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1.  PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS 
Southey, Melissa C | Goldgar, David E | Winqvist, Robert | Pylkäs, Katri | Couch, Fergus | Tischkowitz, Marc | Foulkes, William D | Dennis, Joe | Michailidou, Kyriaki | van Rensburg, Elizabeth J | Heikkinen, Tuomas | Nevanlinna, Heli | Hopper, John L | Dörk, Thilo | Claes, Kathleen BM | Reis-Filho, Jorge | Teo, Zhi Ling | Radice, Paolo | Catucci, Irene | Peterlongo, Paolo | Tsimiklis, Helen | Odefrey, Fabrice A | Dowty, James G | Schmidt, Marjanka K | Broeks, Annegien | Hogervorst, Frans B | Verhoef, Senno | Carpenter, Jane | Clarke, Christine | Scott, Rodney J | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federik | Burwinkel, Barbara | Yang, Rongxi | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Bojesen, Stig | Nielsen, Sune F | Flyger, Henrik | Benitez, Javier | Zamora, M Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan | Ziogas, Argyrios | Clarke, Christina A | Brenner, Hermann | Arndt, Volker | Stegmaier, Christa | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Bogdanova, Natalia V | Antonenkova, Natalia N | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Spurdle, Amanda B | Wauters, Els | Smeets, Dominiek | Beuselinck, Benoit | Floris, Giuseppe | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Olson, Janet E | Vachon, Celine | Pankratz, Vernon S | McLean, Catriona | Haiman, Christopher A | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Kristensen, Vessela | Alnæs, Grethe Grenaker | Zheng, Wei | Hunter, David J | Lindstrom, Sara | Hankinson, Susan E | Kraft, Peter | Andrulis, Irene | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Jukkola-Vuorinen, Arja | Grip, Mervi | Kauppila, Saila | Devilee, Peter | Tollenaar, Robert A E M | Seynaeve, Caroline | Hollestelle, Antoinette | Garcia-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J | Lissowska, Jolanta | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Eccles, Diana M | Rafiq, Sajjad | Tapper, William J | Gerty, Sue M | Hooning, Maartje J | Martens, John W M | Collée, J Margriet | Tilanus-Linthorst, Madeleine | Hall, Per | Li, Jingmei | Brand, Judith S | Humphreys, Keith | Cox, Angela | Reed, Malcolm W R | Luccarini, Craig | Baynes, Caroline | Dunning, Alison M | Hamann, Ute | Torres, Diana | Ulmer, Hans Ulrich | Rüdiger, Thomas | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Slager, Susan | Toland, Amanda E | Ambrosone, Christine B | Yannoukakos, Drakoulis | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Álvarez, Nuria | Herrero, Daniel | Tessier, Daniel C | Vincent, Daniel | Bacot, Francois | Simard, Jacques | Dumont, Martine | Soucy, Penny | Eeles, Rosalind | Muir, Kenneth | Wiklund, Fredrik | Gronberg, Henrik | Schleutker, Johanna | Nordestgaard, Børge G | Weischer, Maren | Travis, Ruth C | Neal, David | Donovan, Jenny L | Hamdy, Freddie C | Khaw, Kay-Tee | Stanford, Janet L | Blot, William J | Thibodeau, Stephen | Schaid, Daniel J | Kelley, Joseph L | Maier, Christiane | Kibel, Adam S | Cybulski, Cezary | Cannon-Albright, Lisa | Butterbach, Katja | Park, Jong | Kaneva, Radka | Batra, Jyotsna | Teixeira, Manuel R | Kote-Jarai, Zsofia | Al Olama, Ali Amin | Benlloch, Sara | Renner, Stefan P | Hartmann, Arndt | Hein, Alexander | Ruebner, Matthias | Lambrechts, Diether | Van Nieuwenhuysen, Els | Vergote, Ignace | Lambretchs, Sandrina | Doherty, Jennifer A | Rossing, Mary Anne | Nickels, Stefan | Eilber, Ursula | Wang-Gohrke, Shan | Odunsi, Kunle | Sucheston-Campbell, Lara E | Friel, Grace | Lurie, Galina | Killeen, Jeffrey L | Wilkens, Lynne R | Goodman, Marc T | Runnebaum, Ingo | Hillemanns, Peter A | Pelttari, Liisa M | Butzow, Ralf | Modugno, Francesmary | Edwards, Robert P | Ness, Roberta B | Moysich, Kirsten B | du Bois, Andreas | Heitz, Florian | Harter, Philipp | Kommoss, Stefan | Karlan, Beth Y | Walsh, Christine | Lester, Jenny | Jensen, Allan | Kjaer, Susanne Krüger | Høgdall, Estrid | Peissel, Bernard | Bonanni, Bernardo | Bernard, Loris | Goode, Ellen L | Fridley, Brooke L | Vierkant, Robert A | Cunningham, Julie M | Larson, Melissa C | Fogarty, Zachary C | Kalli, Kimberly R | Liang, Dong | Lu, Karen H | Hildebrandt, Michelle A T | Wu, Xifeng | Levine, Douglas A | Dao, Fanny | Bisogna, Maria | Berchuck, Andrew | Iversen, Edwin S | Marks, Jeffrey R | Akushevich, Lucy | Cramer, Daniel W | Schildkraut, Joellen | Terry, Kathryn L | Poole, Elizabeth M | Stampfer, Meir | Tworoger, Shelley S | Bandera, Elisa V | Orlow, Irene | Olson, Sara H | Bjorge, Line | Salvesen, Helga B | van Altena, Anne M | Aben, Katja K H | Kiemeney, Lambertus A | Massuger, Leon F A G | Pejovic, Tanja | Bean, Yukie | Brooks-Wilson, Angela | Kelemen, Linda E | Cook, Linda S | Le, Nhu D | Górski, Bohdan | Gronwald, Jacek | Menkiszak, Janusz | Høgdall, Claus K | Lundvall, Lene | Nedergaard, Lotte | Engelholm, Svend Aage | Dicks, Ed | Tyrer, Jonathan | Campbell, Ian | McNeish, Iain | Paul, James | Siddiqui, Nadeem | Glasspool, Rosalind | Whittemore, Alice S | Rothstein, Joseph H | McGuire, Valerie | Sieh, Weiva | Cai, Hui | Shu, Xiao-Ou | Teten, Rachel T | Sutphen, Rebecca | McLaughlin, John R | Narod, Steven A | Phelan, Catherine M | Monteiro, Alvaro N | Fenstermacher, David | Lin, Hui-Yi | Permuth, Jennifer B | Sellers, Thomas A | Chen, Y Ann | Tsai, Ya-Yu | Chen, Zhihua | Gentry-Maharaj, Aleksandra | Gayther, Simon A | Ramus, Susan J | Menon, Usha | Wu, Anna H | Pearce, Celeste L | Van Den Berg, David | Pike, Malcolm C | Dansonka-Mieszkowska, Agnieszka | Plisiecka-Halasa, Joanna | Moes-Sosnowska, Joanna | Kupryjanczyk, Jolanta | Pharoah, Paul DP | Song, Honglin | Winship, Ingrid | Chenevix-Trench, Georgia | Giles, Graham G | Tavtigian, Sean V | Easton, Doug F | Milne, Roger L
Journal of medical genetics  2016;53(12):800-811.
Background
The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.
Methods
We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.
Results
For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.
Conclusions
This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
doi:10.1136/jmedgenet-2016-103839
PMCID: PMC5200636  PMID: 27595995
2.  rs2735383, located at a microRNA binding site in the 3’UTR of NBS1, is not associated with breast cancer risk 
Liu, Jingjing | Lončar, Ivona | Collée, J. Margriet | Bolla, Manjeet K. | Dennis, Joe | Michailidou, Kyriaki | Wang, Qin | Andrulis, Irene L. | Barile, Monica | Beckmann, Matthias W. | Behrens, Sabine | Benitez, Javier | Blomqvist, Carl | Boeckx, Bram | Bogdanova, Natalia V. | Bojesen, Stig E. | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Broeks, Annegien | Burwinkel, Barbara | Chang-Claude, Jenny | Chen, Shou-Tung | Chenevix-Trench, Georgia | Cheng, Ching Y. | Choi, Ji-Yeob | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Cuk, Katarina | Czene, Kamila | Dörk, Thilo | dos-Santos-Silva, Isabel | Fasching, Peter A. | Figueroa, Jonine | Flyger, Henrik | García-Closas, Montserrat | Giles, Graham G. | Glendon, Gord | Goldberg, Mark S. | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hart, Steven N. | Hartman, Mikael | Hatse, Sigrid | Hopper, John L. | Ito, Hidemi | Jakubowska, Anna | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela N. | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lophatananon, Artitaya | Jan Lubinski,  | Mannermaa, Arto | Matsuo, Keitaro | Milne, Roger L. | Neuhausen, Susan L. | Nevanlinna, Heli | Orr, Nick | Perez, Jose I. A. | Peto, Julian | Putti, Thomas C. | Pylkäs, Katri | Radice, Paolo | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schneeweiss, Andreas | Shen, Chen-Yang | Shrubsole, Martha J. | Shu, Xiao-Ou | Simard, Jacques | Southey, Melissa C. | Swerdlow, Anthony | Teo, Soo H. | Tessier, Daniel C. | Thanasitthichai, Somchai | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-Chen | Vachon, Celine | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Zheng, Wei | Hall, Per | Dunning, Alison M. | Easton, Douglas F. | Hooning, Maartje J. | van den Ouweland, Ans M. W. | Martens, John W. M. | Hollestelle, Antoinette
Scientific Reports  2016;6:36874.
NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3′-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936–1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969–1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905–1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.
doi:10.1038/srep36874
PMCID: PMC5109293  PMID: 27845421
3.  FANCM c.5101C>T mutation associates with breast cancer survival and treatment outcome 
International Journal of Cancer  2016;139(12):2760-2770.
