
24. Risk of Cancer by ATM Missense Mutations in the General Population
- Author
-
Anne Tybjjrg-Hansen, Maren Weischer, Stig E. Bojesen, Sarah Louise Dombernowsky, Børge G. Nordestgaard, and Kristine H. Allin
- Subjects
Adult ,Male ,Oncology ,Heterozygote ,Cancer Research ,medicine.medical_specialty ,Pathology ,Denmark ,Population ,Mutation, Missense ,Breast Neoplasms ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Loss of heterozygosity ,Prostate cancer ,Breast cancer ,Neoplasms ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Prospective Studies ,Risk factor ,education ,Prospective cohort study ,education.field_of_study ,business.industry ,Tumor Suppressor Proteins ,Hazard ratio ,Cancer ,Middle Aged ,medicine.disease ,DNA-Binding Proteins ,Female ,business - Abstract
Purpose Truncating and missense mutations in the ATM gene, which cause insufficient DNA damage surveillance, allow damaged cells to proceed into mitosis, which eventually results in increased cancer susceptibility. We tested the hypotheses that ATM Ser49Cys and ATM Ser707Pro heterozygosity increase the risk of cancer overall, of breast cancer, and of 26 other cancer subtypes in the general population. Patients and Methods We genotyped 10,324 individuals from the Danish general population who were observed prospectively for 36 years, during which 2,056 developed cancer. Results Multifactorially adjusted hazard ratios for ATM Ser49Cys heterozygotes versus noncarriers were 1.2 (95% CI, 0.9 to 1.5) for cancer overall, 0.8 (95% CI, 0.3 to 2.0) for breast cancer, 4.8 (95% CI, 2.2 to 11) for melanoma, 2.3 (95% CI, 1.1 to 5.0) for prostate cancer, and 3.4 (95% CI, 1.1 to 11) for cancer of the oral cavity/pharynx. Multifactorially adjusted hazard ratios for ATM Ser707Pro heterozygotes versus noncarriers were 0.8 (95% CI, 0.6 to 1.2) for cancer overall, 0.6 (95% CI, 0.2 to 1.6) for breast cancer, 10 (95% CI, 1.1 to 93) for thyroid/other endocrine tumors, and 2.7 (95% CI, 1.0 to 7.6) for cancer of corpus uteri. Conclusion ATM missense mutations do not increase the risk of cancer overall or of breast cancer in the general population; however, we observed in exploratory analyses that ATM missense mutations may be associated with an increased risk of other cancer subtypes. As we did multiple comparisons, some of these findings could represent chance findings rather than real phenomena.
- Published
- 2008
- Full Text
- View/download PDF
25. CHEK2*1100delC Genotyping for Clinical Assessment of Breast Cancer Risk: Meta-Analyses of 26,000 Patient Cases and 27,000 Controls
- Author
-
Maren Weischer, Anne Tybjærg-Hansen, Stig E. Bojesen, Christina Ellervik, and Børge G. Nordestgaard
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Genotype ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,Risk Assessment ,Breast cancer ,Internal medicine ,Humans ,Medicine ,Genetic Predisposition to Disease ,Genetic Testing ,skin and connective tissue diseases ,CHEK2 ,Aged ,BRCA2 Protein ,Gynecology ,BRCA1 Protein ,business.industry ,Genetic Carrier Screening ,Case-control study ,Cancer ,Odds ratio ,medicine.disease ,Checkpoint Kinase 2 ,Case-Control Studies ,Meta-analysis ,Mutation ,Female ,Apoptosis Regulatory Proteins ,business ,Risk assessment - Abstract
Purpose CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice. Patients and Methods We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EMBASE, and Web of Science. Aggregated risk estimates were compared with previous estimates for BRCA1 and BRCA2 mutation heterozygotes. Results By using fixed-effect models for CHEK2*1100delC heterozygotes versus noncarriers, we found aggregated odds ratios of 2.7 (95% CI, 2.1 to 3.4) for unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) for early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes. Conclusion These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer–predisposing gene, which increases the risk three- to five-fold. Because the cumulative risk of breast cancer at age 70 years among familial patient cases for CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes, genotyping for CHEK2*1100delC should be considered together with BRCA1 and BRCA2 mutation screening in women with a family history of breast cancer.
