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1.  A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease 
Amin Al Olama, Ali | Kote-Jarai, Zsofia | Schumacher, Fredrick R. | Wiklund, Fredrik | Berndt, Sonja I. | Benlloch, Sara | Giles, Graham G. | Severi, Gianluca | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Hunter, David J. | Henderson, Brian E. | Thun, Michael J. | Gaziano, Michael | Giovannucci, Edward L. | Siddiq, Afshan | Travis, Ruth C. | Cox, David G. | Canzian, Federico | Riboli, Elio | Key, Timothy J. | Andriole, Gerald | Albanes, Demetrius | Hayes, Richard B. | Schleutker, Johanna | Auvinen, Anssi | Tammela, Teuvo L.J. | Weischer, Maren | Stanford, Janet L. | Ostrander, Elaine A. | Cybulski, Cezary | Lubinski, Jan | Thibodeau, Stephen N. | Schaid, Daniel J. | Sorensen, Karina D. | Batra, Jyotsna | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Gardiner, Robert A. | Maier, Christiane | Vogel, Walther | Dörk, Thilo | Brenner, Hermann | Habuchi, Tomonori | Ingles, Sue | John, Esther M. | Dickinson, Joanne L. | Cannon-Albright, Lisa | Teixeira, Manuel R. | Kaneva, Radka | Zhang, Hong-Wei | Lu, Yong-Jie | Park, Jong Y. | Cooney, Kathleen A. | Muir, Kenneth R. | Leongamornlert, Daniel A. | Saunders, Edward | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | Govindasami, Koveela | O'Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Dudderidge, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Artitaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Virtamo, Jarmo | Le Marchand, Loic | Campa, Daniele | Kaaks, Rudolf | Lindstrom, Sara | Diver, W. Ryan | Gapstur, Susan | Yeager, Meredith | Cox, Angela | Stern, Mariana C. | Corral, Roman | Aly, Markus | Isaacs, William | Adolfsson, Jan | Xu, Jianfeng | Zheng, S. Lilly | Wahlfors, Tiina | Taari, Kimmo | Kujala, Paula | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Frikke-Schmidt, Ruth | Bojesen, Stig E. | FitzGerald, Liesel M. | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Rinckleb, Antje | Luedeke, Manuel | Herkommer, Kathleen | Meyer, Andreas | Serth, Jürgen | Marthick, James R. | Patterson, Briony | Wokolorczyk, Dominika | Spurdle, Amanda | Lose, Felicity | McDonnell, Shannon K. | Joshi, Amit D. | Shahabi, Ahva | Pinto, Pedro | Santos, Joana | Ray, Ana | Sellers, Thomas A. | Lin, Hui-Yi | Stephenson, Robert A. | Teerlink, Craig | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Chanock, Stephen | Gronberg, Henrik | Haiman, Christopher A. | Kraft, Peter | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2012;22(2):408-415.
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.
doi:10.1093/hmg/dds425
PMCID: PMC3526158  PMID: 23065704
2.  Genome-wide association study identifies a common variant associated with risk of endometrial cancer 
Nature genetics  2011;43(5):451-454.
Endometrial cancer is the most common malignancy of the female genital tract in developed countries. To identify genetic variants associated with endometrial cancer risk, we undertook a genome-wide association study involving 1,265 endometrial cancer cases from Australia and the UK and 5,190 controls from the Wellcome Trust Case Control Consortium. Genotype frequencies in cases and controls were compared for 519,655 SNPs. Forty-seven SNPs that showed evidence of association with endometrial cancer in stage 1 were genotyped in 3,957 additional cases and 6,886 controls. We identified an endometrial cancer susceptibility locus close to HNF1B on chromosome 17q (SNP rs4430796: P=7.1×10−10), that is also associated with risk of prostate cancer and is inversely associated with type 2 diabetes.
doi:10.1038/ng.812
PMCID: PMC3770523  PMID: 21499250
3.  Genome-wide association study identifies five new breast cancer susceptibility loci 
Nature genetics  2010;42(6):504-507.
Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 × 10−7 to P = 3.2 × 10−15). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 × 10−6), 8q24 (rs1562430, P = 5.8 × 10−7) and LSP1 (rs909116, P = 7.3 × 10−7) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
doi:10.1038/ng.586
PMCID: PMC3632836  PMID: 20453838
4.  Haplotype structure in Ashkenazi Jewish BRCA1 and BRCA2 mutation carriers 
Im, Kate M. | Kirchhoff, Tomas | Wang, Xianshu | Green, Todd | Chow, Clement Y. | Vijai, Joseph | Korn, Joshua | Gaudet, Mia M. | Fredericksen, Zachary | Pankratz, V. Shane | Guiducci, Candace | Crenshaw, Andrew | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Mai, Phuong L. | Greene, Mark H. | Piedmonte, Marion | Rubinstein, Wendy S. | Hogervorst, Frans B. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Asperen, Christi J. | Meijers-Heijboer, Hanne E. J. | Van Roozendaal, Cees E. | Caldes, Trinidad | Perez-Segura, Pedro | Jakubowska, Anna | Lubinski, Jan | Huzarski, Tomasz | Blecharz, Paweł | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Barkardottir, Rosa B. | Montagna, Marco | D'Andrea, Emma | Devilee, Peter | Olopade, Olufunmilayo I. | Neuhausen, Susan L. | Peissel, Bernard | Bonanni, Bernardo | Peterlongo, Paolo | Singer, Christian F. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda Ewart | Caligo, Maria Adelaide | Beattie, Mary S. | Chan, Salina | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Timothy R. | Phelan, Catherine | Narod, Steven | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary-Beth | Tung, Nadine | Hansen, Thomas v. O. | Osorio, Ana | Benitez, Javier | Durán, Mercedes | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Platte, Radka | Evans, D. Gareth | Eeles, Ros | Izatt, Louise | Paterson, Joan | Brewer, Carole | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary | Walker, Lisa | Rogers, Mark T. | Side, Lucy E. | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Laitman, Yael | Meindl, Alfons | Deissler, Helmut | Varon-Mateeva, Raymonda | Preisler-Adams, Sabine | Kast, Karin | Venat-Bouvet, Laurence | Stoppa-Lyonnet, Dominique | Chenevix-Trench, Georgia | Easton, Douglas F. | Klein, Robert J. | Daly, Mark J. | Friedman, Eitan | Dean, Michael | Clark, Andrew G. | Altshuler, David M. | Antoniou, Antonis C. | Couch, Fergus J. | Offit, Kenneth | Gold, Bert
Human genetics  2011;130(5):685-699.