Breast cancer (BC) is a heterogeneous disease, and different tumor characteristics and genetic variation may affect the clinical outcome. The FANCM c.5101C > T nonsense mutation in the Finnish population associates with increased risk of breast cancer, especially for triple‐negative breast cancer patients. To investigate the association of the mutation with disease prognosis, we studied tumor phenotype, treatment outcome, and patient survival in 3,933 invasive breast cancer patients, including 101 FANCM c.5101C > T mutation carriers and 3,832 non‐carriers. We also examined association of the mutation with nuclear immunohistochemical staining of DNA repair markers in 1,240 breast tumors. The FANCM c.5101C > T mutation associated with poor 10‐year breast cancer‐specific survival (hazard ratio (HR)=1.66, 95% confidence interval (CI) 1.09–2.52, p = 0.018), with a more pronounced survival effect among familial cases (HR = 2.93, 95% CI 1.5–5.76, p = 1.80 × 10−3). Poor disease outcome of the carriers was also found among the estrogen receptor (ER) positive subgroup of patients (HR = 1.8, 95% CI 1.09–2.98, p = 0.021). Reduced survival was seen especially among patients who had not received radiotherapy (HR = 3.43, 95% CI 1.6–7.34, p = 1.50 × 10−3) but not among radiotherapy treated patients (HR = 1.35, 95% CI 0.82–2.23, p = 0.237). Significant interaction was found between the mutation and radiotherapy (p = 0.040). Immunohistochemical analyses show that c.5101C > T carriers have reduced PAR‐activity. Our results suggest that FANCM c.5101C > T nonsense mutation carriers have a reduced breast cancer survival but postoperative radiotherapy may diminish this survival disadvantage.
What's new?
Variations in DNA repair genes can predispose individuals to breast cancer, with one example being FANCM c.5101C > T, a nonsense mutation in the Fanconi Anemia DNA repair pathway. In previous work, FANCM c.5101C > T was associated with increased breast cancer risk in the Finnish population. Here, the mutation is further shown to be associated with adverse breast cancer outcome. Mutation‐positive Finnish patients exhibited reduced long‐term survival and increased risk of disease recurrence. Survival was worse particularly for patients who were not treated with radiotherapy, indicating that FANCM c.5101C>T may interact with radiotherapy to improve disease outcome in mutation carriers.
doi:10.1002/ijc.30394
PMCID: PMC5095781  PMID: 27542569
FANCM; breast cancer; survival; DNA repair; radiotherapy
4.  Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk 
Guo, Xingyi | Long, Jirong | Zeng, Chenjie | Michailidou, Kyriaki | Ghoussaini, Maya | Bolla, Manjeet K. | Wang, Qin | Milne, Roger L. | Shu, Xiao-Ou | Cai, Qiuyin | Beesley, Jonathan | Kar, Siddhartha P. | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Blot, William | Bogdanova, Natalia | Bojesen, Stig E. | Brauch, Hiltrud | Brenner, Hermann | Brinton, Louise | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Cai, Hui | Canisius, Sander | Chang-Claude, Jenny | Choi, Ji-Yeob | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Darabi, Hatef | Devilee, Peter | Droit, Arnaud | Dörk, Thilo | Fasching, Peter A. | Fletcher, Olivia | Flyger, Henrik | Fostira, Florentia | Gaborieau, Valerie | García-Closas, Montserrat | Giles, Graham G. | Grip, Mervi | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hartman, Mikael | Hollestelle, Antoinette | Hopper, John L. | Hsiung, Chia-Ni | Ito, Hidemi | Jakubowska, Anna | Johnson, Nichola | Kabisch, Maria | Kang, Daehee | Khan, Sofia | Knight, Julia A. | Kosma, Veli-Matti | Lambrechts, Diether | Marchand, Loic Le | Li, Jingmei | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Matsuo, Keitaro | McLean, Catriona A. | Meindl, Alfons | Muir, Kenneth | Neuhausen, Susan L. | Nevanlinna, Heli | Nord, Silje | Olson, Janet E. | Orr, Nick | Peterlongo, Paolo | Putti, Thomas Choudary | Rudolph, Anja | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Shen, Chen-Yang | Shi, Jiajun | Shrubsole, Martha J | Southey, Melissa C. | Swerdlow, Anthony | Teo, Soo Hwang | Thienpont, Bernard | Toland, Amanda Ewart | Tollenaar, Robert A.E.M. | Tomlinson, Ian P.M. | Truong, Thérèse | Tseng, Chiu-chen | van den Ouweland, Ans | Wen, Wanqing | Winqvist, Robert | Wu, Anna | Yip, Cheng Har | Zamora, M. Pilar | Zheng, Ying | Hall, Per | Pharoah, Paul D.P. | Simard, Jacques | Chenevix-Trench, Georgia | Dunning, Alison M. | Easton, Douglas F. | Zheng, Wei
Background
A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored.
Methods
We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium.
Results
Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 (conditional p = 2.51 × 10−4; OR = 1.04; 95% CI 1.02–1.07) and rs77928427 (p = 1.86 × 10−4; OR = 1.04; 95% CI 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue.