- Published
- 2008
- Full Text
- View/download PDF
26. Increased Risk of Breast Cancer Associated With CHEK2*1100delC
- Author
-
C K Axelsson, Stig E. Bojesen, Anne Tybjærg-Hansen, Maren Weischer, and Børge G. Nordestgaard
- Subjects
Adult ,Male ,Risk ,Oncology ,Heterozygote ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Denmark ,Population ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,Prostate cancer ,Breast cancer ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,skin and connective tissue diseases ,education ,Prospective cohort study ,CHEK2 ,Aged ,Aged, 80 and over ,education.field_of_study ,Polymorphism, Genetic ,business.industry ,Prostatic Neoplasms ,Cancer ,Odds ratio ,Middle Aged ,medicine.disease ,Checkpoint Kinase 2 ,Case-Control Studies ,Female ,Colorectal Neoplasms ,business ,Gene Deletion - Abstract
Purpose CHEK2*1100delC heterozygosity has been associated with increased risk of breast, prostate, and colorectal cancer in case-control studies. We tested the hypothesis that CHEK2*1100delC heterozygosity in the general population increases the risk of cancer in general, and breast, prostate, and colorectal cancer in particular. Patients and Methods We performed a prospective study of 9,231 individuals from the Danish general population, who were observed for 34 years, and we performed a case-control study including 1,101 cases of breast cancer and 4,665 controls. Results Of the general population, 0.5% were heterozygotes and 99.5% were noncarriers. In the prospective study, multifactorially adjusted hazard ratios by CHEK2*1100delC heterozygosity versus noncarriers were 1.2 (95% CI, 0.7 to 2.1) for all cancers, 3.2 (95% CI, 1.0 to 9.9) for breast cancer, 2.3 (95% CI, 0.6 to 9.5) for prostate cancer, and 1.6 (95% CI, 0.4 to 6.5) for colorectal cancer. In the case-control study, age-matched odds ratio for breast cancer by CHEK2*1100delC heterozygosity versus noncarriers was 2.6 (95% CI, 1.3 to 5.4). The absolute 10-year risk of breast cancer in CHEK2*1100delC heterozygotes amounted to 24% in women older than 60 years undergoing hormone replacement therapy, with a body mass index of 25 kg/m2 or higher. Conclusion CHEK2*1100delC heterozygosity is associated with a three-fold risk of breast cancer in women in the general population.
- Published
- 2007
- Full Text
- View/download PDF
27. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci
- Author
-
Karina Dalsgaard Sørensen, Rosemary A. Wilkinson, Jong Y. Park, Johanna Schleutker, Cezary Cybulski, Rosalind A. Eeles, John L. Hopper, Melissa C. Southey, Janet L. Stanford, Torben F. Ørntoft, Radka Kaneva, Jenny L Donovan, Thilo Doerk, Paul D.P. Pharoah, David E. Neal, Hongwei Zhang, Sarah J. Little, Emma J. Sawyer, Nora Pashayan, Tomonori Habuchi, Kathleen Herkommer, Maurice P. Zeegers, Antonis C. Antoniou, Brian E. Henderson, Kenneth Muir, Fredrick R. Schumacher, Charnita Zeigler-Johnson, Koveela Govindasami, Christopher A. Haiman, Freddie C. Hamdy, Judith A. Clements, Jyotsna Batra, Ali Amin Al Olama, Joanne L. Dickinson, Gianluca Severi, Yong-Jie Lu, Maren Weischer, Sara Benlloch, Malgorzata Tymrakiewicz, Edward J. Saunders, Sue A. Ingles, Michelle Guy, Timothy R. Rebbeck, Stephen N. Thibodeau, Zsofia Kote-Jarai, Amanda B. Spurdle, Lisa A. Cannon-Albright, Pierre Hutter, Daniel Leongamornlert, Robert A. Stephenson, Elaine A. Ostrander, Liesel M. FitzGerald, Hermann Brenner, Kathleen A. Cooney, Aritaya Lophatonanon, Antje E. Rinckleb, Angela Cox, Tokhir Dadaev, Pierre O. Chappuis, Børge G. Nordestgaard, William D. Foulkes, Douglas F. Easton, Suzanne K. Chambers, Christiane Maier, Graham G. Giles, Complexe Genetica, and RS: NUTRIM - R4 - Gene-environment interaction
- Subjects
Oncology ,Risk analysis ,medicine.medical_specialty ,Epidemiology ,PREDICTION ,VARIANTS ,urologic and male genital diseases ,Article ,Prostate cancer ,MULTIPLE LOCI ,Breast cancer ,Internal medicine ,medicine ,BREAST-CANCER ,GENOME-WIDE ASSOCIATION ,Gynecology ,IDENTIFICATION ,business.industry ,Absolute risk reduction ,Cancer ,Odds ratio ,medicine.disease ,BRCA2 ,Relative risk ,business ,Risk assessment - Abstract
Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.
- Published
- 2015
- Full Text
- View/download PDF
28. No Evidence for Increased Skin Cancer Risk in Psoriasis Patients Treated with Broadband or Narrowband UVB Phototherapy: A First Retrospective Study
- Author
-
Maren Weischer, Martin Röcken, Andreas Blum, Frank Eberhard, and Mark Berneburg
- Subjects
Male ,Risk ,medicine.medical_specialty ,Skin Neoplasms ,genetic structures ,Pilot Projects ,Dermatology ,Psoriasis ,medicine ,Ultraviolet light ,Humans ,Narrowband UVB phototherapy ,Risk factor ,Melanoma ,Retrospective Studies ,integumentary system ,business.industry ,Incidence ,Incidence (epidemiology) ,Retrospective cohort study ,General Medicine ,Middle Aged ,medicine.disease ,Female ,Ultraviolet Therapy ,Skin cancer ,business ,Carcinoma in Situ - Abstract
Phototherapy of skin diseases such as psoriasis is an effective and safe treatment modality. However, increasing the risk of skin cancer by phototherapy is a serious concern. An increased skin cancer risk occurs after prolonged photochemotherapy (PUVA). In contrast, the role of broadband UVB or narrowband UVB therapy in skin carcinogenesis of humans with psoriasis is less clear. Therefore, we investigated the incidence of skin tumours in a total of 195 psoriasis patients, receiving broadband (n~69) or narrowband (n~126) UVB from 1994 to 2000 with follow-up until 2003. Data were raised from the regional interdisciplinary cancer centre of the University of Tuebingen, Germany and compared with the tumour incidences given for the German population. In this study, with 80% statistical power to detect a 6 – 7-fold increase in skin cancer with broadband UVB and 83% power to detect a 5 – 6-fold increase with narrow band UVB at p~0.05, only one patient developed skin cancer – an in situ melanoma. The tumour occurred within the same year that phototherapy was initiated. Thus, the present study does not provide evidence for an increased skin cancer risk for patients treated with either broadband or narrowband UVB phototherapy Key words: broadband UVB; narrowband UVB; phototherapy; psoriasis; retrospective study; skin cancer risk; ultraviolet light.
