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1.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
2.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
3.  Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions 
Schoeps, Anja | Rudolph, Anja | Seibold, Petra | Dunning, Alison M. | Milne, Roger L. | Bojesen, Stig E. | Swerdlow, Anthony | Andrulis, Irene | Brenner, Hermann | Behrens, Sabine | Orr, Nicholas | Jones, Michael | Ashworth, Alan | Li, Jingmei | Cramp, Helen | Connley, Dan | Czene, Kamila | Darabi, Hatef | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Knight, Julia | Glendon, Gord | Mulligan, Anna M. | Dumont, Martine | Severi, Gianluca | Baglietto, Laura | Olson, Janet | Vachon, Celine | Purrington, Kristen | Moisse, Matthieu | Neven, Patrick | Wildiers, Hans | Spurdle, Amanda | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Hamann, Ute | Ko, Yon-Dschun | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Malats, Núria | Arias Perez, JoséI. | Benítez, Javier | Flyger, Henrik | Nordestgaard, Børge G. | Truong, Théresè | Cordina-Duverger, Emilie | Menegaux, Florence | Silva, Isabel dos Santos | Fletcher, Olivia | Johnson, Nichola | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Braaf, Linde | Atsma, Femke | van den Broek, Alexandra J. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Cox, Angela | Simard, Jacques | Giles, Graham G. | Lambrechts, Diether | Mannermaa, Arto | Brauch, Hiltrud | Guénel, Pascal | Peto, Julian | Fasching, Peter A. | Hopper, John | Flesch-Janys, Dieter | Couch, Fergus | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Schmidt, Marjanka K. | Hall, Per | Easton, Douglas F. | Chang-Claude, Jenny
Genetic epidemiology  2013;38(1):84-93.
Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.
doi:10.1002/gepi.21771
PMCID: PMC3995140  PMID: 24248812
breast cancer risk; gene-environment interaction; polymorphisms; body mass index; case-control study
4.  Genetic Predisposition to In Situ and Invasive Lobular Carcinoma of the Breast 
Sawyer, Elinor | Roylance, Rebecca | Petridis, Christos | Brook, Mark N. | Nowinski, Salpie | Papouli, Efterpi | Fletcher, Olivia | Pinder, Sarah | Hanby, Andrew | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Swann, Ruth | Dwek, Miriam | Perkins, Katherine-Anne | Gillett, Cheryl | Houlston, Richard | Ross, Gillian | De Ieso, Paolo | Southey, Melissa C. | Hopper, John L. | Provenzano, Elena | Apicella, Carmel | Wesseling, Jelle | Cornelissen, Sten | Keeman, Renske | Fasching, Peter A. | Jud, Sebastian M. | Ekici, Arif B. | Beckmann, Matthias W. | Kerin, Michael J. | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Milne, Roger L. | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Benitez, Javier | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Lochmann, Magdalena | Brauch, Hiltrud | Fischer, Hans-Peter | Ko, Yon-Dschun | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Investigators, kConFab | Lambrechts, Diether | Weltens, Caroline | Van Limbergen, Erik | Hatse, Sigrid | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Bonanni, Bernardo | Volorio, Sara | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Kristensen, Vessela | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Devillee, Peter | Tollenaar, Rob A. E. M. | Seynaeve, Caroline M. | Kriege, Mieke | Figueroa, Jonine | Chanock, Stephen J. | Sherman, Mark E. | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | van Deurzen, Carolien H. M. | Li, Jingmei | Czene, Kamila | Humphreys, Keith | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Shah, Mitul | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Swerdlow, Anthony | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk | Couch, Fergus J. | Hallberg, Emily | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Dunning, Alison M. | Hall, Per | Easton, Doug | Pharoah, Paul | Schmidt, Marjanka K. | Tomlinson, Ian | Garcia-Closas, Montserrat
PLoS Genetics  2014;10(4):e1004285.