Conclusion
Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2.
Impact
Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
doi:10.1158/1055-9965.EPI-15-0363
PMCID: PMC4633342  PMID: 26354892
Breast Cancer; Genetics; GWAS; 4q24; TET2
5.  Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization 
Zhang, Ben | Shu, Xiao-Ou | Delahanty, Ryan J. | Zeng, Chenjie | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Wen, Wanqing | Long, Jirong | Li, Chun | Dunning, Alison M. | Chang-Claude, Jenny | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Wildiers, Hans | Floris, Giuseppe | Schmidt, Marjanka K. | Rookus, Matti A. | van den Hurk, Katja | de Kort, Wim L. A. M. | Couch, Fergus J. | Olson, Janet E. | Hallberg, Emily | Vachon, Celine | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Li, Jingmei | Humphreys, Keith | Brand, Judith | Guénel, Pascal | Truong, Thérèse | Cordina-Duverger, Emilie | Menegaux, Florence | Burwinkel, Barbara | Marme, Frederik | Yang, Rongxi | Surowy, Harald | Benitez, Javier | Zamora, M. Pilar | Perez, Jose I. A. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Chenevix-Trench, Georgia | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Marchand, Loic Le | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Martens, John W. M. | Tilanus-Linthorst, Madeleine M. A. | Collée, J. Margriet | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony J. | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Garcia-Closas, Montserrat | Brinton, Louise | Lissowska, Jolanta | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Radice, Paolo | Bogdanova, Natalia | Antonenkova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubiński, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Hamann, Ute | Torres, Diana | Schmutzler, Rita K. | Neuhausen, Susan L. | Anton-Culver, Hoda | Kristensen, Vessela N. | Grenaker Alnæs, Grethe I. | Pierce, Brandon L. | Kraft, Peter | Peters, Ulrike | Lindstrom, Sara | Seminara, Daniela | Burgess, Stephen | Ahsan, Habibul | Whittemore, Alice S. | John, Esther M. | Gammon, Marilie D. | Malone, Kathleen E. | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Pharoah, Paul D. P. | Simard, Jacques | Hall, Per | Hunter, David J. | Easton, Douglas F. | Zheng, Wei
Background:
Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear.
Methods:
We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5216302 women, including 113178 events. In a consortium with individual-level data from 46325 case patients and 42482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16003 case patients and 41335 control subjects.
Results:
The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor–positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5×10–8.
Conclusions:
Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.
doi:10.1093/jnci/djv219
PMCID: PMC4643630  PMID: 26296642
6.  No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing 
Easton, Douglas F | Lesueur, Fabienne | Decker, Brennan | Michailidou, Kyriaki | Li, Jun | Allen, Jamie | Luccarini, Craig | Pooley, Karen A | Shah, Mitul | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Ahmad, Jamil | Thompson, Ella R | Damiola, Francesca | Pertesi, Maroulio | Voegele, Catherine | Mebirouk, Noura | Robinot, Nivonirina | Durand, Geoffroy | Forey, Nathalie | Luben, Robert N | Ahmed, Shahana | Aittomäki, Kristiina | Anton-Culver, Hoda | Arndt, Volker | Baynes, Caroline | Beckman, Matthias W | Benitez, Javier | Van Den Berg, David | Blot, William J | Bogdanova, Natalia V | Bojesen, Stig E | Brenner, Hermann | Chang-Claude, Jenny | Chia, Kee Seng | Choi, Ji-Yeob | Conroy, Don M | Cox, Angela | Cross, Simon S | Czene, Kamila | Darabi, Hatef | Devilee, Peter | Eriksson, Mikael | Fasching, Peter A | Figueroa, Jonine | Flyger, Henrik | Fostira, Florentia | García-Closas, Montserrat | Giles, Graham G | Glendon, Gord | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A | Hall, Per | Hart, Steven N | Hartman, Mikael | Hooning, Maartje J | Hsiung, Chia-Ni | Ito, Hidemi | Jakubowska, Anna | James, Paul A | John, Esther M | Johnson, Nichola | Jones, Michael | Kabisch, Maria | Kang, Daehee | Kosma, Veli-Matti | Kristensen, Vessela | Lambrechts, Diether | Li, Na | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Meindl, Alfons | Mitchell, Gillian | Muir, Kenneth | Nevelsteen, Ines | van den Ouweland, Ans | Peterlongo, Paolo | Phuah, Sze Yee | Pylkäs, Katri | Rowley, Simone M | Sangrajrang, Suleeporn | Schmutzler, Rita K | Shen, Chen-Yang | Shu, Xiao-Ou | Southey, Melissa C | Surowy, Harald | Swerdlow, Anthony | Teo, Soo H | Tollenaar, Rob A E M | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Vachon, Celine | Verhoef, Senno | Wong-Brown, Michelle | Zheng, Wei | Zheng, Ying | Nevanlinna, Heli | Scott, Rodney J | Andrulis, Irene L | Wu, Anna H | Hopper, John L | Couch, Fergus J | Winqvist, Robert | Burwinkel, Barbara | Sawyer, Elinor J | Schmidt, Marjanka K | Rudolph, Anja | Dörk, Thilo | Brauch, Hiltrud | Hamann, Ute | Neuhausen, Susan L | Milne, Roger L | Fletcher, Olivia | Pharoah, Paul D P | Campbell, Ian G | Dunning, Alison M | Le Calvez-Kelm, Florence | Goldgar, David E | Tavtigian, Sean V | Chenevix-Trench, Georgia
Journal of medical genetics  2016;53(5):298-309.