- Published
- 2004
- Full Text
- View/download PDF
29. Short telomere length, cancer survival, and cancer risk in 47102 individuals
- Author
-
Stig E. Bojesen, Maren Weischer, Jacob J. Freiberg, Richard M. Cawthon, Anne Tybjærg-Hansen, and Børge G. Nordestgaard
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Denmark ,Population ,Age adjustment ,Biology ,Risk Assessment ,Risk Factors ,Internal medicine ,Neoplasms ,medicine ,Leukocytes ,Odds Ratio ,Humans ,Prospective Studies ,Prospective cohort study ,education ,Survival rate ,Telomere Shortening ,Aged ,Genetics ,education.field_of_study ,Incidence ,Hazard ratio ,Age Factors ,Cancer ,Odds ratio ,Middle Aged ,Telomere ,medicine.disease ,Survival Analysis ,Survival Rate ,Multivariate Analysis ,Linear Models ,Population study ,Female ,Follow-Up Studies - Abstract
Background Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. Methods We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. Results Telomere length decreased linearly with increasing age (P
- Published
- 2013
30. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression
- Author
-
Don M. Conroy, David E. Neal, Jong Y. Park, Johanna Schleutker, Gerald L. Andriole, Amanda B. Spurdle, Peter Kraft, Alison M. Dunning, Esther M. John, Angela Morgan, Kenneth Muir, Douglas F. Easton, Fredrick R. Schumacher, Susan M. Gapstur, Rosalind A. Eeles, Stig E. Bojesen, Zsofia Kote-Jarai, Paul D.P. Pharoah, Francois Bacot, Jan Lubinski, Janet L. Stanford, Hermann Brenner, Cezary Cybulski, Caroline Baynes, Judith A. Clements, Jenny L Donovan, Ruth C. Travis, Edward J. Saunders, Kay-Tee Khaw, Silvia Halim, Demetrius Albanes, Stephen J. Chanock, Malgorzata Tymrakiewicz, Manuel R. Teixeira, D J Schaid, Sara Lindström, Loic Le Marchand, Sarah Jugurn-Little, Stephen N. Thibodeau, Fredrik Wiklund, Lisa A. Cannon-Albright, Maren Weischer, David J. Hunter, Graham G. Giles, Brian E. Henderson, Rosemary A. Wilkinson, Lisa B. Signorello, Michelle Guy, Craig Luccarini, Daniel Leongamornlert, Elio Riboli, Henrik Grönberg, Timothy J. Key, Christiane Maier, Joe Dennis, Walther Vogel, Ali Amin Al Olama, Helen Ross-Adams, Sonja I. Berndt, Ed Dicks, Sara Benlloch, Daniel Vincent, Freddie C. Hamdy, Sue A. Ingles, D. Campa, Rudolf Kaaks, Adam S. Kibel, Gianluca Severi, Daniel C. Tessier, Tokhir Dadaev, Christopher A. Haiman, Richard B. Hayes, Radka Kaneva, Koveela Govindasami, Emma J. Sawyer, Jyotsna Batra, Roslin Russel, Elaine A. Ostrander, and Federico Canzian
- Subjects
Male ,Linkage disequilibrium ,genetic association ,cancer risk ,urologic and male genital diseases ,Bioinformatics ,Linkage Disequilibrium ,Prostate cancer ,0302 clinical medicine ,single nucleotide polymorphism ,chromosome 5p ,Genotype ,genetic variability ,Promoter Regions, Genetic ,Telomerase ,Genetics (clinical) ,Genetics ,Prostate cancer risk ,0303 health sciences ,gene ,gene expression ,gene locus ,gene mapping ,human ,human tissue ,priority journal ,prostate cancer ,TERT gene ,030302 biochemistry & molecular biology ,Chromosome Mapping ,General Medicine ,030220 oncology & carcinogenesis ,HMG-CoA reductase ,Chromosomes, Human, Pair 5 ,Corrigendum ,Adult ,medicine.medical_specialty ,Single-nucleotide polymorphism ,Computational biology ,Biology ,ta3111 ,Polymorphism, Single Nucleotide ,RC0254 ,03 medical and health sciences ,Molecular genetics ,Genetic variation ,medicine ,Humans ,Telomerase reverse transcriptase ,Genetic Predisposition to Disease ,Genotyping ,QH426 ,Molecular Biology ,030304 developmental biology ,Prostatic Neoplasms ,medicine.disease ,ta3122 ,Case-Control Studies ,biology.protein ,Imputation (genetics) - Abstract
Associations between single nucleotide polymorphisms (snps) at 5p15 and multiple cancer types have been reported. we have previously shown evidence for a strong association between prostate cancer (prca) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (tert) gene that encodes tert. to comprehensively evaluate the association between genetic variation across this region and prca, we performed a fine-mapping analysis by genotyping 134 snps using a custom illumina iselect array or sequenom massarray iplex, followed by imputation of 1094 snps in 22 301 prca cases and 22 320 controls in the practical consortium. multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of tert that independently associated with prca risk. gene expression analysis of normal prostate tissue showed evidence that snps within one of these regions also associated with tert expression, providing a potential mechanism for predisposition to disease. © The author 2013. Published by Oxford University Press.