Invasive lobular breast cancer (ILC) accounts for 10–15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09–1.18), P = 6.0×10−10; P-het for ILC vs IDC ER+ tumors = 1.8×10−4). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.
Author Summary
Invasive lobular breast cancer (ILC) accounts for 10–15% of invasive breast cancer and is generally ER positive (ER+). To date, none of the genome-wide association studies that have identified loci that predispose to breast cancer in general or to ER+ or ER-negative breast cancer have focused on lobular breast cancer. In this lobular breast cancer study we identified a new variant that appears to be specific to this morphological subtype. We also ascertained which of the known variants predisposes specifically to lobular breast cancer and show for the first time that some of these loci are also associated with lobular carcinoma in situ, a non-obligate precursor of breast cancer and also a risk factor for contralateral breast cancer. Our study shows that the genetic pathways of invasive lobular cancer and ER+ ductal carcinoma mostly overlap, but there are important differences that are likely to provide insights into the biology of lobular breast tumors.
doi:10.1371/journal.pgen.1004285
PMCID: PMC3990493  PMID: 24743323
5.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729
6.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
7.  A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication 
Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
doi:10.1007/s10549-013-2443-z
PMCID: PMC3781176  PMID: 23423446
Postmenopausal breast cancer risk; Menopausal hormone therapy; Polymorphisms; Gene-environment interaction; Genome-wide association study; Case-only study
8.  9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium 
Warren, Helen | Dudbridge, Frank | Fletcher, Olivia | Orr, Nick | Johnson, Nichola | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Mahmoodi, Maryam | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linda M. | Muir, Kenneth R. | Lophatananon, Artitaya | Chaiwerawattana, Arkom | Wiangnon, Surapon | Fasching, Peter A. | Beckmann, Matthias W. | Ekici, Arif B. | Schulz-Wendtland, Ruediger | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Bojesen, Stig E | Nielsen, Sune F. | Flyger, Henrik | Nordestgaard, Børge G | Milne, Roger L. | Benítez, Javier | Arias-Pérez, José-Ignacio | Zamora, M. Pilar | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Langheinz, Anne | Meindl, Alfons | Golatta, Michael | Bartram, Claus R. | Schmutzler, Rita K. | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Yuriy | Bermisheva, Marina | Prokofyeva, Darya | Zinnatullina, Guzel | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Hartikainen, Jaana M. | Kataja, Vesa | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Lambrechts, Diether | Smeets, Ann | Paridaens, Robert | Weltens, Caroline | Flesch-Janys, Dieter | Buck, Katharina | Behrens, Sabine | Peterlongo, Paolo | Bernard, Loris | Manoukian, Siranoush | Radice, Paolo | Couch, Fergus J. | Vachon, Celine | Wang, Xianshu | Olson, Janet | Giles, Graham | Baglietto, Laura | McLean, Cariona A. | Severi, Gianluca | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene L. | Knight, Julia A. | Mulligan, Anna Marie | Weerasooriya, Nayana | Devilee, Peter | Tollenaar, Robert A.E.M. | Martens, John W.M. | Seynaeve, Caroline M. | Hooning, Maartje J. | Hollestelle, Antoinette | Jager, Agnes | Tilanus-Linthorst, Madeleine M.A. | Hall, Per | Czene, Kamila | Liu, Jianjun | Li, Jingmei | Cox, Angela | Cross, Simon S. | Brock, Ian W. | Reed, Malcolm W.R. | Pharoah, Paul | Blows, Fiona M. | Dunning, Alison M. | Ghoussaini, Maya | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Schoemaker, Minouk | Easton, Douglas F. | Humphreys, Manjeet | Wang, Qin | Peto, Julian | dos-Santos-Silva, Isabel
Background
Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).
Methods
To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls).
Results
This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10–29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10–143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10–22) but less strongly, if at all, with ER-negative (ER–) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10–6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors.
Conclusions
This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer.