Background
BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction.
Methods
We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia.
Results
The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75).
Conclusions
These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
doi:10.1136/jmedgenet-2015-103529
PMCID: PMC4938802  PMID: 26921362
7.  Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups 
Background
The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists’ visual scores available in a subset of patients.
Methods
We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan–Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors.
Results
Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31–2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86–1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16–5.27)) and node-positive (1.74 (1.05–2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02–2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources.
Conclusions
Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0765-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0765-6
PMCID: PMC5070183  PMID: 27756439
Breast cancer; Automated KI67; Visual KI67; Prognostication
8.  Patient survival and tumor characteristics associated with CHEK2:p.I157T – findings from the Breast Cancer Association Consortium 
Background
P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.
Methods
We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models.
Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.
Results
P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.
Conclusions
Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0758-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0758-5
PMCID: PMC5048645  PMID: 27716369
Breast cancer; CHEK2; CHK2; I157T; 1100delC; Survival; Pathology; Gene expression
9.  Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170 
Dunning, Alison M | Michailidou, Kyriaki | Kuchenbaecker, Karoline B | Thompson, Deborah | French, Juliet D | Beesley, Jonathan | Healey, Catherine S | Kar, Siddhartha | Pooley, Karen A | Lopez-Knowles, Elena | Dicks, Ed | Barrowdale, Daniel | Sinnott-Armstrong, Nicholas A | Sallari, Richard C | Hillman, Kristine M | Kaufmann, Susanne | Sivakumaran, Haran | Marjaneh, Mahdi Moradi | Lee, Jason S | Hills, Margaret | Jarosz, Monika | Drury, Suzie | Canisius, Sander | Bolla, Manjeet K | Dennis, Joe | Wang, Qin | Hopper, John L | Southey, Melissa C | Broeks, Annegien | Schmidt, Marjanka K | Lophatananon, Artitaya | Muir, Kenneth | Beckmann, Matthias W | Fasching, Peter A | dos-Santos-Silva, Isabel | Peto, Julian | Sawyer, Elinor J | Tomlinson, Ian | Burwinkel, Barbara | Marme, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E | Flyger, Henrik | González-Neira, Anna | Perez, Jose I A | Anton-Culver, Hoda | Eunjung, Lee | Arndt, Volker | Brenner, Hermann | Meindl, Alfons | Schmutzler, Rita K | Brauch, Hiltrud | Hamann, Ute | Aittomäki, Kristiina | Blomqvist, Carl | Ito, Hidemi | Matsuo, Keitaro | Bogdanova, Natasha | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Kosma, Veli-Matti | Mannermaa, Arto | Tseng, Chiu-chen | Wu, Anna H | Lambrechts, Diether | Wildiers, Hans | Chang-Claude, Jenny | Rudolph, Anja | Peterlongo, Paolo | Radice, Paolo | Olson, Janet E | Giles, Graham G | Milne, Roger L | Haiman, Christopher A | Henderson, Brian E | Goldberg, Mark S | Teo, Soo H | Yip, Cheng Har | Nord, Silje | Borresen-Dale, Anne-Lise | Kristensen, Vessela | Long, Jirong | Zheng, Wei | Pylkäs, Katri | Winqvist, Robert | Andrulis, Irene L | Knight, Julia A | Devilee, Peter | Seynaeve, Caroline | Figueroa, Jonine | Sherman, Mark E | Czene, Kamila | Darabi, Hatef | Hollestelle, Antoinette | van den Ouweland, Ans M W | Humphreys, Keith | Gao, Yu-Tang | Shu, Xiao-Ou | Cox, Angela | Cross, Simon S | Blot, William | Cai, Qiuyin | Ghoussaini, Maya | Perkins, Barbara J | Shah, Mitul | Choi, Ji-Yeob | Kang, Daehee | Lee, Soo Chin | Hartman, Mikael | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Brennan, Paul | Sangrajrang, Suleeporn | Ambrosone, Christine B | Toland, Amanda E | Shen, Chen-Yang | Wu, Pei-Ei | Orr, Nick | Swerdlow, Anthony | McGuffog, Lesley | Healey, Sue | Lee, Andrew | Kapuscinski, Miroslav | John, Esther M | Terry, Mary Beth | Daly, Mary B | Goldgar, David E | Buys, Saundra S | Janavicius, Ramunas | Tihomirova, Laima | Tung, Nadine | Dorfling, Cecilia M | van Rensburg, Elizabeth J | Neuhausen, Susan L | Ejlertsen, Bent | Hansen, Thomas V O | Osorio, Ana | Benitez, Javier | Rando, Rachel | Weitzel, Jeffrey N | Bonanni, Bernardo | Peissel, Bernard | Manoukian, Siranoush | Papi, Laura | Ottini, Laura | Konstantopoulou, Irene | Apostolou, Paraskevi | Garber, Judy | Rashid, Muhammad Usman | Frost, Debra | Izatt, Louise | Ellis, Steve | Godwin, Andrew K | Arnold, Norbert | Niederacher, Dieter | Rhiem, Kerstin | Bogdanova-Markov, Nadja | Sagne, Charlotte | Stoppa-Lyonnet, Dominique | Damiola, Francesca | Sinilnikova, Olga M | Mazoyer, Sylvie | Isaacs, Claudine | Claes, Kathleen B M | De Leeneer, Kim | de la Hoya, Miguel | Caldes, Trinidad | Nevanlinna, Heli | Khan, Sofia | Mensenkamp, Arjen R | Hooning, Maartje J | Rookus, Matti A | Kwong, Ava | Olah, Edith | Diez, Orland | Brunet, Joan | Pujana, Miquel Angel | Gronwald, Jacek | Huzarski, Tomasz | Barkardottir, Rosa B | Laframboise, Rachel | Soucy, Penny | Montagna, Marco | Agata, Simona | Teixeira, Manuel R | Park, Sue Kyung | Lindor, Noralane | Couch, Fergus J | Tischkowitz, Marc | Foretova, Lenka | Vijai, Joseph | Offit, Kenneth | Singer, Christian F | Rappaport, Christine | Phelan, Catherine M | Greene, Mark H | Mai, Phuong L | Rennert, Gad | Imyanitov, Evgeny N | Hulick, Peter J | Phillips, Kelly-Anne | Piedmonte, Marion | Mulligan, Anna Marie | Glendon, Gord | Bojesen, Anders | Thomassen, Mads | Caligo, Maria A | Yoon, Sook-Yee | Friedman, Eitan | Laitman, Yael | Borg, Ake | von Wachenfeldt, Anna | Ehrencrona, Hans | Rantala, Johanna | Olopade, Olufunmilayo I | Ganz, Patricia A | Nussbaum, Robert L | Gayther, Simon A | Nathanson, Katherine L | Domchek, Susan M | Arun, Banu K | Mitchell, Gillian | Karlan, Beth Y | Lester, Jenny | Maskarinec, Gertraud | Woolcott, Christy | Scott, Christopher | Stone, Jennifer | Apicella, Carmel | Tamimi, Rulla | Luben, Robert | Khaw, Kay-Tee | Helland, Åslaug | Haakensen, Vilde | Dowsett, Mitch | Pharoah, Paul D P | Simard, Jacques | Hall, Per | García-Closas, Montserrat | Vachon, Celine | Chenevix-Trench, Georgia | Antoniou, Antonis C | Easton, Douglas F | Edwards, Stacey L
Nature genetics  2016;48(4):374-386.
We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER+ or ER−) and human ERBB2 (HER2+ or HER2−) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER− tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
doi:10.1038/ng.3521
PMCID: PMC4938803  PMID: 26928228
10.  Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs) 
Darabi, Hatef | Beesley, Jonathan | Droit, Arnaud | Kar, Siddhartha | Nord, Silje | Moradi Marjaneh, Mahdi | Soucy, Penny | Michailidou, Kyriaki | Ghoussaini, Maya | Fues Wahl, Hanna | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Alonso, M. Rosario | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Benitez, Javier | Bogdanova, Natalia V. | Bojesen, Stig E. | Brauch, Hiltrud | Brenner, Hermann | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Chang-Claude, Jenny | Choi, Ji-Yeob | Conroy, Don M. | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Devilee, Peter | Dörk, Thilo | Easton, Douglas F. | Fasching, Peter A. | Figueroa, Jonine | Fletcher, Olivia | Flyger, Henrik | Galle, Eva | García-Closas, Montserrat | Giles, Graham G. | Goldberg, Mark S. | González-Neira, Anna | Guénel, Pascal | Haiman, Christopher A. | Hallberg, Emily | Hamann, Ute | Hartman, Mikael | Hollestelle, Antoinette | Hopper, John L. | Ito, Hidemi | Jakubowska, Anna | Johnson, Nichola | Kang, Daehee | Khan, Sofia | Kosma, Veli-Matti | Kriege, Mieke | Kristensen, Vessela | Lambrechts, Diether | Le Marchand, Loic | Lee, Soo Chin | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Matsuo, Keitaro | Mayes, Rebecca | McKay, James | Meindl, Alfons | Milne, Roger L. | Muir, Kenneth | Neuhausen, Susan L. | Nevanlinna, Heli | Olswold, Curtis | Orr, Nick | Peterlongo, Paolo | Pita, Guillermo | Pylkäs, Katri | Rudolph, Anja | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Seynaeve, Caroline | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Southey, Melissa C. | Stram, Daniel O. | Surowy, Harald | Swerdlow, Anthony | Teo, Soo H. | Tessier, Daniel C. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Vachon, Celine M. | Vincent, Daniel | Winqvist, Robert | Wu, Anna H. | Wu, Pei-Ei | Yip, Cheng Har | Zheng, Wei | Pharoah, Paul D. P. | Hall, Per | Edwards, Stacey L. | Simard, Jacques | French, Juliet D. | Chenevix-Trench, Georgia | Dunning, Alison M.
