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1.  CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer–Specific Death, and Increased Risk of a Second Breast Cancer 
Journal of Clinical Oncology  2012;30(35):4308-4316.
Purpose
We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer–specific death, and risk of a second breast cancer in women with a first breast cancer.
Patients and Methods
From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer–specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.
Results
CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor–positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer–specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor–positive first breast cancer only.
Conclusion
Among women with estrogen receptor–positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer–specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
doi:10.1200/JCO.2012.42.7336
PMCID: PMC3515767  PMID: 23109706
2.  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
3.  The angiogenic switch occurs at the adenoma stage of the adenoma–carcinoma sequence in colorectal cancer 
Gut  2007;56(10):1426-1432.
Objective
The aim of this study was to examine the relationship between tissue factor (TF), vascular endothelial growth factor (VEGF) and the onset of angiogenesis in the adenoma–carcinoma sequence (ACS), the stepwise process encompassing colorectal cancer (CRC) disease progression.
Patients and methods
210 surgical specimens comprising the ACS were immunohistochemically stained for endothelial cells (CD31), VEGF and TF. Angiogenesis quantified using Chalkley grid analysis (microvascular density; MVD), and VEGF/TF expression were semiquantitatively graded and correlated with standard prognostic indicators including 5 year follow‐up. VEGF and TF were measured by ELISA in tumour specimens and normal mucosa from an additional 90 CRC patients.
Results
There was a significant increase in MVD across the ACS (p < 0.0005) with significant correlations with Dukes' stage (p  =  0.01) and lymph node involvement (p  =  0.02). The greatest increase in MVD was related to the onset of dysplasia, with an associated significant increase in VEGF expression (p < 0.0005). There was a significant relationship between VEGF and TF expression in the initial phase of the ACS (k  =  0.44, p < 0.005), although no correlation between VEGF or TF, and MVD, tumour size, Dukes' classification, lymph node involvement or survival was found.
Conclusions
These findings are the first to suggest that the angiogenic switch occurs at the onset of dysplasia in the ACS, and provide further evidence of the close association between VEGF and TF in the early stages of CRC development.
doi:10.1136/gut.2007.125286
PMCID: PMC2000239  PMID: 17566019
angiogenesis; haemostasis; VEGF; tissue factor; colorectal cancer
5.  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
6.  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
7.  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
8.  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
9.  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
10.  The role of genetic breast cancer susceptibility variants as prognostic factors 
Fasching, Peter A. | Pharoah, Paul D.P. | Cox, Angela | Nevanlinna, Heli | Bojesen, Stig E. | Karn, Thomas | Broeks, Annegien | van Leeuwen, Flora E. | van 't Veer, Laura J. | Udo, Renate | Dunning, Alison M. | Greco, Dario | Aittomäki, Kristiina | Blomqvist, Carl | Shah, Mitul | Nordestgaard, Børge G. | Flyger, Henrik | Hopper, John L. | Southey, Melissa C. | Apicella, Carmel | Garcia-Closas, Montserrat | Sherman, Mark | Lissowska, Jolanta | Seynaeve, Caroline | Huijts, Petra E.A. | Tollenaar, Rob A.E.M. | Ziogas, Argyrios | Ekici, Arif B. | Rauh, Claudia | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Andrulis, Irene L. | Ozcelik, Hilmi | Mulligan, Anna-Marie | Glendon, Gord | Hall, Per | Czene, Kamila | Liu, Jianjun | Chang-Claude, Jenny | Wang-Gohrke, Shan | Eilber, Ursula | Nickels, Stefan | Dörk, Thilo | Schiekel, Maria | Bremer, Michael | Park-Simon, Tjoung-Won | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Hooning, Maartje J. | Martens, John W.M. | Jager, Agnes | Kriege, Mieke | Lindblom, Annika | Margolin, Sara | Couch, Fergus J. | Stevens, Kristen N. | Olson, Janet E. | Kosel, Matthew | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W.R. | Miron, Alexander | John, Esther M. | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Chenevix-Trench, Georgia | Lambrechts, Diether | Dieudonne, Anne-Sophie | Hatse, Sigrid | van Limbergen, Erik | Benitez, Javier | Milne, Roger L. | Zamora, M. Pilar | Pérez, José Ignacio Arias | Bonanni, Bernardo | Peissel, Bernard | Loris, Bernard | Peterlongo, Paolo | Rajaraman, Preetha | Schonfeld, Sara J. | Anton-Culver, Hoda | Devilee, Peter | Beckmann, Matthias W. | Slamon, Dennis J. | Phillips, Kelly-Anne | Figueroa, Jonine D. | Humphreys, Manjeet K. | Easton, Douglas F. | Schmidt, Marjanka K.