Abstract Three founder mutations in BRCA1 and BRCA2 contribute to the risk of hereditary breast and ovarian cancer in Ashkenazi Jews (AJ). They are observed at increased frequency in the AJ compared to other BRCA mutations in Caucasian non-Jews (CNJ). Several authors have proposed that elevated allele frequencies in the surrounding genomic regions reflect adaptive or balancing selection. Such proposals predict long-range linkage dis-equilibrium (LD) resulting from a selective sweep, although genetic drift in a founder population may also act to create long-distance LD. To date, few studies have used the tools of statistical genomics to examine the likelihood of long-range LD at a deleterious locus in a population that faced a genetic bottleneck. We studied the genotypes of hundreds of women from a large international consortium of BRCA1 and BRCA2 mutation carriers and found that AJ women exhibited long-range haplotypes compared to CNJ women. More than 50% of the AJ chromosomes with the BRCA1 185delAG mutation share an identical 2.1 Mb haplotype and nearly 16% of AJ chromosomes carrying the BRCA2 6174delT mutation share a 1.4 Mb haplotype. Simulations based on the best inference of Ashkenazi population demography indicate that long-range haplotypes are expected in the context of a genome-wide survey. Our results are consistent with the hypothesis that a local bottleneck effect from population size constriction events could by chance have resulted in the large haplotype blocks observed at high frequency in the BRCA1 and BRCA2 regions of Ashkenazi Jews.
doi:10.1007/s00439-011-1003-z
PMCID: PMC3196382  PMID: 21597964
5.  How to survive an 11-storey fall 
BMJ Case Reports  2010;2010:bcr0320102850.
Survival from a high fall is rarely possible. We report an unusual case of a patient who fell over 100 ft on to boggy ground and survived. A successful outcome was achieved by the use of aggressive blood product resuscitation and the early application of a pelvic fixator.
doi:10.1136/bcr.03.2010.2850
PMCID: PMC3029988  PMID: 22791478
6.  Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) 
Hein, Rebecca | Maranian, Melanie | Hopper, John L. | Kapuscinski, Miroslaw K. | Southey, Melissa C. | Park, Daniel J. | Schmidt, Marjanka K. | Broeks, Annegien | Hogervorst, Frans B. L. | Bueno-de-Mesquit, H. Bas | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marmee, Frederick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Cordina-Duverger, Emilie | Menegaux, Florence | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Zamora, M. Pilar | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Rahman, Nazneen | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Wang-Gohrke, Shan | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Zalutsky, Iosif V. | Antonenkova, Natalia N. | Bermisheva, Marina | Prokovieva, Darya | Farahtdinova, Albina | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana | Chen, Xiaoqing | Beesley, Jonathan | Investigators, kConFab | Lambrechts, Diether | Zhao, Hui | Neven, Patrick | Wildiers, Hans | Nickels, Stefan | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A. | Severi, Gianluca | Offit, Kenneth | Robson, Mark | Gaudet, Mia M. | Vijai, Joseph | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Figueroa, Jonine D. | García-Closas, Montserrat | Lissowska, Jolanta | Sherman, Mark E. | Hooning, Maartje | Martens, John W. M. | Seynaeve, Caroline | Collée, Margriet | Hall, Per | Humpreys, Keith | Czene, Kamila | Liu, Jianjun | Cox, Angela | Brock, Ian W. | Cross, Simon S. | Reed, Malcolm W. R. | Ahmed, Shahana | Ghoussaini, Maya | Pharoah, Paul DP. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hou, Ming-Feng | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Trentham-Dietz, Amy | Newcomb, Polly A. | Titus, Linda | Egan, Kathleen M. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Humphreys, Manjeet K. | Morrison, Jonathan | Chang-Claude, Jenny | Easton, Douglas F. | Dunning, Alison M.
PLoS ONE  2012;7(10):10.1371/annotation/e5de602c-0ffc-4e6f-a2ed-f79913c2e57c.
doi:10.1371/annotation/e5de602c-0ffc-4e6f-a2ed-f79913c2e57c
PMCID: PMC3525690
7.  Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC) 
Hein, Rebecca | Maranian, Melanie | Hopper, John L. | Kapuscinski, Miroslaw K. | Southey, Melissa C. | Park, Daniel J. | Schmidt, Marjanka K. | Broeks, Annegien | Hogervorst, Frans B. L. | Bueno-de-Mesquit, H. Bas | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Marmee, Frederick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Cordina-Duverger, Emilie | Menegaux, Florence | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Zamora, M. Pilar | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Rahman, Nazneen | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Wang-Gohrke, Shan | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Zalutsky, Iosif V. | Antonenkova, Natalia N. | Bermisheva, Marina | Prokovieva, Darya | Farahtdinova, Albina | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana | Chen, Xiaoqing | Beesley, Jonathan | Investigators, kConFab | Lambrechts, Diether | Zhao, Hui | Neven, Patrick | Wildiers, Hans | Nickels, Stefan | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A. | Severi, Gianluca | Offit, Kenneth | Robson, Mark | Gaudet, Mia M. | Vijai, Joseph | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Figueroa, Jonine D. | García-Closas, Montserrat | Lissowska, Jolanta | Sherman, Mark E. | Hooning, Maartje | Martens, John W. M. | Seynaeve, Caroline | Collée, Margriet | Hall, Per | Humpreys, Keith | Czene, Kamila | Liu, Jianjun | Cox, Angela | Brock, Ian W. | Cross, Simon S. | Reed, Malcolm W. R. | Ahmed, Shahana | Ghoussaini, Maya | Pharoah, Paul DP. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Złowocka, Elżbieta | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hou, Ming-Feng | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Trentham-Dietz, Amy | Newcomb, Polly A. | Titus, Linda | Egan, Kathleen M. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Humphreys, Manjeet K. | Morrison, Jonathan | Chang-Claude, Jenny | Easton, Douglas F. | Dunning, Alison M.
PLoS ONE  2012;7(8):e42380.
The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER−) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26–1.48), p = 7.6×10−14 in Asians and 1.09 (95% CI 1.07–1.11), p = 6.8×10−18 in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19–1.41), p = 1.2×10−9 in Asians and 1.12 (95% CI 1.08–1.17), p = 3.8×10−9 in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER− than ER+ tumours in Europeans [OR (ER−) = 1.20 (95% CI 1.15–1.25), p = 1.8×10−17 versus OR (ER+) = 1.07 (95% CI 1.04–1.1), p = 1.3×10−7, pheterogeneity = 5.1×10−6]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER− tumours.