Scientific Reports  2016;6:32512.
Genome-wide association studies have found SNPs at 17q22 to be associated with breast cancer risk. To identify potential causal variants related to breast cancer risk, we performed a high resolution fine-mapping analysis that involved genotyping 517 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of genotypes for 3,134 SNPs in more than 89,000 participants of European ancestry from the Breast Cancer Association Consortium (BCAC). We identified 28 highly correlated common variants, in a 53 Kb region spanning two introns of the STXBP4 gene, that are strong candidates for driving breast cancer risk (lead SNP rs2787486 (OR = 0.92; CI 0.90–0.94; P = 8.96 × 10−15)) and are correlated with two previously reported risk-associated variants at this locus, SNPs rs6504950 (OR = 0.94, P = 2.04 × 10−09, r2 = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10−11, r2 = 0.83 with lead SNP). Analyses indicate only one causal SNP in the region and several enhancer elements targeting STXBP4 are located within the 53 kb association signal. Expression studies in breast tumor tissues found SNP rs2787486 to be associated with increased STXBP4 expression, suggesting this may be a target gene of this locus.
doi:10.1038/srep32512
PMCID: PMC5013272  PMID: 27600471
11.  Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast–ovarian cancer susceptibility locus 
Lawrenson, Kate | Kar, Siddhartha | McCue, Karen | Kuchenbaeker, Karoline | Michailidou, Kyriaki | Tyrer, Jonathan | Beesley, Jonathan | Ramus, Susan J. | Li, Qiyuan | Delgado, Melissa K. | Lee, Janet M. | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Bandera, Elisa V. | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Matthias W. | Benitez, Javier | Berchuck, Andrew | Bisogna, Maria | Bjorge, Line | Blomqvist, Carl | Blot, William | Bogdanova, Natalia | Bojesen, Anders | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Bruinsma, Fiona | Brunet, Joan | Buhari, Shaik Ahmad | Burwinkel, Barbara | Butzow, Ralf | Buys, Saundra S. | Cai, Qiuyin | Caldes, Trinidad | Campbell, Ian | Canniotto, Rikki | Chang-Claude, Jenny | Chiquette, Jocelyne | Choi, Ji-Yeob | Claes, Kathleen B. M. | Cook, Linda S. | Cox, Angela | Cramer, Daniel W. | Cross, Simon S. | Cybulski, Cezary | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Dansonka-Mieszkowska, Agnieszka | Darabi, Hatef | Dennis, Joe | Devilee, Peter | Diez, Orland | Doherty, Jennifer A. | Domchek, Susan M. | Dorfling, Cecilia M. | Dörk, Thilo | Dumont, Martine | Ehrencrona, Hans | Ejlertsen, Bent | Ellis, Steve | Engel, Christoph | Lee, Eunjung | Evans, D. Gareth | Fasching, Peter A. | Feliubadalo, Lidia | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Foretova, Lenka | Fostira, Florentia | Foulkes, William D. | Fridley, Brooke L. | Friedman, Eitan | Frost, Debra | Gambino, Gaetana | Ganz, Patricia A. | Garber, Judy | García-Closas, Montserrat | Gentry-Maharaj, Aleksandra | Ghoussaini, Maya | Giles, Graham G. | Glasspool, Rosalind | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Goode, Ellen L. | Goodman, Marc T. | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Haiman, Christopher A. | Hall, Per | Hallberg, Emily | Hamann, Ute | Hansen, Thomas V. O. | Harrington, Patricia A. | Hartman, Mikael | Hassan, Norhashimah | Healey, Sue | Heitz, Florian | Herzog, Josef | Høgdall, Estrid | Høgdall, Claus K. | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hopper, John L. | Hulick, Peter J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Ito, Hidemi | Jakubowska, Anna | Janavicius, Ramunas | Jensen, Allan | John, Esther M. | Johnson, Nichola | Kabisch, Maria | Kang, Daehee | Kapuscinski, Miroslav | Karlan, Beth Y. | Khan, Sofia | Kiemeney, Lambertus A. | Kjaer, Susanne Kruger | Knight, Julia A. | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kupryjanczyk, Jolanta | Kwong, Ava | de la Hoya, Miguel | Laitman, Yael | Lambrechts, Diether | Le, Nhu | De Leeneer, Kim | Lester, Jenny | Levine, Douglas A. | Li, Jingmei | Lindblom, Annika | Long, Jirong | Lophatananon, Artitaya | Loud, Jennifer T. | Lu, Karen | Lubinski, Jan | Mannermaa, Arto | Manoukian, Siranoush | Le Marchand, Loic | Margolin, Sara | Marme, Frederik | Massuger, Leon F. A. G. | Matsuo, Keitaro | Mazoyer, Sylvie | McGuffog, Lesley | McLean, Catriona | McNeish, Iain | Meindl, Alfons | Menon, Usha | Mensenkamp, Arjen R. | Milne, Roger L. | Montagna, Marco | Moysich, Kirsten B. | Muir, Kenneth | Mulligan, Anna Marie | Nathanson, Katherine L. | Ness, Roberta B. | Neuhausen, Susan L. | Nevanlinna, Heli | Nord, Silje | Nussbaum, Robert L. | Odunsi, Kunle | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Olswold, Curtis | O'Malley, David | Orlow, Irene | Orr, Nick | Osorio, Ana | Park, Sue Kyung | Pearce, Celeste L. | Pejovic, Tanja | Peterlongo, Paolo | Pfeiler, Georg | Phelan, Catherine M. | Poole, Elizabeth M. | Pylkäs, Katri | Radice, Paolo | Rantala, Johanna | Rashid, Muhammad Usman | Rennert, Gad | Rhenius, Valerie | Rhiem, Kerstin | Risch, Harvey A. | Rodriguez, Gus | Rossing, Mary Anne | Rudolph, Anja | Salvesen, Helga B. | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schildkraut, Joellen M. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Sellers, Thomas A. | Seynaeve, Caroline | Shah, Mitul | Shen, Chen-Yang | Shu, Xiao-Ou | Sieh, Weiva | Singer, Christian F. | Sinilnikova, Olga M. | Slager, Susan | Song, Honglin | Soucy, Penny | Southey, Melissa C. | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Sutter, Christian | Swerdlow, Anthony | Tchatchou, Sandrine | Teixeira, Manuel R. | Teo, Soo H. | Terry, Kathryn L. | Terry, Mary Beth | Thomassen, Mads | Tibiletti, Maria Grazia | Tihomirova, Laima | Tognazzo, Silvia | Toland, Amanda Ewart | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Tseng, Chiu-chen | Tung, Nadine | Tworoger, Shelley S. | Vachon, Celine | van den Ouweland, Ans M. W. | van Doorn, Helena C. | van Rensburg, Elizabeth J. | Van't Veer, Laura J. | Vanderstichele, Adriaan | Vergote, Ignace | Vijai, Joseph | Wang, Qin | Wang-Gohrke, Shan | Weitzel, Jeffrey N. | Wentzensen, Nicolas | Whittemore, Alice S. | Wildiers, Hans | Winqvist, Robert | Wu, Anna H. | Yannoukakos, Drakoulis | Yoon, Sook-Yee | Yu, Jyh-Cherng | Zheng, Wei | Zheng, Ying | Khanna, Kum Kum | Simard, Jacques | Monteiro, Alvaro N. | French, Juliet D. | Couch, Fergus J. | Freedman, Matthew L. | Easton, Douglas F. | Dunning, Alison M. | Pharoah, Paul D. | Edwards, Stacey L. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Gayther, Simon A.
Nature Communications  2016;7:12675.
A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10−20), ER-negative BC (P=1.1 × 10−13), BRCA1-associated BC (P=7.7 × 10−16) and triple negative BC (P-diff=2 × 10−5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10−3) and ABHD8 (P<2 × 10−3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
A region on chromosome 19p13 is associated with the risk of developing ovarian and breast cancer. Here, the authors genotyped SNPs in this region in thousands of breast and ovarian cancer patients and identified SNPs associated with three genes, which were analysed with functional studies.
doi:10.1038/ncomms12675
PMCID: PMC5023955  PMID: 27601076
12.  Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus 
Horne, Hisani N. | Chung, Charles C. | Zhang, Han | Yu, Kai | Prokunina-Olsson, Ludmila | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Muir, Kenneth | Lophatananon, Artitaya | Fasching, Peter A. | Beckmann, Matthias W. | Fletcher, Olivia | Johnson, Nichola | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marme, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Benitez, Javier | González-Neira, Anna | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Khan, Sofia | Matsuo, Keitaro | Iwata, Hiroji | Dörk, Thilo | Bogdanova, Natalia V. | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kosma, Veli-Matti | Chenevix-Trench, Georgia | Wu, Anna H. | ven den Berg, David | Smeets, Ann | Zhao, Hui | Chang-Claude, Jenny | Rudolph, Anja | Radice, Paolo | Barile, Monica | Couch, Fergus J. | Vachon, Celine | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Marchand, Loic Le | Goldberg, Mark S. | Teo, Soo H. | Taib, Nur A. M. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Shrubsole, Martha | Winqvist, Robert | Jukkola-Vuorinen, Arja | Andrulis, Irene L. | Knight, Julia A. | Devilee, Peter | Seynaeve, Caroline | García-Closas, Montserrat | Czene, Kamila | Darabi, Hatef | Hollestelle, Antoinette | Martens, John W. M. | Li, Jingmei | Lu, Wei | Shu, Xiao-Ou | Cox, Angela | Cross, Simon S. | Blot, William | Cai, Qiuyin | Shah, Mitul | