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author:("vataja, Vesa")
1.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
2.  Overexpression of MicroRNA-200c Predicts Poor Outcome in Patients with PR-Negative Breast Cancer 
PLoS ONE  2014;9(10):e109508.
Micro-RNAs are small, noncoding RNAs that act as tumor suppressors or oncogenes. MiR-200c is a member of the miR-200 family; it is known to be dysregulated in invasive breast carcinoma. MiR-200c maintains the epithelial-mesenchymal transition and inhibits cell migration and invasion. Recent studies showed that miR-200c regulated steroid hormone receptors, estrogen receptors (ER), and progesterone receptors (PR). The present study aimed to detect miR-200c in 172 invasive breast carcinoma cases selected from a prospective cohort enrolled in Kuopio, Eastern Finland, between 1990 and 1995. MiR-200c expression was determined with relative q-PCR, and results were compared to clinicopathological variables and patient outcome. We found that PR status combined with miR-200c expression was a significant marker of outcome. High miR-200c expression was associated with reduced survival in PR-negative cases (n = 68); low miR-200c expression indicated reduced survival in PR-positive cases (n = 86) (Cox regression: P = 0.002, OR = 3.433; and P = 0.004, OR = 4.176, respectively). In PR-negative cases, high miR-200c expression was associated with shortened relapse-free survival (Cox regression: P = 0.001, OR = 3.613); increased local/distant recurrence (Logistic regression: P = 0.006, OR = 3.965); and more frequent distant metastasis (Logistic regression: P = 0.015, OR = 3.390). We also found that high grade and low stage tumors were positively correlated with high miR-200c expression (Logistic regression for high grade tumors: P = 0.002, OR = 2.791 and for high stage tumors: P = 0.035, OR = 0.285). Our results indicated that miR-200c may play a role in invasive breast carcinoma. Furthermore, miR-200c combined with PR status provided a refined predictor of outcome. In future, a larger study is required to confirm our results. This data may provide a basis for new research target–progesterone receptor–regulated microRNAs in breast cancer.
doi:10.1371/journal.pone.0109508
PMCID: PMC4199599  PMID: 25329395
3.  Confirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer 
Milne, Roger L. | Goode, Ellen L. | García-Closas, Montserrat | Couch, Fergus J. | Severi, Gianluca | Hein, Rebecca | Fredericksen, Zachary | Malats, Núria | Zamora, M. Pilar | Pérez, Jose Ignacio Arias | Benítez, Javier | Dörk, Thilo | Schürmann, Peter | Karstens, Johann H. | Hillemanns, Peter | Cox, Angela | Brock, Ian W. | Elliot, Graeme | Cross, Simon S. | Seal, Sheila | Turnbull, Clare | Renwick, Anthony | Rahman, Nazneen | Shen, Chen-Yang | Yu, Jyh-Cherng | Huang, Chiun-Sheng | Hou, Ming-Feng | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Lambrechts, Diether | Yesilyurt, Betül T. | Floris, Giuseppe | Leunen, Karin | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Chang-Claude, Jenny | Wang-Gohrke, Shan | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Barile, Monica | Giles, Graham G. | Baglietto, Laura | John, Esther M. | Miron, Alexander | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Figueroa, Jonine D. | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Zalutsky, Iosif V. | Rogov, Yuri I. | Fasching, Peter A. | Bayer, Christian M. | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Meindl, Alfons | Heil, Joerg | Bartram, Claus R. | Schmutzler, Rita K. | Thomas, Gilles D. | Hoover, Robert N. | Fletcher, Olivia | Gibson, Lorna J. | Silva, Isabel dos Santos | Peto, Julian | Nickels, Stefan | Flesch-Janys, Dieter | Anton-Culver, Hoda | Ziogas, Argyrios | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Schmidt, Marjanka K. | Broeks, Annegien | Van ‘t Veer, Laura J. | Tollenaar, Rob A.E.M. | Pharoah, Paul D.P. | Dunning, Alison M. | Pooley, Karen A. | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Ahn, Sei-Hyun | Hunter, David J. | Hankinson, Susan E. | Kraft, Peter | Lindstrom, Sara | Chen, Xiaoqing | Beesley, Jonathan | Hamann, Ute | Harth, Volker | Justenhoven, Christina | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Hooning, Maartje | Hollestelle, Antoinette | Oldenburg, Rogier A. | Tilanus-Linthorst, Madeleine | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Farahtdinova, Albina | Olson, Janet E. | Wang, Xianshu | Humphreys, Manjeet K. | Wang, Qin | Chenevix-Trench, Georgia | Easton, Douglas F.
Background
The single nucleotide polymorphism 5p12-rs10941679has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium.
Methods
Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS) and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression.
Results
For white Europeans, the per-allele odds ratio (OR) associated with 5p12-rs10941679 was 1.11 (95% confidence interval [CI] =1.08–1.14, P=7×10−18) for invasive breast cancer and 1.10 (95%CI=1.01–1.21, P=0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR=1.07, 95%CI=0.99–1.15, P=0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR=1.16, 95%CI=1.12–1.20, P=1×10−18 versus OR=1.03, 95%CI=0.99–1.07, P=0.2 for PR-negative disease; P-heterogeneity=2×10−7); heterogeneity by estrogen receptor status was not observed (P=0.2) once PR status was accounted for. The association was also stronger for lower-grade tumors (per-allele OR [95%CI]=1.20 [1.14–1.25], 1.13 [1.09–1.16] and 1.04 [0.99–1.08] for grade 1, 2 and 3/4, respectively; P–trend=5×10−7).
Conclusion
5p12 is a breast cancer susceptibility locus for PR-positive, lower gradebreast cancer.
Impact
Multi-centre fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants.
doi:10.1158/1055-9965.EPI-11-0569
PMCID: PMC4164116  PMID: 21795498
Breast cancer; SNP; susceptibility; disease subtypes
4.  Type II Transmembrane Serine Protease Gene Variants Associate with Breast Cancer 
PLoS ONE  2014;9(7):e102519.
Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer–specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (Ptrend = 0.008–0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004–0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4–5 alleles present compared to 0–2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39–3.94). Women with 6–8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1–3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58–6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer.
doi:10.1371/journal.pone.0102519
PMCID: PMC4100901  PMID: 25029565
5.  Somatic Mutation Profiling and Associations With Prognosis and Trastuzumab Benefit in Early Breast Cancer 
Background
Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset.
Methods
The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)–positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two-sided.
Results
Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (P interaction: DDFS P = .14; OS P = .24).
Conclusions
In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit.
doi:10.1093/jnci/djt121
PMCID: PMC3699437  PMID: 23739063
6.  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
7.  Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene-Environment Interactions 
Schoeps, Anja | Rudolph, Anja | Seibold, Petra | Dunning, Alison M. | Milne, Roger L. | Bojesen, Stig E. | Swerdlow, Anthony | Andrulis, Irene | Brenner, Hermann | Behrens, Sabine | Orr, Nicholas | Jones, Michael | Ashworth, Alan | Li, Jingmei | Cramp, Helen | Connley, Dan | Czene, Kamila | Darabi, Hatef | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Knight, Julia | Glendon, Gord | Mulligan, Anna M. | Dumont, Martine | Severi, Gianluca | Baglietto, Laura | Olson, Janet | Vachon, Celine | Purrington, Kristen | Moisse, Matthieu | Neven, Patrick | Wildiers, Hans | Spurdle, Amanda | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Hamann, Ute | Ko, Yon-Dschun | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Malats, Núria | Arias Perez, JoséI. | Benítez, Javier | Flyger, Henrik | Nordestgaard, Børge G. | Truong, Théresè | Cordina-Duverger, Emilie | Menegaux, Florence | Silva, Isabel dos Santos | Fletcher, Olivia | Johnson, Nichola | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Braaf, Linde | Atsma, Femke | van den Broek, Alexandra J. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Cox, Angela | Simard, Jacques | Giles, Graham G. | Lambrechts, Diether | Mannermaa, Arto | Brauch, Hiltrud | Guénel, Pascal | Peto, Julian | Fasching, Peter A. | Hopper, John | Flesch-Janys, Dieter | Couch, Fergus | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Schmidt, Marjanka K. | Hall, Per | Easton, Douglas F. | Chang-Claude, Jenny
Genetic epidemiology  2013;38(1):84-93.
Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10−07), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m2 (OR = 1.26, 95% CI 1.15–1.38) but not in women with a BMI of 30 kg/m2 or higher (OR = 0.89, 95% CI 0.72–1.11, P for interaction = 3.2 × 10−05). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.
doi:10.1002/gepi.21771
PMCID: PMC3995140  PMID: 24248812
breast cancer risk; gene-environment interaction; polymorphisms; body mass index; case-control study
8.  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
9.  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
10.  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
11.  A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication 
Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values <6 × 10−6 for effect modification of current MHT use. The most significant interaction was observed for rs6707272 (P = 3 × 10−7) on chromosome 2 but was not replicated in the BCAC studies (P = 0.21). The potentially modifying SNPs are in strong linkage disequilibrium with SNPs in TRIP12 and DNER on chromosome 2 and SETBP1 on chromosome 18, previously linked to carcinogenesis. However, none of the interaction effects reached genome-wide significance. The inability to replicate the top SNP × MHT interaction may be due to limited power of the replication phase. Our study, however, suggests that there are unlikely to be SNPs that interact strongly enough with MHT use to be clinically significant in European women.
doi:10.1007/s10549-013-2443-z
PMCID: PMC3781176  PMID: 23423446
Postmenopausal breast cancer risk; Menopausal hormone therapy; Polymorphisms; Gene-environment interaction; Genome-wide association study; Case-only study
12.  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
13.  γ-Secretase Components as Predictors of Breast Cancer Outcome 
PLoS ONE  2013;8(11):e79249.
γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with heterogeneous biochemical and physiological properties. γ-secretase is proposed to have a role in the development and progression of cancer and γ-secretase inhibitors are intensively studied for their probable anti-tumor effects in various types of cancer models. Here, we for the first time determined mRNA expression levels of presenilin-1, presenilin-2, Aph1a, Aph1b, PEN-2, and nicastrin in a set of breast cancer tissue samples (N = 55) by quantitative real-time PCR in order to clarify the clinical significance of the expression of different γ-secretase complex components in breast cancer. We found a high positive correlation between the subunit expression levels implying a common regulation of transcription. Our univariate Kaplan-Meier survival analyses established low expression level of γ-secretase complex as a risk factor for breast cancer specific mortality. The tumors expressing low levels of γ-secretase complex were characterized by high histopathological tumor grade, low or no expression of estrogen and progesterone receptors and consequently high probability to fall into the class of triple negative breast cancer tumors. These results may provide novel tools to further categorize breast cancer tumors, especially the highly aggressive and poorly treatable breast cancer type of triple negative cases, and suggest a significant role for γ-secretase in breast cancer.