Impact
The findings further support the view that genetic susceptibility varies according to tumor subtype.
doi:10.1158/1055-9965.EPI-12-0526
PMCID: PMC3772723  PMID: 22859399
9.  Genome-wide association study identifies a novel variant in RAD51B associated with male breast cancer risk 
Nature genetics  2012;44(11):1182-1184.
We conducted a genome-wide association study of male breast cancer using 823 cases and 2,795 controls of European ancestry with validation in independent sample sets totalling 438 cases and 474 controls. A novel variant in RAD51B (14q24.1) was significantly associated with male breast cancer risk (P = 3.02 ×10−13, odds ratio (OR) = 1.57). TOX3 (16q12.1) was also a susceptibility locus (P = 3.87 ×10−15, OR = 1.50).
doi:10.1038/ng.2417
PMCID: PMC3722904  PMID: 23001122
10.  11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer† 
Lambrechts, Diether | Truong, Therese | Justenhoven, Christina | Humphreys, Manjeet K. | Wang, Jean | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | van Hien, Richard | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Milne, Roger L. | Zamora, M. Pilar | Arias Pérez, José Ignacio | Benítez, Javier | Hamann, Ute | Ko, Yon-Dschun | Brüning, Thomas | Chang-Claude, Jenny | Eilber, Ursel | Hein, Rebecca | Nickels, Stefan | Flesch-Janys, Dieter | Wang-Gohrke, Shan | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Menegaux, Florence | Cordina-Duverger, Emilie | Shen, Chen-Yang | Yu, Jyh-Cherng | Wu, Pei-Ei | Hou, Ming-Feng | Andrulis, Irene L. | Selander, Teresa | Glendon, Gord | Mulligan, Anna Marie | Anton-Culver, Hoda | Ziogas, Argyrios | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Jones, Michael | Orr, Nicholas | Ashworth, Alan | Swerdlow, Anthony | Severi, Gianluca | Baglietto, Laura | Giles, Graham | Southey, Melissa | Marmé, Federik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Yesilyurt, Betul T. | Neven, Patrick | Paridaens, Robert | Wildiers, Hans | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Cox, Angela | Brock, Ian W. | Elliott, Graeme | Cross, Simon S. | Fasching, Peter A. | Schulz-Wendtland, Ruediger | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Peto, Julian | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Rogov, Yuri I. | Karstens, Johann H. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Gancev, Shamil | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline M. | Hooning, Maartje J. | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Hall, Per | Liu, Jianjun | Czene, Kamila | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Lindblom, Annika | Margolin, Sara | Dunning, Alison M. | Pharoah, Paul D.P. | Easton, Douglas F. | Guénel, Pascal | Brauch, Hiltrud
Human Mutation  2012;33(7):1123-1132.
A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10−9) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10−39). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
doi:10.1002/humu.22089
PMCID: PMC3370081  PMID: 22461340
breast cancer susceptibility; polymorphisms; genome wide association; risk factors; hormone receptor status; 11q13
11.  Genome-wide association analysis identifies three new breast cancer susceptibility loci 
Ghoussaini, Maya | Fletcher, Olivia | Michailidou, Kyriaki | Turnbull, Clare | Schmidt, Marjanka K | Dicks, Ed | Dennis, Joe | Wang, Qin | Humphreys, Manjeet K | Luccarini, Craig | Baynes, Caroline | Conroy, Don | Maranian, Melanie | Ahmed, Shahana | Driver, Kristy | Johnson, Nichola | Orr, Nicholas | Silva, Isabel dos Santos | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Chang-Claude, Jenny | Hein, Rebecca | Nickels, Stefan | Flesch-Janys, Dieter | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Hopper, John L | Apicella, Carmel | Park, Daniel J | Southey, Melissa | Hunter, David J | Chanock, Stephen J | Broeks, Annegien | Verhoef, Senno | Hogervorst, Frans BL | Fasching, Peter