- Published
- 2013
31. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer
- Author
-
Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology
- Subjects
Telomerase ,Messenger ,Càncer d'ovari ,Estrogen receptor ,Aetiology, screening and detection [ONCOL 5] ,0302 clinical medicine ,Breast cancer ,Risk Factors ,Alternative Splicing ,Biomarkers, Tumor ,Breast Neoplasms ,Case-Control Studies ,Chromatin ,DNA Methylation ,Female ,Gene Expression Profiling ,Genetic Loci ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,Humans ,Luciferases ,Oligonucleotide Array Sequence Analysis ,Ovarian Neoplasms ,Polymorphism, Single Nucleotide ,RNA, Messenger ,Real-Time Polymerase Chain Reaction ,Reverse Transcriptase Polymerase Chain Reaction ,Telomere ,Genetics ,BUCCAL CELLS ,0303 health sciences ,Tumor ,Telòmer ,GENETIC-VARIATION ,COMMON VARIANTS ,Single Nucleotide ,tert-clptm1l locus ,genome-wide association ,genetic-variation ,susceptibility loci ,buccal cells ,fibroblasts ,common variants ,carcinoma ,reverse-transcriptase htert ,metaanalysis ,Aetiology, screening and detection Immune Regulation [ONCOL 5] ,3. Good health ,Tumor Markers, Biological ,030220 oncology & carcinogenesis ,FIBROBLASTS ,SUSCEPTIBILITY LOCI ,CARCINOMA ,Single-nucleotide polymorphism ,Biology ,Article ,Càncer de mama ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Translational research [ONCOL 3] ,Ovarian cancer ,medicine ,Polymorphism ,Allele ,GENOME-WIDE ASSOCIATION ,METAANALYSIS ,030304 developmental biology ,Molecular epidemiology Aetiology, screening and detection [NCEBP 1] ,Breast cancer susceptibility ,Hereditary cancer and cancer-related syndromes [ONCOL 1] ,Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3] ,medicine.disease ,Molecular biology ,TERT-CLPTM1L LOCUS ,Minor allele frequency ,RNA ,Biomarkers ,REVERSE-TRANSCRIPTASE HTERT - Abstract
Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed
- Published
- 2013
- Full Text
- View/download PDF
32. 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
- Full Text
- View/download PDF
33. Short telomere length, lung function and chronic obstructive pulmonary disease in 46,396 individuals
- Author
-
Børge G. Nordestgaard, Jørgen Vestbo, Maren Weischer, Stig E. Bojesen, and Line Rode
- Subjects
Pulmonary and Respiratory Medicine ,Spirometry ,Adult ,Male ,medicine.medical_specialty ,Vital capacity ,Denmark ,Population ,Vital Capacity ,Polymerase Chain Reaction ,FEV1/FVC ratio ,Pulmonary Disease, Chronic Obstructive ,Internal medicine ,Forced Expiratory Volume ,Prevalence ,Medicine ,Humans ,education ,Aged ,Retrospective Studies ,education.field_of_study ,COPD ,medicine.diagnostic_test ,business.industry ,Retrospective cohort study ,DNA ,respiratory system ,Middle Aged ,Telomere ,medicine.disease ,respiratory tract diseases ,Surgery ,Quartile ,Cardiology ,Female ,business - Abstract
A previous case-control study of 100 individuals found that short telomere length was associated with a 28-fold increased risk of chronic obstructive pulmonary disease (COPD).To test the hypothesis that short telomere length is associated with reduced lung function and an increased risk of COPD.Observational study of 46 396 individuals from the Danish general population.Leucocyte telomere length and spirometry were measured. COPD was defined using either fixed forced expiratory volume in 1 s (FEV₁)/forced vital capacity (FVC) ratio0.70 as suggested by the Global initiative for chronic Obstructive Lung Disease (GOLD) or FEV₁/FVC below the lower limit of normal (LLN).Telomere length decreased significantly with increasing age (p10(-300)). FEV₁, FVC and FEV1/FVC decreased with decreasing telomere length quartiles (p trend: 5 × 10(-51), 5 × 10(-35) and 6 × 10(-137), respectively), but the associations attenuated after age and multivariable adjustment. The risk of COPD increased with decreasing telomere length quartile (p trend: p=7 × 10(-92) for GOLD; p=8 × 10(-44) for FEV₁/FVC below LLN), but associations also attenuated after adjustment. Unadjusted and multivariable adjusted OR for shortest versus longest telomere length quartiles were 2.06 (95% CI 1.91 to 2.22) and 1.15 (95% CI 1.06 to 1.25) for GOLD and 1.73 (95% CI 1.60 to 1.88) and 1.19 (95% CI 1.09 to 1.30) for FEV₁/FVC below LLN, respectively. Per 1000 base pairs decrease in telomere length, the multivariable adjusted OR was 1.07 (95% CI 1.03 to 1.10) for GOLD and 1.07 (95% CI 1.03 to 1.11) for FEV₁/FVC below LLN.Short telomere length is associated with decreased lung function and with increased risk of COPD, but the associations are markedly attenuated after adjustment. Our data support a modest correlation between telomere length and the lung function indices examined.