doi:10.1371/journal.pone.0079249
PMCID: PMC3815159  PMID: 24223915
14.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
15.  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
16.  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
17.  11q13 is a Susceptibility Locus for Hormone Receptor Positive Breast Cancer† 
Lambrechts, Diether | Truong, Therese | Justenhoven, Christina | Humphreys, Manjeet K. | Wang, Jean | Hopper, John L. | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | van Hien, Richard | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Milne, Roger L. | Zamora, M. Pilar | Arias Pérez, José Ignacio | Benítez, Javier | Hamann, Ute | Ko, Yon-Dschun | Brüning, Thomas | Chang-Claude, Jenny | Eilber, Ursel | Hein, Rebecca | Nickels, Stefan | Flesch-Janys, Dieter | Wang-Gohrke, Shan | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Chenevix-Trench, Georgia | Beesley, Jonathan | Chen, Xiaoqing | Menegaux, Florence | Cordina-Duverger, Emilie | Shen, Chen-Yang | Yu, Jyh-Cherng | Wu, Pei-Ei | Hou, Ming-Feng | Andrulis, Irene L. | Selander, Teresa | Glendon, Gord | Mulligan, Anna Marie | Anton-Culver, Hoda | Ziogas, Argyrios | Muir, Kenneth R. | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Puttawibul, Puttisak | Jones, Michael | Orr, Nicholas | Ashworth, Alan | Swerdlow, Anthony | Severi, Gianluca | Baglietto, Laura | Giles, Graham | Southey, Melissa | Marmé, Federik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Yesilyurt, Betul T. | Neven, Patrick | Paridaens, Robert | Wildiers, Hans | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Schott, Sarah | Bartram, Claus R. | Schmutzler, Rita K. | Cox, Angela | Brock, Ian W. | Elliott, Graeme | Cross, Simon S. | Fasching, Peter A. | Schulz-Wendtland, Ruediger | Ekici, Arif B. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | Silva, Isabel dos Santos | Peto, Julian | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Rogov, Yuri I. | Karstens, Johann H. | Khusnutdinova, Elza | Bermisheva, Marina | Prokofieva, Darya | Gancev, Shamil | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bernard, Loris | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Fredericksen, Zachary | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børresen-Dale, Anne-Lise | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline M. | Hooning, Maartje J. | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Hall, Per | Liu, Jianjun | Czene, Kamila | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Lindblom, Annika | Margolin, Sara | Dunning, Alison M. | Pharoah, Paul D.P. | Easton, Douglas F. | Guénel, Pascal | Brauch, Hiltrud
Human Mutation  2012;33(7):1123-1132.
A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10 and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10−9) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10−39). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
doi:10.1002/humu.22089
PMCID: PMC3370081  PMID: 22461340
breast cancer susceptibility; polymorphisms; genome wide association; risk factors; hormone receptor status; 11q13
18.  The UGT1A6_19_GG genotype is a breast cancer risk factor 
Frontiers in Genetics  2013;4:104.
Validation of an association between the UGT1A6_19_T>G (rs6759892) polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA). An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS), Germany (BBCC), and Sweden (SASBAC). The pooled analysis included 7418 cases and 8720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05–1.22; p = 0.001). The pooled study showed a similar effect (OR 1.09, 95% CI 1.04–1.14; p = 0.001). The risk effect on the basis of allele frequencies was highly significant, the pooled analysis showed an OR of 1.11 (95% CI 1.06–1.16; p = 5.8 × 10−6). We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.
doi:10.3389/fgene.2013.00104
PMCID: PMC3677984  PMID: 23781229