A. | Lux, Michael P. | Beckmann, Matthias W. | Ekici, Arif B. | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L. | Alonso, M. Rosario | González-Neira, Anna | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Justenhoven, Christina | Brauch, Hiltrud | Brüning, Thomas | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Rogov, Yuri I. | Karstens, Johann H. | Bermisheva, Marina | Prokofieva, Darya | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Manoukian, Siranoush | Bonanni, Bernardo | Fortuzzi, Stefano | Peterlongo, Paolo | Couch, Fergus J | Wang, Xianshu | Stevens, Kristen | Lee, Adam | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | McLean, Catriona | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Glendon, Gord | Mulligan, Anna Marie | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Figueroa, Jonine D | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Hooning, Maartje J. | Hollestelle, Antoinette | Oldenburg, Rogier A. | van den Ouweland, Ans M.W. | Cox, Angela | Reed, Malcolm WR | Shah, Mitul | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Jones, Michael | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Beesley, Jonathan | Chen, Xiaoqing | Muir, Kenneth R | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Chaiwerawattana, Arkom | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Shen, Chen-Yang | Yu, Jyh-Cherng | Wu, Pei-Ei | Hsiung, Chia-Ni | Perkins, Annie | Swann, Ruth | Velentzis, Louiza | Eccles, Diana M | Tapper, Will J | Gerty, Susan M | Graham, Nikki J | Ponder, Bruce A. J. | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Lathrop, Mark | Dunning, Alison M. | Rahman, Nazneen | Peto, Julian | Easton, Douglas F
Nature genetics  2012;44(3):312-318.
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth.
doi:10.1038/ng.1049
PMCID: PMC3653403  PMID: 22267197
12.  Common Breast Cancer Susceptibility Variants in LSP1 and RAD51L1 Are Associated with Mammographic Density Measures that Predict Breast Cancer Risk 
Vachon, Celine M. | Scott, Christopher G. | Fasching, Peter A. | Hall, Per | Tamimi, Rulla M. | Li, Jingmei | Stone, Jennifer | Apicella, Carmel | Odefrey, Fabrice | Gierach, Gretchen L. | Jud, Sebastian M. | Heusinger, Katharina | Beckmann, Matthias W. | Pollan, Marina | Fernández-Navarro, Pablo | González-Neira, Anna | Benítez, Javier | van Gils, Carla H. | Lokate, Mariëtte | Onland-Moret, N. Charlotte | Peeters, Petra H.M. | Brown, Judith | Leyland, Jean | Varghese, Jajini S. | Easton, Douglas F. | Thompson, Deborah J. | Luben, Robert N. | Warren, Ruth ML | Wareham, Nicholas J. | Loos, Ruth JF | Khaw, Kay-Tee | Ursin, Giske | Lee, Eunjung | Gayther, Simon A. | Ramus, Susan J. | Eeles, Rosalind A. | Leach, Martin O. | Kwan-Lim, Gek | Couch, Fergus J. | Giles, Graham G. | Baglietto, Laura | Krishnan, Kavitha | Southey, Melissa C. | Le Marchand, Loic | Kolonel, Laurence N. | Woolcott, Christy | Maskarinec, Gertraud | Haiman, Christopher A | Walker, Kate | Johnson, Nichola | McCormack, Valerie A. | Biong, Margarethe | Alnæs, Grethe I.G. | Gram, Inger Torhild | Kristensen, Vessela N. | Børresen-Dale, Anne-Lise | Lindström, Sara | Hankinson, Susan E. | Hunter, David J. | Andrulis, Irene L. | Knight, Julia A. | Boyd, Norman F. | Figueroa, Jonine D. | Lissowska, Jolanta | Wesolowska, Ewa | Peplonska, Beata | Bukowska, Agnieszka | Reszka, Edyta | Liu, JianJun | Eriksson, Louise | Czene, Kamila | Audley, Tina | Wu, Anna H. | Pankratz, V. Shane | Hopper, John L. | dos-Santos-Silva, Isabel
Background
Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biological mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to inter-individual differences in mammographic density measures.
Methods
We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and non-dense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, body mass index (BMI) and menopausal status.