doi:10.1371/journal.pone.0042380
PMCID: PMC3413660  PMID: 22879957
8.  Seven novel prostate cancer susceptibility loci identified by a multi-stage genome-wide association study 
Kote-Jarai, Zsofia | Olama, Ali Amin Al | Giles, Graham G. | Severi, Gianluca | Schleutker, Johanna | Weischer, Maren | Canzian, Frederico | Riboli, Elio | Key, Tim | Gronberg, Henrik | Hunter, David J. | Kraft, Peter | Thun, Michael J | Ingles, Sue | Chanock, Stephen | Albanes, Demetrius | Hayes, Richard B | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Pharoah, Paul | Schumacher, Fredrick | Henderson, Brian E. | Stanford, Janet L. | Ostrander, Elaine A. | Sorensen, Karina Dalsgaard | Dörk, Thilo | Andriole, Gerald | Dickinson, Joanne L. | Cybulski, Cezary | Lubinski, Jan | Spurdle, Amanda | Clements, Judith A. | Chambers, Suzanne | Aitken, Joanne | Frank Gardiner, R. A. | Thibodeau, Stephen N. | Schaid, Dan | John, Esther M. | Maier, Christiane | Vogel, Walther | Cooney, Kathleen A. | Park, Jong Y. | Cannon-Albright, Lisa | Brenner, Hermann | Habuchi, Tomonori | Zhang, Hong-Wei | Lu, Yong-Jie | Kaneva, Radka | Muir, Ken | Benlloch, Sara | Leongamornlert, Daniel A. | Saunders, Edward J. | Tymrakiewicz, Malgorzata | Mahmud, Nadiya | Guy, Michelle | O’Brien, Lynne T. | Wilkinson, Rosemary A. | Hall, Amanda L. | Sawyer, Emma J. | Dadaev, Tokhir | Morrison, Jonathan | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Christmas, Tim | Ogden, Chris | Cooper, Colin S. | Lophatonanon, Aritaya | Southey, Melissa C. | Hopper, John L. | English, Dallas | Wahlfors, Tiina | Tammela, Teuvo LJ | Klarskov, Peter | Nordestgaard, Børge G. | Røder, M. Andreas | Tybjærg-Hansen, Anne | Bojesen, Stig E. | Travis, Ruth | Campa, Daniele | Kaaks, Rudolf | Wiklund, Fredrik | Aly, Markus | Lindstrom, Sara | Diver, W Ryan | Gapstur, Susan | Stern, Mariana C | Corral, Roman | Virtamo, Jarmo | Cox, Angela | Haiman, Christopher A. | Le Marchand, Loic | FitzGerald, Liesel | Kolb, Suzanne | Kwon, Erika M. | Karyadi, Danielle M. | Orntoft, Torben Falck | Borre, Michael | Meyer, Andreas | Serth, Jürgen | Yeager, Meredith | Berndt, Sonja I. | Marthick, James R | Patterson, Briony | Wokolorczyk, Dominika | Batra, Jyotsna | Lose, Felicity | McDonnell, Shannon K | Joshi, Amit D. | Shahabi, Ahva | Rinckleb, Antje E. | Ray, Ana | Sellers, Thomas A. | Lin, Huo-Yi | Stephenson, Robert A | Farnham, James | Muller, Heiko | Rothenbacher, Dietrich | Tsuchiya, Norihiko | Narita, Shintaro | Cao, Guang-Wen | Slavov, Chavdar | Mitev, Vanio | Easton, Douglas F. | Eeles, Rosalind A.
Nature Genetics  2011;43(8):785-791.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we conducted a multi-stage genome-wide association study and previously reported the results of the first two stages, which identified 16 novel susceptibility loci for PrCa. Here we report the results of stage 3 in which we evaluated 1,536 SNPs in 4,574 cases and 4,164 controls. Ten novel association signals were followed up through genotyping in 51,311 samples in 30 studies through the international PRACTICAL consortium. In addition to previously reported loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2p, 3q, 5p, 6p, 12q and Xq (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.
doi:10.1038/ng.882
PMCID: PMC3396006  PMID: 21743467
9.  Utility of admission physiology in the surgical triage of isolated ballistic battlefield torso trauma 
Background:
An assessment of hemodynamic stability is central to surgical decision-making in the management of battlefield ballistic torso trauma (BBTT).
Aims:
To analyse the utility of admission physiological parameters in characterising hemodynamic stability.
Settings and Design:
A retrospective analysis of consecutive admissions, with BBTT, to forward surgical facility in Afghanistan.
Materials and Methods:
The cohorts’ admission physiology, need for operative intervention, and mortality data were collected retrospectively. The cohort was divided into patients requiring surgery for Life-Threatening Torso Hemorrhage (LTTH) and those not requiring immediate surgery (non-LTTH).
Statistical Analysis:
Parameters were compared using two sample t tests, Mann–Whitney, Fisher's exact, and Chi-square tests. Receiver operator characteristic curves were used to identify significant parameters and determine optimum cut-off values.
Results:
A total of 103 patients with isolated BBTT were identified: 44 in the LTTH group and 59 in the non-LTTH group. The mean New Injury Severity Score ± Standard Deviation (NISS±SD) was 28±14 and 13±12, respectively. The heart rate, systolic blood pressure (SBP), pulse pressure, shock index (SI=heart rate/SBP) and base excess were analysed. SI correlated best with the need for surgical torso hemorrhage control, P<0.05. An optimal cut-off of 0.9 was identified, producing a positive and negative predictive value of 81% and 82%, respectively.
Conclusions:
Shock index (SI) is a useful parameter for helping military surgeons triage BBTT, identifying patients requiring operative torso hemorrhage control. SI performance requires a normal physiological response to hypovolemia, and thus should always be considered in clinical context.