Human Molecular Genetics  2012;21(17):3926-3939.
Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P<0.01. The genotypic-specific survival for rs3803662 suggested a recessive mode of action [hazard ratio (HR) of rare homozygous carriers=1.21; 95% CI: 1.09–1.35, P=0.0002 and HR=1.29; 95% CI: 1.12–1.47, P=0.0003 for OS and BCS, respectively]. This association was seen similarly in all analyzed tumor subgroups defined by nodal status, tumor size, grade and estrogen receptor. Breast tumor expression of these genes was not associated with prognosis. With the exception of rs3803662 (TOX3), there was no evidence that any of the SNPs associated with BC susceptibility were associated with the BC survival. Survival may be influenced by a distinct set of germline variants from those influencing susceptibility.
doi:10.1093/hmg/dds159
PMCID: PMC3412377  PMID: 22532573
11.  Associations of ATR and CHEK1 Single Nucleotide Polymorphisms with Breast Cancer 
PLoS ONE  2013;8(7):e68578.
DNA damage and replication checkpoints mediated by the ATR-CHEK1 pathway are key to the maintenance of genome stability, and both ATR and CHEK1 have been proposed as potential breast cancer susceptibility genes. Many novel variants recently identified by the large resequencing projects have not yet been thoroughly tested in genome-wide association studies for breast cancer susceptibility. We therefore used a tagging SNP (tagSNP) approach based on recent SNP data available from the 1000 genomes projects, to investigate the roles of ATR and CHEK1 in breast cancer risk and survival. ATR and CHEK1 tagSNPs were genotyped in the Sheffield Breast Cancer Study (SBCS; 1011 cases and 1024 controls) using Illumina GoldenGate assays. Untyped SNPs were imputed using IMPUTE2, and associations between genotype and breast cancer risk and survival were evaluated using logistic and Cox proportional hazard regression models respectively on a per allele basis. Significant associations were further examined in a meta-analysis of published data or confirmed in the Utah Breast Cancer Study (UBCS). The most significant associations for breast cancer risk in SBCS came from rs6805118 in ATR (p=7.6x10-5) and rs2155388 in CHEK1 (p=3.1x10-6), but neither remained significant after meta-analysis with other studies. However, meta-analysis of published data revealed a weak association between the ATR SNP rs1802904 (minor allele frequency is 12%) and breast cancer risk, with a summary odds ratio (confidence interval) of 0.90 (0.83-0.98) [p=0.0185] for the minor allele. Further replication of this SNP in larger studies is warranted since it is located in the target region of 2 microRNAs. No evidence of any survival effects of ATR or CHEK1 SNPs were identified. We conclude that common alleles of ATR and CHEK1 are not implicated in breast cancer risk or survival, but we cannot exclude effects of rare alleles and of common alleles with very small effect sizes.
doi:10.1371/journal.pone.0068578
PMCID: PMC3700940  PMID: 23844225
12.  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
13.  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
14.  Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium 
Broeks, Annegien | Schmidt, Marjanka K. | Sherman, Mark E. | Couch, Fergus J. | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Smith, Letitia D. | Hammet, Fleur | Southey, Melissa C. | Van ’t Veer, Laura J. | de Groot, Renate | Smit, Vincent T.H.B.M. | Fasching, Peter A. | Beckmann, Matthias W. | Jud, Sebastian | Ekici, Arif B. | Hartmann, Arndt | Hein, Alexander | Schulz-Wendtland, Ruediger | Burwinkel, Barbara | Marme, Frederik | Schneeweiss, Andreas | Sinn, Hans-Peter | Sohn, Christof | Tchatchou, Sandrine | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Ørsted, David D. | Kaur-Knudsen, Diljit | Milne, Roger L. | Pérez, Jose I. Arias | Zamora, Pilar | Rodríguez, Primitiva Menéndez | Benítez, Javier | Brauch, Hiltrud | Justenhoven, Christina | Ko, Yon-Dschun | Hamann, Ute | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Chang-Claude, Jenny | Wang-Gohrke, Shan | Bremer, Michael | Karstens, Johann H. | Hillemanns, Peter | Dörk, Thilo | Nevanlinna, Heli A. | Heikkinen, Tuomas | Heikkilä, Päivi | Blomqvist, Carl | Aittomäki, Kristiina | Aaltonen, Kirsimari | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana M. | Kataja, Vesa | Auvinen, Päivi | Eskelinen, Matti | Soini, Ylermi | Chenevix-Trench, Georgia | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Holland, Helene | Lambrechts, Diether | Claes, Bart | Vandorpe, Thijs | Neven, Patrick | Wildiers, Hans | Flesch-Janys, Dieter | Hein, Rebecca | Löning, Thomas | Kosel, Matthew | Fredericksen, Zachary S. | Wang, Xianshu | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | McLean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Grenaker Alnæs, Grethe | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Hunter, David J. | Hankinson, Susan E. | Andrulis, Irene L. | Marie Mulligan, Anna | O'Malley, Frances P. | Devilee, Peter | Huijts, Petra E.A. | Tollenaar, Rob A.E.M. | Van Asperen, Christi J. | Seynaeve, Caroline S. | Chanock, Stephen J. | Lissowska, Jolanta | Brinton, Louise | Peplonska, Beata | Figueroa, Jonine | Yang, Xiaohong R. | Hooning, Maartje J. | Hollestelle, Antoinette | Oldenburg, Rogier A. | Jager, Agnes | Kriege, Mieke | Ozturk, Bahar | van Leenders, Geert J.L.H. | Hall, Per | Czene, Kamila | Humphreys, Keith | Liu, Jianjun | Cox, Angela | Connley, Daniel | Cramp, Helen E. | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W.R. | Dunning, Alison M. | Easton, Douglas F. | Humphreys, Manjeet K. | Caldas, Carlos | Blows, Fiona | Driver, Kristy | Provenzano, Elena | Lubinski, Jan | Jakubowska, Anna | Huzarski, Tomasz | Byrski, Tomasz | Cybulski, Cezary | Gorski, Bohdan | Gronwald, Jacek | Brennan, Paul | Sangrajrang, Suleeporn | Gaborieau, Valerie | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Hou, Ming-Feng | Huang, Chiun-Sheng | Anton-Culver, Hoda | Ziogas, Argyrios | Pharoah, Paul D.P. | Garcia-Closas, Montserrat
Human Molecular Genetics  2011;20(16):3289-3303.
Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER− tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10−18), rs3803662 (16q12) (P = 3.7 × 10−5), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10−6 and P = 4.1 × 10−4, respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.
doi:10.1093/hmg/ddr228
PMCID: PMC3140824  PMID: 21596841
15.  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
16.  Fine-mapping CASP8 risk variants in Breast Cancer 
Background
Multiple genome-wide and candidate gene association studies have been performed in search of common risk variants for breast cancer. Recent large meta analyses, consolidating evidence from these studies, have been consistent in highlighting the caspase-8 (CASP8) gene as important in this regard. In order to define a risk haplotype and map the CASP8 gene region with respect to underlying susceptibility variant/s, we screened four genes in the CASP8 region on 2q33-q34 for breast cancer risk.
Methods
Two independent data sets from the United Kingdom and the United States, including 3,888 breast cancer cases and controls, were genotyped for 45 tagging single nucleotide polymorphisms (tSNP) in the expanded CASP8 region. SNP and haplotype association tests were carried out using Monte Carlo based methods.
Results
We identified a three-SNP haplotype across rs3834129, rs6723097 and rs3817578 that was significantly associated with breast cancer (p<5×10−6), with a dominant risk ratio and 95% confidence interval of 1.28 (1.21–1.35) and frequency of 0.29 in controls. Evidence for this risk haplotype was extremely consistent across the two study sites and also consistent with previous data.
Conclusions
This three-SNP risk haplotype represents the best characterization so far of the chromosome upon which the susceptibility variant resides.
Impact
Characterization of the risk haplotype provides a strong foundation for re-sequencing efforts to identify the underlying risk variant, which may prove useful for individual-level risk prediction, and provide novel insights into breast carcinogenesis.