Results
Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (p=0.00005) and adjusted percent density (p=0.001) whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (p=0.003), but not with adjusted dense area (p=0.07).
Conclusion
We identified two common breast cancer susceptibility variants associated with mammographic measures of radio-dense tissue in the breast gland.
Impact
We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association.
doi:10.1158/1055-9965.EPI-12-0066
PMCID: PMC3569092  PMID: 22454379
breast density; breast cancer; genetics; biomarkers; mammography
13.  Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium† 
Figueroa, Jonine D. | Garcia-Closas, Montserrat | Humphreys, Manjeet | Platte, Radka | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Hammet, Fleur | Schmidt, Marjanka K. | Broeks, Annegien | Tollenaar, Rob A.E.M. | Van't Veer, Laura J. | Fasching, Peter A. | Beckmann, Matthias W. | Ekici, Arif B. | Strick, Reiner | Peto, Julian | dos Santos Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Burwinkel, Barbara | Marme, Federik | Schneeweiss, Andreas | Sohn, Christof | Bojesen, Stig | Flyger, Henrik | Nordestgaard, Børge G. | Benítez, Javier | Milne, Roger L. | Ignacio Arias, Jose | Zamora, M. Pilar | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Rahman, Nazneen | Turnbull, Clare | Seal, Sheila | Renwick, Anthony | Brauch, Hiltrud | Justenhoven, Christina | Brüning, Thomas | Chang-Claude, Jenny | Hein, Rebecca | Wang-Gohrke, Shan | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Yuri I. | Karstens, Johann Hinrich | Bermisheva, Marina | Prokofieva, Darya | Hanafievich Gantcev, Shamil | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Soini, Ylermi | Kataja, Vesa | Lambrechts, Diether | Yesilyurt, Betül T. | Chrisiaens, Marie-Rose | Peeters, Stephanie | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Couch, Fergus | Lee, Adam M. | Diasio, Robert | Wang, Xianshu | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Maclean, Catriona | Offit, Ken | Robson, Mark | Joseph, Vijai | Gaudet, Mia | John, Esther M. | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Andrulis, Irene | Knight, Julia A. | Marie Mulligan, Anna | O'Malley, Frances P. | Brinton, Louise A. | Sherman, Mark E. | Lissowska, Jolanta | Chanock, Stephen J. | Hooning, Maartje | Martens, John W.M. | van den Ouweland, Ans M.W. | Collée, J. Margriet | Hall, Per | Czene, Kamila | Cox, Angela | Brock, Ian W. | Reed, Malcolm W.R. | Cross, Simon S. | Pharoah, Paul | Dunning, Alison M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Shen, Chen-Yang | Ding, Shian-ling | Hsu, Huan-Ming | Yu, Jyh-Cherng | Anton-Culver, Hoda | Ziogas, Argyrios | Ashworth, Alan | Swerdlow, Anthony | Jones, Michael | Orr, Nick | Trentham-Dietz, Amy | Egan, Kathleen | Newcomb, Polly | Titus-Ernstoff, Linda | Easton, Doug | Spurdle, Amanda B.
Human Molecular Genetics  2011;20(23):4693-4706.
A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r2= 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10–1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98–1.07, case-only P-heterogeneity = 7.6 × 10−5]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P= 6.7 × 10−3) and lobular histology (case-only P= 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.