- Published
- 2012
- Full Text
- View/download PDF
34. CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer
- Author
-
Vessela N. Kristensen, Peter A. Fasching, Mieke Kriege, Laura J. van't Veer, Graham G. Giles, Frederik Marmé, Montserrat Garcia-Closas, Melissa C. Southey, Henrik Flyger, Douglas F. Easton, Arto Mannermaa, Per Hall, Maren Weischer, Stig E. Bojesen, Malcolm W.R. Reed, Marie Rose Christiaens, Jonine D. Figueroa, Karin Leunen, Simon S. Cross, Julia A. Knight, Vesa Kataja, Paul D.P. Pharoah, Alexander Miron, Xianshu Wang, Thilo Dörk, Jianjun Liu, J. M. Collee, Taru A. Muranen, Arif B. Ekici, Christof Sohn, Diether Lambrechts, Kelly-Anne Phillips, Laura Baglietto, Janet E. Olson, Grethe I. Grenaker Alnæs, Børge G. Nordestgaard, Qin Wang, Jingmei Li, Gord Glendon, Gianluca Severi, Barbara Burwinkel, Hoda Anton-Culver, Veli-Matti Kosma, Sara Margolin, Kamila Czene, Andreas Meyer, Peter Devilee, Mitul Shah, Matthias W. Beckmann, Manjeet K. Bolla, Annegien Broeks, Annika Lindblom, Natalia Bogdanova, Mark E. Sherman, Carl Blomqvist, Richard van Hien, John L. Hopper, Alison M. Dunning, Irene L. Andrulis, Anne Lise Børresen-Dale, Rob A. E. M. Tollenaar, Fergus J. Couch, Esther M. John, Marjanka K. Schmidt, Argyrios Ziogas, Caroline Seynaeve, Heli Nevanlinna, Angela Cox, Maartje J. Hooning, Clinical Genetics, and Medical Oncology
- Subjects
Oncology ,Cancer Research ,Loss of heterozygosity ,0302 clinical medicine ,Neoplasms ,Prospective Studies ,Prospective cohort study ,skin and connective tissue diseases ,Estrogen Receptor Status ,Cancer ,0303 health sciences ,Hazard ratio ,Neoplasms, Second Primary ,Middle Aged ,Protein-Serine-Threonine Kinases ,Prognosis ,3. Good health ,Second Primary ,030220 oncology & carcinogenesis ,Female ,medicine.medical_specialty ,Heterozygote ,Genotype ,medicine.drug_class ,Clinical Sciences ,Oncology and Carcinogenesis ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,Breast cancer ,SDG 3 - Good Health and Well-being ,Clinical Research ,Internal medicine ,Original Reports ,Breast Cancer ,medicine ,Genetics ,Humans ,Genetic Predisposition to Disease ,Oncology & Carcinogenesis ,CHEK2 ,Germ-Line Mutation ,030304 developmental biology ,business.industry ,Prevention ,Case-control study ,medicine.disease ,Estrogen ,Checkpoint Kinase 2 ,Case-Control Studies ,business - Abstract
Purpose We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and Methods From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only. Conclusion Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
- Published
- 2012
- Full Text
- View/download PDF
35. CHEK2*1100delC and Risk of Malignant Melanoma: Danish and German Studies and Meta-Analysis
- Author
-
Lars Bastholt, Claus Garbe, Thomas Eigentler, Maren Weischer, Helle Klyver, Martin Röcken, Lisbet Rosenkrantz Hölmich, Børge G. Nordestgaard, Stig E. Bojesen, Henrik Schmidt, and Ida M. Heerfordt
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Heterozygote ,Skin Neoplasms ,Denmark ,Dermatology ,Protein Serine-Threonine Kinases ,Biochemistry ,Danish ,Loss of heterozygosity ,Risk Factors ,Internal medicine ,Germany ,medicine ,Humans ,skin and connective tissue diseases ,CHEK2 ,Molecular Biology ,Melanoma ,Aged ,business.industry ,Case-control study ,Odds ratio ,Cell Biology ,Middle Aged ,medicine.disease ,Protein-Serine-Threonine Kinases ,Confidence interval ,language.human_language ,Checkpoint Kinase 2 ,Meta-analysis ,Case-Control Studies ,language ,Female ,business ,Receptor, Melanocortin, Type 1 - Abstract
It is possible that reduced function of DNA repair and cell-cycle control genes increases the individual susceptibility to malignant melanoma. As CHEK2 is a cell-cycle master controller, we tested the hypothesis that heterozygosity for the frameshift alteration CHEK2*1100delC is associated with increased risk of malignant melanoma. First, we performed case-control studies of 1,152 Danish and 752 German individuals with malignant melanoma compared with 9,142 Danish and 3,718 German controls. Second, we performed a meta-analysis of CHEK2*1100delC and malignant melanoma, involving 2,619 cases and 17,481 controls. Third, we examined the risk of malignant melanoma associated with CHEK2*1100delC heterozygosity in an analysis stratified for sun exposure, as well as for subtype and location on the body. The odds ratios for malignant melanoma for CHEK2(*)1100del heterozygotes compared with those for noncarriers were 2.01 (95% confidence interval (CI), 1.03-3.91) in Danes, 1.42 (95% CI, 0.46-4.31) in Germans, and 1.79 (95% CI, 1.02-3.17) in Danes and Germans combined. In a meta-analysis, the odds ratio of malignant melanoma for CHEK2*1100delC heterozygotes compared with that for noncarriers was 1.81 (95% CI, 1.07-3.05). Stratifications did not alter these results. CHEK2*1100delC heterozygotes have a twofold risk of malignant melanoma compared with noncarriers.Journal of Investigative Dermatology advance online publication, 29 September 2011; doi:10.1038/jid.2011.303.