doi:10.4103/0974-2700.99690
PMCID: PMC3440889  PMID: 22988401
Battlefield torso trauma; shock index; trauma surgery; triage
10.  A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population 
Antoniou, Antonis C | Wang, Xianshu | Fredericksen, Zachary S | McGuffog, Lesley | Tarrell, Robert | Sinilnikova, Olga M | Healey, Sue | Morrison, Jonathan | Kartsonaki, Christiana | Lesnick, Timothy | Ghoussaini, Maya | Barrowdale, Daniel | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Eccles, Diana | Evans, D Gareth | Eeles, Ros | Izatt, Louise | Chu, Carol | Douglas, Fiona | Paterson, Joan | Stoppa-Lyonnet, Dominique | Houdayer, Claude | Mazoyer, Sylvie | Giraud, Sophie | Lasset, Christine | Remenieras, Audrey | Caron, Olivier | Hardouin, Agnès | Berthet, Pascaline | Hogervorst, Frans B L | Rookus, Matti A | Jager, Agnes | van den Ouweland, Ans | Hoogerbrugge, Nicoline | van der Luijt, Rob B | Meijers-Heijboer, Hanne | García, Encarna B Gómez | Devilee, Peter | Vreeswijk, Maaike P G | Lubinski, Jan | Jakubowska, Anna | Gronwald, Jacek | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Cybulski, Cezary | Spurdle, Amanda B | Holland, Helene | Goldgar, David E | John, Esther M | Hopper, John L | Southey, Melissa | Buys, Saundra S | Daly, Mary B | Terry, Mary-Beth | Schmutzler, Rita K | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Preisler-Adams, Sabine | Arnold, Norbert | Niederacher, Dieter | Sutter, Christian | Domchek, Susan M | Nathanson, Katherine L | Rebbeck, Timothy | Blum, Joanne L | Piedmonte, Marion | Rodriguez, Gustavo C | Wakeley, Katie | Boggess, John F | Basil, Jack | Blank, Stephanie V | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Andrulis, Irene L | Glendon, Gord | Ozcelik, Hilmi | Kirchhoff, Tomas | Vijai, Joseph | Gaudet, Mia M | Altshuler, David | Guiducci, Candace | Loman, Niklas | Harbst, Katja | Rantala, Johanna | Ehrencrona, Hans | Gerdes, Anne-Marie | Thomassen, Mads | Sunde, Lone | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Viel, Alessandra | Radice, Paolo | Caldes, Trinidad | de la Hoya, Miguel | Singer, Christian F | Fink-Retter, Anneliese | Greene, Mark H | Mai, Phuong L | Loud, Jennifer T | Guidugli, Lucia | Lindor, Noralane M | Hansen, Thomas V O | Nielsen, Finn C | Blanco, Ignacio | Lazaro, Conxi | Garber, Judy | Ramus, Susan J | Gayther, Simon A | Phelan, Catherine | Narod, Stephen | Szabo, Csilla I | Benitez, Javier | Osorio, Ana | Nevanlinna, Heli | Heikkinen, Tuomas | Caligo, Maria A | Beattie, Mary S | Hamann, Ute | Godwin, Andrew K | Montagna, Marco | Casella, Cinzia | Neuhausen, Susan L | Karlan, Beth Y | Tung, Nadine | Toland, Amanda E | Weitzel, Jeffrey | Olopade, Olofunmilayo | Simard, Jacques | Soucy, Penny | Rubinstein, Wendy S | Arason, Adalgeir | Rennert, Gad | Martin, Nicholas G | Montgomery, Grant W | Chang-Claude, Jenny | Flesch-Janys, Dieter | Brauch, Hiltrud | Severi, Gianluca | Baglietto, Laura | Cox, Angela | Cross, Simon S | Miron, Penelope | Gerty, Sue M | Tapper, William | Yannoukakos, Drakoulis | Fountzilas, George | Fasching, Peter A | Beckmann, Matthias W | Silva, Isabel dos Santos | Peto, Julian | Lambrechts, Diether | Paridaens, Robert | Rüdiger, Thomas | Försti, Asta | Winqvist, Robert | Pylkäs, Katri | Diasio, Robert B | Lee, Adam M | Eckel-Passow, Jeanette | Vachon, Celine | Blows, Fiona | Driver, Kristy | Dunning, Alison | Pharoah, Paul P D | Offit, Kenneth | Pankratz, V Shane | Hakonarson, Hakon | Chenevix-Trench, Georgia | Easton, Douglas F | Couch, Fergus J
Nature genetics  2010;42(10):885-892.
Germline BRCA1 mutations predispose to breast cancer. To identify genetic modifiers of this risk, we performed a genome-wide association study in 1,193 individuals with BRCA1 mutations who were diagnosed with invasive breast cancer under age 40 and 1,190 BRCA1 carriers without breast cancer diagnosis over age 35. We took forward 96 SNPs for replication in another 5,986 BRCA1 carriers (2,974 individuals with breast cancer and 3,012 unaffected individuals). Five SNPs on 19p13 were associated with breast cancer risk (Ptrend = 2.3 × 10−9 to Ptrend = 3.9 × 10−7), two of which showed independent associations (rs8170, hazard ratio (HR) = 1.26, 95% CI 1.17–1.35; rs2363956 HR = 0.84, 95% CI 0.80–0.89). Genotyping these SNPs in 6,800 population-based breast cancer cases and 6,613 controls identified a similar association with estrogen receptor–negative breast cancer (rs2363956 per-allele odds ratio (OR) = 0.83, 95% CI 0.75–0.92, Ptrend = 0.0003) and an association with estrogen receptor–positive disease in the opposite direction (OR = 1.07, 95% CI 1.01–1.14, Ptrend = 0.016). The five SNPs were also associated with triple-negative breast cancer in a separate study of 2,301 triple-negative cases and 3,949 controls (Ptrend = 1 × 10−7 to Ptrend = 8 × 10−5; rs2363956 per-allele OR = 0.80, 95% CI 0.74–0.87, Ptrend = 1.1 × 10−7).
doi:10.1038/ng.669
PMCID: PMC3130795  PMID: 20852631
11.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van 't Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
12.  Missense Variants in ATM in 26,101 Breast Cancer Cases and 29,842 Controls 
Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Orr, Nick | Ashworth, Alan | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Waltes, Regina | Bremer, Michael | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D.P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Investigators, kConFab | Group, AOCS | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Ko, Yon-Dschun | Hamann, Ute | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Milne, Roger L. | Benítez, Javier | Arias, José Ignacio | Pita, Guillermo | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang- Gohrke, Shan | Broeks, Annegien | Schmidt, Marjanka K | van Leeuwen, Flora E | Van ‘t Veer, Laura J | Margolin, Sara | Lindblom, Annika | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F. | Peto, Julian
Background
Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious.
Methods
We have genotyped five polymorphic (MAF 0.9% to 2.6%) missense single nucleotide polymorphisms (SNPs) in ATM (S49C, S707P, F858L, P1054R, L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium (BCAC).
Results
Combining data from all five SNPs, the OR was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR=1.06 (Ptrend=0.04). The trend OR among bilateral and familial cases was 1.12 (95% CI 1.02-1.23; Ptrend=0.02).
Conclusions
In this large combined analysis, these 5 missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer.
Impact
Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.
doi:10.1158/1055-9965.EPI-10-0374
PMCID: PMC2938473  PMID: 20826828
13.  Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study 
Milne, Roger L | Gaudet, Mia M | Spurdle, Amanda B | Fasching, Peter A | Couch, Fergus J | Benítez, Javier | Arias Pérez, José Ignacio | Zamora, M Pilar | Malats, Núria | dos Santos Silva, Isabel | Gibson, Lorna J | Fletcher, Olivia | Johnson, Nichola | Anton-Culver, Hoda | Ziogas, Argyrios | Figueroa, Jonine | Brinton, Louise | Sherman, Mark E | Lissowska, Jolanta | Hopper, John L | Dite, Gillian S | Apicella, Carmel | Southey, Melissa C | Sigurdson, Alice J | Linet, Martha S | Schonfeld, Sara J | Freedman, D Michal | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Auvinen, Päivi | Andrulis, Irene L | Glendon, Gord | Knight, Julia A | Weerasooriya, Nayana | Cox, Angela | Reed, Malcolm WR | Cross, Simon S | Dunning, Alison M | Ahmed, Shahana | Shah, Mitul | Brauch, Hiltrud | Ko, Yon-Dschun | Brüning, Thomas | Lambrechts, Diether | Reumers, Joke | Smeets, Ann | Wang-Gohrke, Shan | Hall, Per | Czene, Kamila | Liu, Jianjun | Irwanto, Astrid K | Chenevix-Trench, Georgia | Holland, Helene | Giles, Graham G | Baglietto, Laura | Severi, Gianluca | Bojensen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | John, Esther M | West, Dee W | Whittemore, Alice S | Vachon, Celine | Olson, Janet E | Fredericksen, Zachary | Kosel, Matthew | Hein, Rebecca | Vrieling, Alina | Flesch-Janys, Dieter | Heinz, Judith | Beckmann, Matthias W | Heusinger, Katharina | Ekici, Arif B | Haeberle, Lothar | Humphreys, Manjeet K | Morrison, Jonathan | Easton, Doug F | Pharoah, Paul D | García-Closas, Montserrat | Goode, Ellen L | Chang-Claude, Jenny
Breast Cancer Research : BCR  2010;12(6):R110.
Introduction
Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.
Methods
We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.
Results
These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.
Conclusions
The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.
doi:10.1186/bcr2797
PMCID: PMC3046455  PMID: 21194473
14.  Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark H. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth
PLoS Genetics  2010;6(11):10.1371/annotation/59ea8540-4e63-4f4a-a79e-f68765fdeac7.
doi:10.1371/annotation/59ea8540-4e63-4f4a-a79e-f68765fdeac7
PMCID: PMC2988688
15.  Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark I. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth
PLoS Genetics  2010;6(11):10.1371/annotation/b28cf02d-7196-4a16-8b36-6562a0b84f75.
doi:10.1371/annotation/b28cf02d-7196-4a16-8b36-6562a0b84f75
PMCID: PMC2999983
16.  Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer 
Gaudet, Mia M. | Kirchhoff, Tomas | Green, Todd | Vijai, Joseph | Korn, Joshua M. | Guiducci, Candace | Segrè, Ayellet V. | McGee, Kate | McGuffog, Lesley | Kartsonaki, Christiana | Morrison, Jonathan | Healey, Sue | Sinilnikova, Olga M. | Stoppa-Lyonnet, Dominique | Mazoyer, Sylvie | Gauthier-Villars, Marion | Sobol, Hagay | Longy, Michel | Frenay, Marc | GEMO Study Collaborators,  | Hogervorst, Frans B. L. | Rookus, Matti A. | Collée, J. Margriet | Hoogerbrugge, Nicoline | van Roozendaal, Kees E. P. | Piedmonte, Marion | Rubinstein, Wendy | Nerenstone, Stacy | Van Le, Linda | Blank, Stephanie V. | Caldés, Trinidad | de la Hoya, Miguel | Nevanlinna, Heli | Aittomäki, Kristiina | Lazaro, Conxi | Blanco, Ignacio | Arason, Adalgeir | Johannsson, Oskar T. | Barkardottir, Rosa B. | Devilee, Peter | Olopade, Olofunmilayo I. | Neuhausen, Susan L. | Wang, Xianshu | Fredericksen, Zachary S. | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Viel, Alessandra | Radice, Paolo | Phelan, Catherine M. | Narod, Steven | Rennert, Gad | Lejbkowicz, Flavio | Flugelman, Anath | Andrulis, Irene L. | Glendon, Gord | Ozcelik, Hilmi | Toland, Amanda E. | Montagna, Marco | D'Andrea, Emma | Friedman, Eitan | Laitman, Yael | Borg, Ake | Beattie, Mary | Ramus, Susan J. | Domchek, Susan M. | Nathanson, Katherine L. | Rebbeck, Tim | Spurdle, Amanda B. | Chen, Xiaoqing | Holland, Helene | John, Esther M. | Hopper, John L. | Buys, Saundra S. | Daly, Mary B. | Southey, Melissa C. | Terry, Mary Beth | Tung, Nadine | Overeem Hansen, Thomas V. | Nielsen, Finn C. | Greene, Mark I. | Mai, Phuong L. | Osorio, Ana | Durán, Mercedes | Andres, Raquel | Benítez, Javier | Weitzel, Jeffrey N. | Garber, Judy | Hamann, Ute | Peock, Susan | Cook, Margaret | Oliver, Clare | Frost, Debra | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Ros | Izatt, Louise | Walker, Lisa | Eason, Jacqueline | Barwell, Julian | Godwin, Andrew K. | Schmutzler, Rita K. | Wappenschmidt, Barbara | Engert, Stefanie | Arnold, Norbert | Gadzicki, Dorothea | Dean, Michael | Gold, Bert | Klein, Robert J. | Couch, Fergus J. | Chenevix-Trench, Georgia | Easton, Douglas F. | Daly, Mark J. | Antoniou, Antonis C. | Altshuler, David M. | Offit, Kenneth
PLoS Genetics  2010;6(10):e1001183.
The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10−5 and 39 SNPs had p-values<10−4. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66–0.86, ) and for rs311499 was 0.72 (95% CI 0.61–0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18–1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.
Author Summary
The risk of breast cancer associated with BRCA2 mutations varies widely. To determine whether common genetic variants modify the penetrance of BRCA2 mutations, we conducted the first genome-wide association study of breast cancer among women with BRCA2 mutations using a two-stage approach. The major finding of the study is that only those loci known to be associated with breast cancer risk in the general population, including FGFR2 (rs2981575), modified BRCA2-associated risk in our high-risk population. Two novel loci, on chromosomes 10 in ZNF365 (rs16917302) and chromosome 20 (rs311499), were shown to modify risk in BRCA2 mutation carriers, although not at a genome-wide level of significance. However, the ZNF365 locus has recently independently been associated with breast cancer risk in sporadic tumors, highlighting the potential significance of this zinc finger-containing gene in breast cancer pathogenesis. Our results indicate that it is unlikely that other common variants have a strong modifying effect on BRCA2 penetrance.