UGT1A6; polymorphism; breast cancer risk; validation; metabolism
19.  Genome-wide association analysis identifies three new breast cancer susceptibility loci 
Ghoussaini, Maya | Fletcher, Olivia | Michailidou, Kyriaki | Turnbull, Clare | Schmidt, Marjanka K | Dicks, Ed | Dennis, Joe | Wang, Qin | Humphreys, Manjeet K | Luccarini, Craig | Baynes, Caroline | Conroy, Don | Maranian, Melanie | Ahmed, Shahana | Driver, Kristy | Johnson, Nichola | Orr, Nicholas | Silva, Isabel dos Santos | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Uitterlinden, Andre G. | Rivadeneira, Fernando | Hall, Per | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Chang-Claude, Jenny | Hein, Rebecca | Nickels, Stefan | Flesch-Janys, Dieter | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Hopper, John L | Apicella, Carmel | Park, Daniel J | Southey, Melissa | Hunter, David J | Chanock, Stephen J | Broeks, Annegien | Verhoef, Senno | Hogervorst, Frans BL | Fasching, Peter A. | Lux, Michael P. | Beckmann, Matthias W. | Ekici, Arif B. | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Bojesen, Stig E | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L. | Alonso, M. Rosario | González-Neira, Anna | Benítez, Javier | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Dur, Christina Clarke | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Justenhoven, Christina | Brauch, Hiltrud | Brüning, Thomas | Wang-Gohrke, Shan | Eilber, Ursula | Dörk, Thilo | Schürmann, Peter | Bremer, Michael | Hillemanns, Peter | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Rogov, Yuri I. | Karstens, Johann H. | Bermisheva, Marina | Prokofieva, Darya | Khusnutdinova, Elza | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Lambrechts, Diether | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Manoukian, Siranoush | Bonanni, Bernardo | Fortuzzi, Stefano | Peterlongo, Paolo | Couch, Fergus J | Wang, Xianshu | Stevens, Kristen | Lee, Adam | Giles, Graham G. | Baglietto, Laura | Severi, Gianluca | McLean, Catriona | Alnæs, Grethe Grenaker | Kristensen, Vessela | Børrensen-Dale, Anne-Lise | John, Esther M. | Miron, Alexander | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Glendon, Gord | Mulligan, Anna Marie | Devilee, Peter | van Asperen, Christie J. | Tollenaar, Rob A.E.M. | Seynaeve, Caroline | Figueroa, Jonine D | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Hooning, Maartje J. | Hollestelle, Antoinette | Oldenburg, Rogier A. | van den Ouweland, Ans M.W. | Cox, Angela | Reed, Malcolm WR | Shah, Mitul | Jakubowska, Ania | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Jones, Michael | Schoemaker, Minouk | Ashworth, Alan | Swerdlow, Anthony | Beesley, Jonathan | Chen, Xiaoqing | Muir, Kenneth R | Lophatananon, Artitaya | Rattanamongkongul, Suthee | Chaiwerawattana, Arkom | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Shen, Chen-Yang | Yu, Jyh-Cherng | Wu, Pei-Ei | Hsiung, Chia-Ni | Perkins, Annie | Swann, Ruth | Velentzis, Louiza | Eccles, Diana M | Tapper, Will J | Gerty, Susan M | Graham, Nikki J | Ponder, Bruce A. J. | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Lathrop, Mark | Dunning, Alison M. | Rahman, Nazneen | Peto, Julian | Easton, Douglas F
Nature genetics  2012;44(3):312-318.
Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ~ 8% of the heritability of the disease. We followed up 72 promising associations from two independent Genome Wide Association Studies (GWAS) in ~70,000 cases and ~68,000 controls from 41 case-control studies and nine breast cancer GWAS. We identified three new breast cancer risk loci on 12p11 (rs10771399; P=2.7 × 10−35), 12q24 (rs1292011; P=4.3×10−19) and 21q21 (rs2823093; P=1.1×10−12). SNP rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) plays a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, while NRIP1 (21q21) encodes an ER co-factor and has a role in the regulation of breast cancer cell growth.
doi:10.1038/ng.1049
PMCID: PMC3653403  PMID: 22267197
20.  Evidence of Gene–Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors 
Nickels, Stefan | Truong, Thérèse | Hein, Rebecca | Stevens, Kristen | Buck, Katharina | Behrens, Sabine | Eilber, Ursula | Schmidt, Martina | Häberle, Lothar | Vrieling, Alina | Gaudet, Mia | Figueroa, Jonine | Schoof, Nils | Spurdle, Amanda B. | Rudolph, Anja | Fasching, Peter A. | Hopper, John L. | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Beckmann, Matthias W. | Ekici, Arif B. | Fletcher, Olivia | Gibson, Lorna | dos Santos Silva, Isabel | Peto, Julian | Humphreys, Manjeet K. | Wang, Jean | Cordina-Duverger, Emilie | Menegaux, Florence | Nordestgaard, Børge G. | Bojesen, Stig E. | Lanng, Charlotte | Anton-Culver, Hoda | Ziogas, Argyrios | Bernstein, Leslie | Clarke, Christina A. | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Harth, Volker | The GENICA Network,  | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | kConFab,  | Group, AOCS Management | Lambrechts, Diether | Smeets, Dominiek | Neven, Patrick | Paridaens, Robert | Flesch-Janys, Dieter | Obi, Nadia | Wang-Gohrke, Shan | Couch, Fergus J. | Olson, Janet E. | Vachon, Celine M. | Giles, Graham G. | Severi, Gianluca | Baglietto, Laura | Offit, Kenneth | John, Esther M. | Miron, Alexander | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Mulligan, Anna Marie | Chanock, Stephen J. | Lissowska, Jolanta | Liu, Jianjun | Cox, Angela | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Dunning, Alison M. | Shah, Mitul | Trentham-Dietz, Amy | Newcomb, Polly | Titus, Linda | Egan, Kathleen | Cahoon, Elizabeth K. | Rajaraman, Preetha | Sigurdson, Alice J. | Doody, Michele M. | Guénel, Pascal | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Hall, Per | Easton, Doug F. | Garcia-Closas, Montserrat | Milne, Roger L. | Chang-Claude, Jenny
PLoS Genetics  2013;9(3):e1003284.
Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer. Data from 24 studies of the Breast Cancer Association Consortium were pooled. Using up to 34,793 invasive breast cancers and 41,099 controls, we examined whether the relative risks associated with 23 single nucleotide polymorphisms were modified by 10 established environmental risk factors (age at menarche, parity, breastfeeding, body mass index, height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, physical activity) in women of European ancestry. We used logistic regression models stratified by study and adjusted for age and performed likelihood ratio tests to assess gene–environment interactions. All statistical tests were two-sided. We replicated previously reported potential interactions between LSP1-rs3817198 and parity (Pinteraction = 2.4×10−6) and between CASP8-rs17468277 and alcohol consumption (Pinteraction = 3.1×10−4). Overall, the per-allele odds ratio (95% confidence interval) for LSP1-rs3817198 was 1.08 (1.01–1.16) in nulliparous women and ranged from 1.03 (0.96–1.10) in parous women with one birth to 1.26 (1.16–1.37) in women with at least four births. For CASP8-rs17468277, the per-allele OR was 0.91 (0.85–0.98) in those with an alcohol intake of <20 g/day and 1.45 (1.14–1.85) in those who drank ≥20 g/day. Additionally, interaction was found between 1p11.2-rs11249433 and ever being parous (Pinteraction = 5.3×10−5), with a per-allele OR of 1.14 (1.11–1.17) in parous women and 0.98 (0.92–1.05) in nulliparous women. These data provide first strong evidence that the risk of breast cancer associated with some common genetic variants may vary with environmental risk factors.
Author Summary
Breast cancer involves combined effects of numerous genetic, environmental, and behavioral risk factors that are unique to each individual. High risk genes, such as BRCA1 and BRCA2, account for only a small proportion of disease occurrence. Recent genome-wide research has identified more than 20 common genetic variants, which individually alter breast cancer risk very moderately. We undertook an international collaborative study to determine whether the effect of these genetic variants vary with environmental factors, such as parity, body mass index (BMI), height, oral contraceptive use, menopausal hormone therapy use, alcohol consumption, cigarette smoking, and physical activity, which are known to affect risk of developing breast cancer. Using pooled data from 24 studies of the Breast Cancer Association Consortium (BCAC), we provide first convincing evidence that the breast cancer risk associated with a genetic variant in LSP1 differs with the number of births and that the risk associated with a CASP8 variant is altered by high alcohol consumption. The effect of an additional genetic variant might also be modified by reproductive factors. This knowledge will stimulate new research towards a better understanding of breast cancer development.
doi:10.1371/journal.pgen.1003284
PMCID: PMC3609648  PMID: 23544014
21.  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
22.  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
23.  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
24.  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
25.  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

Results 1-25 (44)