- Published
- 2012
- Full Text
- View/download PDF
36. Seven novel prostate cancer susceptibility loci identified by a multi-stage genome-wide association study
- Author
-
Liesel M. FitzGerald, Zhang H-W., Gianluca Severi, Tokhir Dadaev, W. R. Diver, Olama Aaa., Shintaro Narita, Michael J. Thun, Brian E. Henderson, Hermann Brenner, Kathleen A. Cooney, Elio Riboli, Aritaya Lophatonanon, Gerald L. Andriole, T. Wahlfors, S. N. Thibodeau, Esther M. John, Joanne L. Dickinson, Ruth C. Travis, Timothy J. Christmas, Cezary Cybulski, Antje E. Rinckleb, Danielle M. Karyadi, Daniele Campa, Dominika Wokołorczyk, Michelle Guy, Anne Tybjærg-Hansen, Susan M. Gapstur, David J. Hunter, Briony Patterson, Demetrius Albanes, Rosalind A. Eeles, Alan Horwich, Jarmo Virtamo, Janet L. Stanford, David E. Neal, Andreas Meyer, Timothy J. Key, Meredith Yeager, Roman Corral, Elaine A. Ostrander, Malgorzata Tymrakiewicz, Fredrik Wiklund, Amanda B. Spurdle, Torben F. Ørntoft, Daniel Leongamornlert, Douglas F. Easton, John L. Hopper, Colin Cooper, Suzanne K. Chambers, Dietrich Rothenbacher, A Ray, R A Wilkinson, Peter Kraft, Norihiko Tsuchiya, G.G. Giles, Jenny L Donovan, Sonja I. Berndt, Zsofia Kote-Jarai, Chris Ogden, Peter Klarskov, Christopher A. Haiman, Vanio Mitev, Jonathan J. Morrison, D J Schaid, Freddie C. Hamdy, Martin Andreas Røder, Jan Lubinski, T A Sellers, Stephen J. Chanock, Loic Le Marchand, Christiane Maier, Thilo Dörk, Lisa A. Cannon-Albright, Lu Y-J., Federico Canzian, N. van As, A. Thompson, Heiko Müller, James R. Marthick, Sara Benlloch, Mariana C. Stern, Radka Kaneva, Jong Y. Park, Jürgen Serth, Joanne F. Aitken, Ed Saunders, Johanna Schleutker, Robert Huddart, Tammela Tlj., E J Sawyer, Sue A. Ingles, Markus Aly, Melissa C. Southey, Børge G. Nordestgaard, Felicity Lose, N. Mahmud, Richard B. Hayes, Fredrick R. Schumacher, Chris Parker, Paul D.P. Pharoah, J. M. Farnham, Tomonori Habuchi, Sara Lindström, Maren Weischer, Judith A. Clements, Suzanne Kolb, C.R.J. Woodhouse, Dallas R. English, Kenneth Muir, Angela Cox, Erika M. Kwon, C. Slavov, Shannon K. McDonnell, Lin H-Y., Amanda L. Hall, Karina Dalsgaard Sørensen, Gardiner Raf., Michael Borre, Amit Joshi, Stig E. Bojesen, Jyotsna Batra, Cao G-W., W. Vogel, Vincent Khoo, Lynne T. O'Brien, Henrik Grönberg, A Shahabi, Rudolph Kaaks, David P. Dearnaley, and Robert A. Stephenson
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Genotype ,Genome-wide association study ,Single-nucleotide polymorphism ,Biology ,urologic and male genital diseases ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Internal medicine ,Genetics ,medicine ,SNP ,Chromosomes, Human ,Humans ,Genotyping ,Telomerase ,030304 developmental biology ,Aged ,Randomized Controlled Trials as Topic ,Aged, 80 and over ,0303 health sciences ,Genome, Human ,Haplotype ,Cancer ,Prostatic Neoplasms ,Middle Aged ,medicine.disease ,3. Good health ,030220 oncology & carcinogenesis ,Case-Control Studies ,Immunology ,Disease Susceptibility ,Genome-Wide Association Study - Abstract
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10-8 to P = 2.7 × 10-24). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining 425% of the familial risk in this disease, have now been identified. © 2011 Nature America, Inc. All rights reserved.