doi:10.1093/hmg/ddr368
PMCID: PMC3209823  PMID: 21852249
14.  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
15.  19p13.1 is a triple negative-specific breast cancer susceptibility locus 
Stevens, Kristen N. | Fredericksen, Zachary | Vachon, Celine M. | Wang, Xianshu | Margolin, Sara | Lindblom, Annika | Nevanlinna, Heli | Greco, Dario | Aittomäki, Kristiina | Blomqvist, Carl | Chang-Claude, Jenny | Vrieling, Alina | Flesch-Janys, Dieter | Sinn, Hans-Peter | Wang-Gohrke, Shan | Nickels, Stefan | Brauch, Hiltrud | Ko, Yon-Dschun | Fischer, Hans-Peter | Schmutzler, Rita K. | Meindl, Alfons | Bartram, Claus R. | Schott, Sarah | Engel, Christof | Godwin, Andrew K. | Weaver, JoEllen | Pathak, Harsh B. | Sharma, Priyanka | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Miron, Penelope | Yannoukakos, Drakoulis | Stavropoulou, Alexandra | Fountzilas, George | Gogas, Helen J. | Swann, Ruth | Dwek, Miriam | Perkins, Annie | Milne, Roger L. | Benítez, Javier | Zamora, M Pilar | Pérez, José Ignacio Arias | Bojesen, Stig E. | Nielsen, Sune F. | Nordestgaard, Børge G | Flyger, Henrik | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Cordina-Duverger, Emilie | Burwinkel, Barbara | Marmé, Frederick | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael J. | Peto, Julian | Johnson, Nichola | Fletcher, Olivia | Silva, Isabel dos Santos | Fasching, Peter A. | Beckmann, Matthias W. | Hartmann, Arndt | Ekici, Arif B. | Lophatananon, Artitaya | Muir, Kenneth | Puttawibul, Puttisak | Wiangnon, Surapon | Schmidt, Marjanka K | Broeks, Annegien | Braaf, Linde M | Rosenberg, Efraim H | Hopper, John L. | Apicella, Carmel | Park, Daniel J. | Southey, Melissa C. | Swerdlow, Anthony J. | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Hsiung, Chia-Ni | Hamann, Ute | Dünnebier, Thomas | Rüdiger, Thomas | Ulmer, Hans Ulrich | Pharoah, Paul P. | Dunning, Alison M | Humphreys, Manjeet K. | Wang, Qin | Cox, Angela | Cross, Simon S. | Reed, Malcom W. | Hall, Per | Czene, Kamila | Ambrosone, Christine B. | Ademuyiwa, Foluso | Hwang, Helena | Eccles, Diana M. | Garcia-Closas, Montserrat | Figueroa, Jonine D. | Sherman, Mark E. | Lissowska, Jolanta | Devilee, Peter | Seynaeve, Caroline | Tollenaar, R.A.E.M. | Hooning, Maartje J. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | John, Esther M. | Miron, Alexander | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Giles, Graham G. | Baglietto, Laura | McLean, Catriona A | Severi, Gianluca | Kosel, Matthew L. | Pankratz, V.S. | Slager, Susan | Olson, Janet E. | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Lambrechts, Diether | Hatse, Sigrid | Dieudonne, Anne-Sophie | Christiaens, Marie-Rose | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Mannermaa, Arto | Kosma, Veli-Matti | Hartikainen, Jaana M. | Soini, Ylermi | Easton, Douglas F. | Couch, Fergus J.
Cancer Research  2012;72(7):1795-1803.
The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
doi:10.1158/0008-5472.CAN-11-3364
PMCID: PMC3319792  PMID: 22331459
genetic susceptibility; association study; subtype; neoplasms; common variant
16.  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
17.  Estimating causal effects of genetic risk variants for breast cancer using marker data from bilateral and familial cases 
Background
Cases with a family history are enriched for genetic risk variants, and the power of association studies can be improved by selecting cases with a family history of disease. However in recent genome-wide association scans utilising familial sampling, the excess relative risk for familial cases is less than predicted when compared to unselected cases. This can be explained by incomplete linkage disequilibrium between the tested marker and the underlying causal variant.
Methods
We show that the allele frequency and effect size of the underlying causal variant can be estimated by combining marker data from studies that ascertain cases based on different family histories. This allows us to learn about the genetic architecture of a complex trait, without having identified any causal variants. We consider several validated common marker alleles for breast cancer, using our own study of high risk, predominantly bilateral cases, cases preferentially selected to have at least two affected first or second degree relatives, and published estimates of relative risk from standard case/control studies.