doi:10.1371/journal.pgen.1001183
PMCID: PMC2965747  PMID: 21060860
17.  Identification of seven new prostate cancer susceptibility loci through a genome-wide association study 
Eeles, Rosalind A. | Kote-Jarai, Zsofia | Olama, Ali Amin Al | Giles, Graham G. | Guy, Michelle | Severi, Gianluca | Muir, Kenneth | Hopper, John L. | Henderson, Brian E. | Haiman, Christopher A. | Schleutker, Johanna | Hamdy, Freddie C. | Neal, David E. | Donovan, Jenny L. | Stanford, Janet L. | Ostrander, Elaine A. | Ingles, Sue A. | John, Esther M. | Thibodeau, Stephen N. | Schaid, Daniel | Park, Jong Y. | Spurdle, Amanda | Clements, Judith | Dickinson, Joanne L. | Maier, Christiane | Vogel, Walther | Dörk, Thilo | Rebbeck, Timothy R. | Cooney, Kathleen A. | Cannon-Albright, Lisa | Chappuis, Pierre O. | Hutter, Pierre | Zeegers, Maurice | Kaneva, Radka | Zhang, Hong-Wei | Lu, Yong-Jie | Foulkes, William D. | English, Dallas R. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Morrison, Jonathan | Ardern-Jones, Audrey T. | Hall, Amanda L. | O’Brien, Lynne T. | Wilkinson, Rosemary A. | Saunders, Edward J. | Page, Elizabeth C. | Sawyer, Emma J. | Edwards, Stephen M. | Dearnaley, David P. | Horwich, Alan | Huddart, Robert A. | Khoo, Vincent S. | Parker, Christopher C. | Van As, Nicholas | Woodhouse, Christopher J. | Thompson, Alan | Christmas, Tim | Ogden, Chris | Cooper, Colin S. | Southey, Melissa C. | Lophatananon, Artitaya | Liu, Jo-Fen | Kolonel, Laurence N. | Le Marchand, Loic | Wahlfors, Tiina | Tammela, Teuvo L. | Auvinen, Anssi | Lewis, Sarah J. | Cox, Angela | FitzGerald, Liesel M. | Koopmeiners, Joseph S. | Karyadi, Danielle M. | Kwon, Erika M. | Stern, Mariana C. | Corral, Roman | Joshi, Amit D. | Shahabi, Ahva | McDonnell, Shannon K. | Sellers, Thomas A | Pow-Sang, Julio | Chambers, Suzanne | Aitken, Joanne | Gardiner, R.A. (Frank) | Batra, Jyotsna | Kedda, Mary Anne | Lose, Felicity | Polanowski, Andrea | Patterson, Briony | Serth, Jürgen | Meyer, Andreas | Luedeke, Manuel | Stefflova, Klara | Ray, Anna M. | Lange, Ethan M. | Farnham, Jim | Khan, Humera | Slavov, Chavdar | Mitkova, Atanaska | Cao, Guangwen | Easton, Douglas F.
Nature genetics  2009;41(10):1116-1121.
Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33).
doi:10.1038/ng.450
PMCID: PMC2846760  PMID: 19767753
18.  Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042 
Milne, Roger L. | Benítez, Javier | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Arias, José Ignacio | Zamora, M. Pilar | Burwinkel, Barbara | Bartram, Claus R. | Meindl, Alfons | Schmutzler, Rita K. | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W. R. | Southey, Melissa C. | Smith, Letitia | Spurdle, Amanda B. | Hopper, John L. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Dörk, Thilo | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A. E. M. | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Yuqing | Ahmed, Shahana | Dunning, Alison M. | Maranian, Melanie | Pharoah, Paul D. P. | Chenevix-Trench, Georgia | Beesley, Jonathan | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Anton-Culver, Hoda | Ziogas, Argyrios | Brauch, Hiltrud | Justenhoven, Christina | Ko, Yon-Dschun | Haas, Susanne | Fasching, Peter A. | Strick, Reiner | Ekici, Arif B. | Beckmann, Matthias W. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Fletcher, Olivia | Johnson, Nichola | dos Santos Silva, Isabel | Peto, Julian | Turnbull, Clare | Hines, Sarah | Renwick, Anthony | Rahman, Nazneen | Nordestgaard, Børge G. | Bojesen, Stig E. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | García-Closas, Montserrat | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise A. | Chang-Claude, Jenny | Wang-Gohrke, Shan | Shen, Chen-Yang | Wang, Hui-Chun | Yu, Jyh-Cherng | Chen, Sou-Tong | Bermisheva, Marina | Nikolaeva, Tatjana | Khusnutdinova, Elza | Humphreys, Manjeet K. | Morrison, Jonathan | Platte, Radka | Easton, Douglas F.
Background
A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.
Methods
2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.
Results
We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 × 10−19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P ≥ .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P  =  .02). An association was observed for both ER-positive (OR  =  1.14, 95% CI  =  1.10 to 1.17; P = 10−15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 × 10−14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002).
Conclusion
The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
doi:10.1093/jnci/djp167
PMCID: PMC2724850  PMID: 19567422
19.  A genome-wide association study of testicular germ cell tumor 
Nature genetics  2009;41(7):807-810.
We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19–1.58), P = 3 × 10−13), chromosome 6 (OR = 1.50 (95% = CI = 1.28–1.75), P = 10−13) and chromosome 12 (OR = 2.55 (95% CI = 2.05–3.19), P = 10−31). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.
doi:10.1038/ng.394
PMCID: PMC2871592  PMID: 19483681
20.  Association of ESR1 gene tagging SNPs with breast cancer risk 
Dunning, Alison M. | Healey, Catherine S. | Baynes, Caroline | Maia, Ana-Teresa | Scollen, Serena | Vega, Ana | Rodríguez, Raquel | Barbosa-Morais, Nuno L. | Ponder, Bruce A.J. | Low, Yen-Ling | Bingham, Sheila | Haiman, Christopher A. | Le Marchand, Loic | Broeks, Annegien | Schmidt, Marjanka K. | Hopper, John | Southey, Melissa | Beckmann, Matthias W. | Fasching, Peter A. | Peto, Julian | Johnson, Nichola | Bojesen, Stig E. | Nordestgaard, Børge | Milne, Roger L. | Benitez, Javier | Hamann, Ute | Ko, Yon | Schmutzler, Rita K. | Burwinkel, Barbara | Schürmann, Peter | Dörk, Thilo | Heikkinen, Tuomas | Nevanlinna, Heli | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Chen, Xiaoqing | Spurdle, Amanda | Change-Claude, Jenny | Flesch-Janys, Dieter | Couch, Fergus J. | Olson, Janet E. | Severi, Gianluca | Baglietto, Laura | Børresen-Dale, Anne-Lise | Kristensen, Vessela | Hunter, David J. | Hankinson, Susan E. | Devilee, Peter | Vreeswijk, Maaike | Lissowska, Jolanta | Brinton, Louise | Liu, Jianjun | Hall, Per | Kang, Daehee | Yoo, Keun-Young | Shen, Chen-Yang | Yu, Jyh-Cherng | Anton-Culver, Hoda | Ziogoas, Argyrios | Sigurdson, Alice | Struewing, Jeff | Easton, Douglas F. | Garcia-Closas, Montserrat | Humphreys, Manjeet K. | Morrison, Jonathan | Pharoah, Paul D.P. | Pooley, Karen A. | Chenevix-Trench, Georgia
Human Molecular Genetics  2009;18(6):1131-1139.