- Published
- 2011
- Full Text
- View/download PDF
37. Calcineurin inhibitors and rapamycin: cancer protection or promotion?
- Author
-
Maren Weischer, Martin Röcken, and Mark Berneburg
- Subjects
medicine.medical_specialty ,DNA Repair ,Ultraviolet Rays ,medicine.medical_treatment ,Calcineurin Inhibitors ,Dermatology ,Biochemistry ,Models, Biological ,Tacrolimus ,Pimecrolimus ,Cyclosporin a ,Neoplasms ,medicine ,Humans ,Intensive care medicine ,Adverse effect ,Molecular Biology ,Sirolimus ,business.industry ,TOR Serine-Threonine Kinases ,Immunosuppression ,Atopic dermatitis ,medicine.disease ,Calcineurin ,Transplantation ,Immunology ,Carcinogens ,Cyclosporine ,business ,Protein Kinases ,Immunosuppressive Agents ,medicine.drug - Abstract
Since the introduction of cyclosporin A (CsA) in the early 1980s, the use of immunosuppressants has markedly increased. Already established drugs have proved effective in the treatment of a wide range of diseases outside transplantation medicine and new immunosuppressants have been developed for more specific indications such as psoriasis and atopic dermatitis. Patients in transplantation medicine as well as in dermatology have benefited significantly from systemic and topical application of both new and established drugs. But are these drugs without risks? Cancer-protecting effects have been reported for some of the available immunosuppressants. Conversely, other publications and the issue of a black box warning by the US Food and Drug Administration have increased concerns about cancer-promoting effects. Knowledge of the specific effects as well as adverse effects is paramount to ensure an application that is safe and beneficial for the patient. Here we review the mechanisms of action and therapeutic potential, and critically review recent literature with respect to possible carcinogenic side effects of systemic and topical CsA, tacrolimus, pimecrolimus and rapamycin.
- Published
- 2007
38. Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer
- Author
-
Douglas F. Easton, Jong Y. Park, Daniel Leongamornlert, Johanna Schleutker, Stephen J. Chanock, Brian E. Henderson, Elio Riboli, Christos Mikropoulos, Graham G. Giles, Paul D.P. Pharoah, Radka Kaneva, Koveela Govindasami, Rosemary A. Wilkinson, Michelle Guy, Henrik Grönberg, Angela Morgan, Jyotsna Batra, Fredrick R. Schumacher, Gerald L. Andriole, Emma J. Sawyer, Rosalind A. Eeles, Gianluca Severi, Esther M. John, Tokhir Dadaev, David E. Neal, Børge G. Nordestgaard, Daniele Campa, Richard B. Hayes, Jenny L Donovan, Judith A. Clements, Christopher A. Haiman, Malgorzata Tymrakiewicz, Jianfeng Xu, Freddie C. Hamdy, Kay-Tee Khaw, Kenneth Muir, Janet L. Stanford, Ali Amin Al Olama, Adam S. Kibel, Cezary Cybulski, Chee L. Goh, Sara Benlloch, Timothy J. Key, Ruth C. Travis, Sue A. Ingles, Markus Aly, Lisa A. Cannon-Albright, Federico Canzian, Sonja I. Berndt, Manuel R. Teixeira, Sara Lindström, Maren Weischer, Lisa B. Signorello, Hermann Brenner, Daniel J. Schaid, David J. Hunter, Elaine A. Ostrander, Zsofia Kote-Jarai, Peter Kraft, S Jugurnauth-Little, Edward J. Saunders, Demetrius Albanes, Stephen N. Thibodeau, Fredrik Wiklund, Susan M. Gapstur, Christiane Maier, Pharoah, Paul [0000-0001-8494-732X], Khaw, Kay-Tee [0000-0002-8802-2903], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
- Subjects
Male ,Cancer Research ,G84E MUTATION ,LOCI ,Genome-wide association study ,QH426-470 ,0302 clinical medicine ,Risk Factors ,INTERNATIONAL CONSORTIUM ,Genetics (clinical) ,Genetics & Heredity ,RISK ,Genetics ,0303 health sciences ,Single Nucleotide ,Penetrance ,GENOME-WIDE SCAN ,3. Good health ,SUSCEPTIBILITY GENES ,030220 oncology & carcinogenesis ,Life Sciences & Biomedicine ,Research Article ,CARCINOMA ,Genotype ,Single-nucleotide polymorphism ,Biology ,ta3111 ,Polymorphism, Single Nucleotide ,RC0254 ,03 medical and health sciences ,Gene mapping ,LINKAGE ,Cancer Genetics ,Humans ,Genetic Predisposition to Disease ,Polymorphism ,Allele ,Molecular Biology ,Genotyping ,METAANALYSIS ,Genetic Variation ,Genome-Wide Association Study ,Homeodomain Proteins ,Prostatic Neoplasms ,Ecology, Evolution, Behavior and Systematics ,Alleles ,030304 developmental biology ,Science & Technology ,Haplotype ,ta3122 ,Imputation (genetics) ,Chromosomes, Human, Pair 17 - Abstract
The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility., Author Summary Genome-wide association studies (GWAS) have identified numerous low penetrance disease susceptibility variants, yet few causal alleles have been unambiguously identified. The underlying causal variants are expected to be predominantly common; however synthetic associations with rare, higher penetrance variants have been hypothesised though not yet observed. Here, we report detection of a novel common, low penetrance prostate cancer association at the HOXB locus at ch17q and show that this signal can actually be attributed to a previously identified rare, moderate penetrance coding variant (G84E) in HOXB13. This study therefore provides the first experimental evidence for the existence of synthetic associations in cancer and shows that where GWAS signals arise through this phenomenon, risk predictions derived using the tag SNP would substantially underestimate the relative risk conferred and overestimate the number of carriers of the causal variant. Synthetic associations at GWAS signals could therefore account for a proportion of the missing heritability of complex diseases.
- Published
- 2014
- Full Text
- View/download PDF
39. In Reply
- Author
-
Maren Weischer, Stig E. Bojesen, Christina Ellervik, Anne Tybiaerg-Hanson, and Børge G. Nordestgaard
- Subjects
Cancer Research ,Oncology - Published
- 2008
- Full Text
- View/download PDF
40. CHEK2 in the Clinical Management of Breast Cancer
- Author
-
Maren Weischer, Stig E. Bojesen, and Børge G. Nordestgaard
- Subjects
Oncology ,CA15-3 ,medicine.medical_specialty ,business.industry ,Cancer ,medicine.disease ,Breast cancer ,Internal medicine ,Epidemiology of cancer ,Medicine ,Surgery ,business ,CHEK2 - Published
- 2008
- Full Text
- View/download PDF
41. Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study.
- Author
-
Zsofia^Kote-Jarai, Ali Amin^Al Olama, Graham G.^Giles, Gianluca^Severi, Johanna^Schleutker, Maren^Weischer, Daniele^Campa, Elio^Riboli, Tim^Key, Henrik^Gronberg, David J.^Hunter, Peter^Kraft, Michael J.^Thun, Sue^Ingles, Stephen^Chanock, Demetrius^Albanes, Richard B.^Hayes, David E.^Neal, Freddie C.^Hamdy, and Jenny L.^Donovan
- Subjects
DIAGNOSIS ,PROSTATE cancer ,CANCER susceptibility ,DISEASE susceptibility ,CHROMOSOMES ,GENETIC research - Abstract
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. We conducted a multi-stage genome-wide association study for PrCa and previously reported the results of the first two stages, which identified 16 PrCa susceptibility loci. We report here the results of stage 3, in which we evaluated 1,536 SNPs in 4,574 individuals with prostate cancer (cases) and 4,164 controls. We followed up ten new association signals through genotyping in 51,311 samples in 30 studies from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. In addition to replicating previously reported loci, we identified seven new prostate cancer susceptibility loci on chromosomes 2p11, 3q23, 3q26, 5p12, 6p21, 12q13 and Xq12 (P = 4.0 × 10
?8 to P = 2.7 × 10?24 ). We also identified a SNP in TERT more strongly associated with PrCa than that previously reported. More than 40 PrCa susceptibility loci, explaining ?25% of the familial risk in this disease, have now been identified. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
42. A genome-wide association scan (GWAS) for mean telomere length within the COGS project: identified loci show little association with hormone-related cancer risk
- Author
-
Zsofia Kote-Jarai, Douglas F. Easton, Qin Wang, Børge G. Nordestgaard, Barbara Burwinkel, Freddie C. Hamdy, Alison M. Dunning, Caroline Baynes, Joe Dennis, Stig E. Bojesen, Manjeet K. Bolla, Kay-Tee Khaw, Mitul Shah, Georgia Chenevix-Trench, Joellen M. Schildkraut, Andrew Berchuck, Sara Benlloch, Kyriaki Michailidou, Ed Dicks, Ali Amin Al Olama, Jonathan Tyrer, Maren Weischer, Deborah J. Thompson, Judith E. Brown, Jenny Chang-Claude, Anja Rudolph, Karen A. Pooley, Tina Audley, Paul D.P. Pharoah, Rosalind A. Eeles, Sune F. Nielsen, Jenny L Donovan, Robert Luben, David E. Neal, and Rongxi Yang
- Subjects
Male ,Risk ,Single-nucleotide polymorphism ,Genome-wide association study ,Biology ,ACYP2 ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Breast cancer ,Neoplasms ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,Molecular Biology ,Genotyping ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Association Studies Articles ,Case-control study ,Cancer ,Chromosome Mapping ,Telomere Homeostasis ,General Medicine ,Telomere ,medicine.disease ,3. Good health ,Genetic Loci ,030220 oncology & carcinogenesis ,Case-Control Studies ,Female ,Genome-Wide Association Study - Abstract
Mean telomere length (TL) in blood cells is heritable and has been reported to be associated with risks of several diseases, including cancer. We conducted a meta-analysis of three GWAS for TL (total n=2240) and selected 1629 variants for replication via the "iCOGS" custom genotyping array. All ~200 000 iCOGS variants were analysed with TL, and those displaying associations in healthy controls (n = 15 065) were further tested in breast cancer cases (n = 11 024). We found a novel TL association (Ptrend < 4 × 10-10) at 3p14.4 close to PXK and evidence (Ptrend < 7 × 10-7) for TL loci at 6p22.1 (ZNF311) and 20q11.2 (BCL2L1). We additionally confirmed (Ptrend < 5 × 10-14) the previously reported loci at 3q26.2 (TERC), 5p15.3 (TERT) and 10q24.3 (OBFC1) and found supportive evidence (Ptrend < 5 × 10-4) for the published loci at 2p16.2 (ACYP2), 4q32.2 (NAF1) and 20q13.3 (RTEL1). SNPs tagging these loci explain TL differences of up to 731 bp (corresponding to 18% of total TL in healthy individuals), however, they display little direct evidence for association with breast, ovarian or prostate cancer risks.
Catalog
Books, media, physical & digital resources
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.