Results
To obtain realistic estimates and to accommodate some prior beliefs, we use Bayesian estimation to infer that the causal variants are probably common, with minor allele frequency >5%, and have small effects, with relative risk around 1.2.
Conclusion
These results strongly support the common disease common variant hypothesis for these specific loci associated with breast cancer.
Impact
Our results agree with recent assertions that synthetic associations of rare variants are unlikely to account for most associations seen in genome-wide studies.
doi:10.1158/1055-9965.EPI-11-0719
PMCID: PMC3272480  PMID: 22028405
Breast cancer; family history; ascertainment bias; causal variant; synthetic association
18.  Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2 
Kirchhoff, Tomas | Gaudet, Mia M. | Antoniou, Antonis C. | McGuffog, Lesley | Humphreys, Manjeet K. | Dunning, Alison M. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Dork, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Couch, Fergus J. | Olson, Janet | Vachon, Celine | Wang, Xianshu | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W.R. | Burwinkel, Barbara | Meindl, Alfons | Brauch, Hiltrud | Hamann, Ute | Ko, Yon-Dschun | Broeks, Annegien | Schmidt, Marjanka K. | Van ‘t Veer, Laura J. | Braaf, Linde M. | Johnson, Nichola | Fletcher, Olivia | Gibson, Lorna | Peto, Julian | Turnbull, Clare | Seal, Sheila | Renwick, Anthony | Rahman, Nazneen | Wu, Pei-Ei | Yu, Jyh-Cherng | Hsiung, Chia-Ni | Shen, Chen-Yang | Southey, Melissa C. | Hopper, John L. | Hammet, Fleur | Van Dorpe, Thijs | Dieudonne, Anne-Sophie | Hatse, Sigrid | Lambrechts, Diether | Andrulis, Irene L. | Bogdanova, Natalia | Antonenkova, Natalia | Rogov, Juri I. | Prokofieva, Daria | Bermisheva, Marina | Khusnutdinova, Elza | van Asperen, Christi J. | Tollenaar, Robert A.E.M. | Hooning, Maartje J. | Devilee, Peter | Margolin, Sara | Lindblom, Annika | Milne, Roger L. | Arias, José Ignacio | Zamora, M. Pilar | Benítez, Javier | Severi, Gianluca | Baglietto, Laura | Giles, Graham G. | kConFab,  | Group, AOCS Study | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Holland, Helene | Healey, Sue | Wang-Gohrke, Shan | Chang-Claude, Jenny | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Agnarsson, Bjarni A. | Caligo, Maria A. | Godwin, Andrew K. | Nevanlinna, Heli | Heikkinen, Tuomas | Fredericksen, Zachary | Lindor, Noralane | Nathanson, Katherine L. | Domchek, Susan M. | SWE-BRCA,  | Loman, Niklas | Karlsson, Per | Askmalm, Marie Stenmark | Melin, Beatrice | von Wachenfeldt, Anna | HEBON,  | Hogervorst, Frans B. L. | Verheus, Martijn | Rookus, Matti A. | Seynaeve, Caroline | Oldenburg, Rogier A. | Ligtenberg, Marjolijn J. | Ausems, Margreet G.E.M. | Aalfs, Cora M. | Gille, Hans J.P. | Wijnen, Juul T. | Gómez García, Encarna B. | EMBRACE,  | Peock, Susan | Cook, Margaret | Oliver, Clare T. | Frost, Debra | Luccarini, Craig | Pichert, Gabriella | Davidson, Rosemarie | Chu, Carol | Eccles, Diana | Ong, Kai-Ren | Cook, Jackie | Douglas, Fiona | Hodgson, Shirley | Evans, D. Gareth | Eeles, Rosalind | Gold, Bert | Pharoah, Paul D.P. | Offit, Kenneth | Chenevix-Trench, Georgia | Easton, Douglas F.
PLoS ONE  2012;7(6):e35706.
Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80–1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
doi:10.1371/journal.pone.0035706
PMCID: PMC3387216  PMID: 22768030
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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