doi:10.1158/1055-9965.EPI-11-0845
PMCID: PMC3253962  PMID: 22056502
Single nucleotide polymorphisms; risk haplotype; breast cancer; CASP8; apoptosis pathway
17.  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
18.  7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium 
Milne, Roger L | Lorenzo-Bermejo, Justo | Burwinkel, Barbara | Malats, Núria | Arias, Jose Ignacio | Zamora, M Pilar | Benítez, Javier | Humphreys, Manjeet K | García-Closas, Montserrat | Chanock, Stephen J | Lissowska, Jolanta | Sherman, Mark E | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Nevanlinna, Heli | Heikkinen, Tuomas | Aittomäki, Kristiina | Blomqvist, Carl | Anton-Culver, Hoda | Ziogas, Argyrios | Devilee, Peter | van Asperen, Christie J | Tollenaar, Rob A E M | Seynaeve, Caroline | Hall, Per | Czene, Kamila | Liu, Jianjun | Irwanto, Astrid K | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Couch, Fergus J | Olson, Janet E | Wang, Xianshu | Fredericksen, Zachary | Nordestgaard, Børge G | Bojesen, Stig E | Flyger, Henrik | Margolin, Sara | Lindblom, Annika | Fasching, Peter A | Schulz-Wendtland, Ruediger | Ekici, Arif B | Beckmann, Matthias W | Wang-Gohrke, Shan | Shen, Chen-Yang | Yu, Jyh-Cherng | Hsu, Huan-Ming | Wu, Pei-Ei | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | English, Dallas R | Cox, Angela | Brock, Ian | Elliott, Graeme | Reed, Malcolm W R | Beesley, Jonathan | Chen, Xiaoqing | Fletcher, Olivia | Gibson, Lorna | Silva, Isabel dos Santos | Peto, Julian | Frank, Bernd | Heil, Joerg | Meindl, Alfons | Chang-Claude, Jenny | Hein, Rebecca | Vrieling, Alina | Flesch-Janys, Dieter | Southey, Melissa C | Smith, Letitia | Apicella, Carmel | Hopper, John L | Dunning, Alison M | Pooley, Karen A | Pharoah, Paul D P | Hamann, Ute | Pesch, Beate | Ko, Yon-Dschun | Easton, Douglas F | Chenevix-Trench, Georgia
Journal of Medical Genetics  2011;48(10):698-702.
Background
Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies.
Methods
The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression.
Results
For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p = 0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p = 0.001). The OR was greater at younger ages (p trend = 0.01).
Conclusion
This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
doi:10.1136/jmedgenet-2011-100303
PMCID: PMC3371608  PMID: 21931171
19.  Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies 
Yang, Xiaohong R. | Chang-Claude, Jenny | Goode, Ellen L. | Couch, Fergus J. | Nevanlinna, Heli | Milne, Roger L. | Gaudet, Mia | Schmidt, Marjanka K. | Broeks, Annegien | Cox, Angela | Fasching, Peter A. | Hein, Rebecca | Spurdle, Amanda B. | Blows, Fiona | Driver, Kristy | Flesch-Janys, Dieter | Heinz, Judith | Sinn, Peter | Vrieling, Alina | Heikkinen, Tuomas | Aittomäki, Kristiina | Heikkilä, Päivi | Blomqvist, Carl | Lissowska, Jolanta | Peplonska, Beata | Chanock, Stephen | Figueroa, Jonine | Brinton, Louise | Hall, Per | Czene, Kamila | Humphreys, Keith | Darabi, Hatef | Liu, Jianjun | Van ‘t Veer, Laura J. | van Leeuwen, Flora E. | Andrulis, Irene L. | Glendon, Gord | Knight, Julia A. | Mulligan, Anna Marie | O’Malley, Frances P. | Weerasooriya, Nayana | John, Esther M. | Beckmann, Matthias W. | Hartmann, Arndt | Weihbrecht, Sebastian B. | Wachter, David L. | Jud, Sebastian M. | Loehberg, Christian R. | Baglietto, Laura | English, Dallas R. | Giles, Graham G. | McLean, Catriona A. | Severi, Gianluca | Lambrechts, Diether | Vandorpe, Thijs | Weltens, Caroline | Paridaens, Robert | Smeets, Ann | Neven, Patrick | Wildiers, Hans | Wang, Xianshu | Olson, Janet E. | Cafourek, Victoria | Fredericksen, Zachary | Kosel, Matthew | Vachon, Celine | Cramp, Helen E. | Connley, Daniel | Cross, Simon S. | Balasubramanian, Sabapathy P. | Reed, Malcolm W. R. | Dörk, Thilo | Bremer, Michael | Meyer, Andreas | Karstens, Johann H. | Ay, Aysun | Park-Simon, Tjoung-Won | Hillemanns, Peter | Arias Pérez, Jose Ignacio | Rodríguez, Primitiva Menéndez | Zamora, Pilar | Benítez, Javier | Ko, Yon-Dschun | Fischer, Hans-Peter | Hamann, Ute | Pesch, Beate | Brüning, Thomas | Justenhoven, Christina | Brauch, Hiltrud | Eccles, Diana M. | Tapper, William J. | Gerty, Sue M. | Sawyer, Elinor J. | Tomlinson, Ian P. | Jones, Angela | Kerin, Michael | Miller, Nicola | McInerney, Niall | Anton-Culver, Hoda | Ziogas, Argyrios | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Yang, Show-Lin | Yu, Jyh-Cherng | Chen, Shou-Tung | Hsu, Giu-Cheng | Haiman, Christopher A. | Henderson, Brian E. | Le Marchand, Loic | Kolonel, Laurence N. | Lindblom, Annika | Margolin, Sara | Jakubowska, Anna | Lubiński, Jan | Huzarski, Tomasz | Byrski, Tomasz | Górski, Bohdan | Gronwald, Jacek | Hooning, Maartje J. | Hollestelle, Antoinette | van den Ouweland, Ans M. W. | Jager, Agnes | Kriege, Mieke | Tilanus-Linthorst, Madeleine M. A. | Collée, Margriet | Wang-Gohrke, Shan | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Mononen, Kari | Grip, Mervi | Hirvikoski, Pasi | Winqvist, Robert | Mannermaa, Arto | Kosma, Veli-Matti | Kauppinen, Jaana | Kataja, Vesa | Auvinen, Päivi | Soini, Ylermi | Sironen, Reijo | Bojesen, Stig E. | Dynnes Ørsted, David | Kaur-Knudsen, Diljit | Flyger, Henrik | Nordestgaard, Børge G. | Holland, Helene | Chenevix-Trench, Georgia | Manoukian, Siranoush | Barile, Monica | Radice, Paolo | Hankinson, Susan E. | Hunter, David J. | Tamimi, Rulla | Sangrajrang, Suleeporn | Brennan, Paul | McKay, James | Odefrey, Fabrice | Gaborieau, Valerie | Devilee, Peter | Huijts, P.E.A. | Tollenaar, RAEM. | Seynaeve, C. | Dite, Gillian S. | Apicella, Carmel | Hopper, John L. | Hammet, Fleur | Tsimiklis, Helen | Smith, Letitia D. | Southey, Melissa C. | Humphreys, Manjeet K. | Easton, Douglas | Pharoah, Paul | Sherman, Mark E. | Garcia-Closas, Montserrat
Background
Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors.
Methods
We pooled tumor marker and epidemiological risk factor data from 35 568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case–case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case–control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided.
Results
In case–case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR− than PR+ tumors (P = .001). Nulliparity (P = 3 × 10−6) and increasing age at first birth (P = 2 × 10−9) were less frequent in ER− than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER−/PR− than in ER+/PR+ tumors (P = 1 × 10−7), whereas obesity in older women (>50 years) was less frequent in PR− than in PR+ tumors (P = 6 × 10−4). The triple-negative (ER−/PR−/HER2−) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case–control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR+ tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors.
Conclusions
This study shows that reproductive factors and BMI are most clearly associated with hormone receptor–positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
doi:10.1093/jnci/djq526
PMCID: PMC3107570  PMID: 21191117
20.  The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer 
Journal of Medical Screening  2011;18(4):210-212.
The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50–70 years regularly screened over a ten-year period.
doi:10.1258/jms.2011.011134
PMCID: PMC3266234  PMID: 22184734
21.  Transforming Growth Factor-β and Endoglin Signaling Orchestrate Wound Healing 
Physiological wound healing is a complex process requiring the temporal and spatial co-ordination of various signaling networks, biomechanical forces, and biochemical signaling pathways in both hypoxic and non-hypoxic conditions. Although a plethora of factors are required for successful physiological tissue repair, transforming growth factor beta (TGF-β) expression has been demonstrated throughout wound healing and shown to regulate many processes involved in tissue repair, including production of ECM, proteases, protease inhibitors, migration, chemotaxis, and proliferation of macrophages, fibroblasts of the granulation tissue, epithelial and capillary endothelial cells. TGF-β mediates these effects by stimulating signaling pathways through a receptor complex which contains Endoglin. Endoglin is expressed in a broad spectrum of proliferating and stem cells with elevated expression during hypoxia, and regulates important cellular functions such as proliferation and adhesion via Smad signaling. This review focuses on how the TGF-β family and Endoglin, regulate stem cell availability, and modulate cellular behavior within the wound microenvironment, includes current knowledge of the signaling pathways involved, and explores how this information may be applicable to inflammatory and/or angiogenic diseases such as fibrosis, rheumatoid arthritis and metastatic cancer.
doi:10.3389/fphys.2011.00089
PMCID: PMC3230065  PMID: 22164144
TGFβ; endoglin; wound healing; stem cells; progenitor cells; angiogenesis
22.  Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor–Negative Breast Cancer Survival 
Background
Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival.
Methods
We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case–control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided.
Results
In the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor–negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10−5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10−4).
Conclusion
The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor–negative breast cancer.
doi:10.1093/jnci/djq057
PMCID: PMC2864289  PMID: 20308648
23.  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
24.  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
25.  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

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