We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55 000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02–1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.
doi:10.1093/hmg/ddn429
PMCID: PMC2722230  PMID: 19126777
21.  Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 
Ahmed, Shahana | Thomas, Gilles | Ghoussaini, Maya | Healey, Catherine S | Humphreys, Manjeet K | Platte, Radka | Morrison, Jonathan | Maranian, Melanie | Pooley, Karen A | Luben, Robert | Eccles, Diana | Evans, D Gareth | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Peto, Julian | Stratton, Michael R | Rahman, Nazneen | Jacobs, Kevin | Prentice, Ross | Anderson, Garnet L | Rajkovic, Aleksandar | Curb, J David | Ziegler, Regina G | Berg, Christine D | Buys, Saundra S | McCarty, Catherine A | Feigelson, Heather Spencer | Calle, Eugenia E | Thun, Michael J | Diver, W Ryan | Bojesen, Stig | Nordestgaard, Børge G | Flyger, Henrik | Dörk, Thilo | Schürmann, Peter | Hillemanns, Peter | Karstens, Johann H | Bogdanova, Natalia V | Antonenkova, Natalia N | Zalutsky, Iosif V | Bermisheva, Marina | Fedorova, Sardana | Khusnutdinova, Elza | Kang, Daehee | Yoo, Keun-Young | Noh, Dong Young | Ahn, Sei-Hyun | Devilee, Peter | van Asperen, Christi J | Tollenaar, R A E M | Seynaeve, Caroline | Garcia-Closas, Montserrat | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Hopper, John L | Southey, Melissa C | Smith, Letitia | Spurdle, Amanda B | Schmidt, Marjanka K | Broeks, Annegien | van Hien, Richard R | Cornelissen, Sten | Milne, Roger L | Ribas, Gloria | González-Neira, Anna | Benitez, Javier | Schmutzler, Rita K | Burwinkel, Barbara | Bartram, Claus R | Meindl, Alfons | Brauch, Hiltrud | Justenhoven, Christina | Hamann, Ute | Chang-Claude, Jenny | Hein, Rebecca | Wang-Gohrke, Shan | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Hankinson, Susan E | Cox, David G | Kraft, Peter | Vatten, Lars J | Hveem, Kristian | Kumle, Merethe | Sigurdson, Alice | Doody, Michele | Bhatti, Parveen | Alexander, Bruce H | Hooning, Maartje J | van den Ouweland, Ans M W | Oldenburg, Rogier A | Schutte, Mieke | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Yuqing | Cox, Angela | Elliott, Graeme | Brock, Ian | Reed, Malcolm W R | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Giu-Cheng | Chen, Shou-Tung | Anton-Culver, Hoda | Ziogas, Argyrios | Andrulis, Irene L | Knight, Julia A | kConFab | Beesley, Jonathan | Goode, Ellen L | Couch, Fergus | Chenevix-Trench, Georgia | Hoover, Robert N | Ponder, Bruce A J | Hunter, David J | Pharoah, Paul D P | Dunning, Alison M | Chanock, Stephen J | Easton, Douglas F
Nature genetics  2009;41(5):585-590.
Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage1. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08–1.13, P = 4.1 × 10−23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92–0.97, P = 1.4 × 10−8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.
doi:10.1038/ng.354
PMCID: PMC2748125  PMID: 19330027
22.  Five Polymorphisms and Breast Cancer Risk: Results from the Breast Cancer Association Consortium 
Gaudet, Mia M. | Milne, Roger L. | Cox, Angela | Camp, Nicola J. | Goode, Ellen L. | Humphreys, Manjeet K. | Dunning, Alison M. | Morrison, Jonathan | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | English, Dallas R. | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Chang-Claude, Jenny | Flesch-Janys, Dieter | Abbas, Sascha | Salazar, Ramona | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Lindblom, Annika | Margolin, Sara | Heikkinen, Tuomas | Kämpjärvi, Kati | Aaltonen, Kirsimari | Nevanlinna, Heli | Bogdanova, Natalia | Coinac, Irina | Schürmann, Peter | Dörk, Thilo | Bartram, Claus R. | Schmutzler, Rita K. | Tchatchou, Sandrine | Burwinkel, Barbara | Brauch, Hiltrud | Torres, Diana | Hamann, Ute | Justenhoven, Christina | Ribas, Gloria | Arias, José I. | Benitez, Javier | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik L. | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Fasching, Peter A. | Beckmann, Matthias W. | Strick, Reiner | Ekici, Arif B. | Broeks, Annegien | Schmidt, Marjanka K. | van Leeuwen, Flora E. | Van’t Veer, Laura J. | Southey, Melissa C. | Hopper, John L. | Apicella, Carmel | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Kristensen, Vessela | Alnæs, Grethe Grenaker | Hunter, David J. | Kraft, Peter | Cox, David G. | Hankinson, Susan E. | Seynaeve, Caroline | Vreeswijk, Maaike P.G. | Tollenaar, Rob A.E.M. | Devilee, Peter | Chanock, Stephen | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Czene, Kamila | Hall, Per | Li, Yuqing | Liu, Jianjun | Balasubramanian, Sabapathy | Rafii, Saeed | Reed, Malcolm W.R. | Pooley, Karen A. | Conroy, Don | Baynes, Caroline | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Shen, Chen-Yang | Wang, Hui-Chun | Yu, Jyh-Cherng | Wu, Pei-Ei | Anton-Culver, Hoda | Ziogoas, Argyrios | Egan, Kathleen | Newcomb, Polly | Titus-Ernstoff, Linda | Dietz, Amy Trentham | Sigurdson, Alice J. | Alexander, Bruce H. | Bhatti, Parveen | Allen-Brady, Kristina | Cannon-Albright, Lisa A. | Wong, Jathine | Chenevix-Trench, Georgia | Spurdle, Amanda B. | Beesley, Jonathan | Pharoah, Paul D.P. | Easton, Doug F. | Garcia-Closas, Montserrat
Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97–1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95–1.06), 5.0%; CASP10 1.02 (0.98–1.07), 6.5%; PGR 1.02 (0.99–1.06), 15.3%; and BID 0.98 (0.86–1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent.
doi:10.1158/1055-9965.EPI-08-0745
PMCID: PMC2737177  PMID: 19423537
23.  Genome-wide association study identifies novel breast cancer susceptibility loci 
Easton, Douglas F. | Pooley, Karen A. | Dunning, Alison M. | Pharoah, Paul D. P. | Thompson, Deborah | Ballinger, Dennis G. | Struewing, Jeffery P. | Morrison, Jonathan | Field, Helen | Luben, Robert | Wareham, Nicholas | Ahmed, Shahana | Healey, Catherine S. | Bowman, Richard | Meyer, Kerstin B. | Haiman, Christopher A. | Kolonel, Laurence K. | Henderson, Brian E. | Marchand, Loic Le | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Odefrey, Fabrice | Shen, Chen-Yang | Wu, Pei-Ei | Wang, Hui-Chun | Eccles, Diana | Evans, D. Gareth | Peto, Julian | Fletcher, Olivia | Johnson, Nichola | Seal, Sheila | Stratton, Michael R. | Rahman, Nazneen | Chenevix-Trench, Georgia | Bojesen, Stig E. | Nordestgaard, Børge G. | Axelsson, Christen K. | Garcia-Closas, Montserrat | Brinton, Louise | Chanock, Stephen | Lissowska, Jolanta | Peplonska, Beata | Nevanlinna, Heli | Fagerholm, Rainer | Eerola, Hannaleena | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Cox, David G. | Hall, Per | Wedren, Sara | Liu, Jianjun | Low, Yen-Ling | Bogdanova, Natalia | Schürmann, Peter | Dörk, Thilo | Tollenaar, Rob A. E. M. | Jacobi, Catharina E. | Devilee, Peter | Klijn, Jan G. M. | Sigurdson, Alice J. | Doody, Michele M. | Alexander, Bruce H. | Zhang, Jinghui | Cox, Angela | Brock, Ian W. | MacPherson, Gordon | Reed, Malcolm W. R. | Couch, Fergus J. | Goode, Ellen L. | Olson, Janet E. | Meijers-Heijboer, Hanne | van den Ouweland, Ans | Uitterlinden, André | Rivadeneira, Fernando | Milne, Roger L. | Ribas, Gloria | Gonzalez-Neira, Anna | Benitez, Javier | Hopper, John L. | McCredie, Margaret | Southey, Melissa | Giles, Graham G. | Schroen, Chris | Justenhoven, Christina | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana | Day, Nicholas E. | Cox, David R. | Ponder, Bruce A. J. | Luccarini, Craig | Conroy, Don | Shah, Mitul | Munday, Hannah | Jordan, Clare | Perkins, Barbara | West, Judy | Redman, Karen | Driver, Kristy | Aghmesheh, Morteza | Amor, David | Andrews, Lesley | Antill, Yoland | Armes, Jane | Armitage, Shane | Arnold, Leanne | Balleine, Rosemary | Begley, Glenn | Beilby, John | Bennett, Ian | Bennett, Barbara | Berry, Geoffrey | Blackburn, Anneke | Brennan, Meagan | Brown, Melissa | Buckley, Michael | Burke, Jo | Butow, Phyllis | Byron, Keith | Callen, David | Campbell, Ian | Chenevix-Trench, Georgia | Clarke, Christine | Colley, Alison | Cotton, Dick | Cui, Jisheng | Culling, Bronwyn | Cummings, Margaret | Dawson, Sarah-Jane | Dixon, Joanne | Dobrovic, Alexander | Dudding, Tracy | Edkins, Ted | Eisenbruch, Maurice | Farshid, Gelareh | Fawcett, Susan | Field, Michael | Firgaira, Frank | Fleming, Jean | Forbes, John | Friedlander, Michael | Gaff, Clara | Gardner, Mac | Gattas, Mike | George, Peter | Giles, Graham | Gill, Grantley | Goldblatt, Jack | Greening, Sian | Grist, Scott | Haan, Eric | Harris, Marion | Hart, Stewart | Hayward, Nick | Hopper, John | Humphrey, Evelyn | Jenkins, Mark | Jones, Alison | Kefford, Rick | Kirk, Judy | Kollias, James | Kovalenko, Sergey | Lakhani, Sunil | Leary, Jennifer | Lim, Jacqueline | Lindeman, Geoff | Lipton, Lara | Lobb, Liz | Maclurcan, Mariette | Mann, Graham | Marsh, Deborah | McCredie, Margaret | McKay, Michael | McLachlan, Sue Anne | Meiser, Bettina | Milne, Roger | Mitchell, Gillian | Newman, Beth | O'Loughlin, Imelda | Osborne, Richard | Peters, Lester | Phillips, Kelly | Price, Melanie | Reeve, Jeanne | Reeve, Tony | Richards, Robert | Rinehart, Gina | Robinson, Bridget | Rudzki, Barney | Salisbury, Elizabeth | Sambrook, Joe | Saunders, Christobel | Scott, Clare | Scott, Elizabeth | Scott, Rodney | Seshadri, Ram | Shelling, Andrew | Southey, Melissa | Spurdle, Amanda | Suthers, Graeme | Taylor, Donna | Tennant, Christopher | Thorne, Heather | Townshend, Sharron | Tucker, Kathy | Tyler, Janet | Venter, Deon | Visvader, Jane | Walpole, Ian | Ward, Robin | Waring, Paul | Warner, Bev | Warren, Graham | Watson, Elizabeth | Williams, Rachael | Wilson, Judy | Winship, Ingrid | Young, Mary Ann | Bowtell, David | Green, Adele | deFazio, Anna | Chenevix-Trench, Georgia | Gertig, Dorota | Webb, Penny
Nature  2007;447(7148):1087-1093.
Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2>0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P<10−7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P<0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.
doi:10.1038/nature05887
PMCID: PMC2714974  PMID: 17529967
24.  Multiple Loci With Different Cancer Specificities Within the 8q24 Gene Desert 
Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported associations of various genetic variants in 8q24 with susceptibility to breast, prostate, and colorectal cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility genes. To investigate the associations of specific loci within 8q24 with specific cancers, we genotyped the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in four case–control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within this gene desert were specifically associated with risks of different cancers. One block was solely associated with risk of breast cancer, three others were associated solely with the risk of prostate cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not breast cancer. We conclude that there are at least five separate functional variants in this region.
doi:10.1093/jnci/djn190
PMCID: PMC2902819  PMID: 18577746
25.  Seq4SNPs: new software for retrieval of multiple, accurately annotated DNA sequences, ready formatted for SNP assay design 
BMC Bioinformatics  2009;10:180.
Background
In moderate-throughput SNP genotyping there was a gap in the workflow, between choosing a set of SNPs and submitting their sequences to proprietary assay design software, which was not met by existing software. Retrieval and formatting of sequences flanking each SNP, prior to assay design, becomes rate-limiting for more than about ten SNPs, especially if annotated for repetitive regions and adjacent variations. We routinely process up to 50 SNPs at once.
Implementation
We created Seq4SNPs, a web-based, walk-away software that can process one to several hundred SNPs given rs numbers as input. It outputs a file of fully annotated sequences formatted for one of three proprietary design softwares: TaqMan's Primer-By-Design FileBuilder, Sequenom's iPLEX or SNPstream's Autoprimer, as well as unannotated fasta sequences. We found genotyping assays to be inhibited by repetitive sequences or the presence of additional variations flanking the SNP under test, and in multiplexes, repetitive sequence flanking one SNP adversely affects multiple assays. Assay design software programs avoid such regions if the input sequences are appropriately annotated, so we used Seq4SNPs to provide suitably annotated input sequences, and improved our genotyping success rate. Adjacent SNPs can also be avoided, by annotating sequences used as input for primer design.
Conclusion
The accuracy of annotation by Seq4SNPs is significantly better than manual annotation (P < 1e-5).
Using Seq4SNPs to incorporate all annotation for additional SNPs and repetitive elements into sequences, for genotyping assay designer software, minimizes assay failure at the design stage, reducing the cost of genotyping. Seq4SNPs provides a rapid route for replacement of poor test SNP sequences. We routinely use this software for assay sequence preparation.
Seq4SNPs is available as a service at and , currently for human SNPs, but easily extended to include any species in dbSNP.
doi:10.1186/1471-2105-10-180
PMCID: PMC2711078  PMID: 19523221

Results 1-25 (28)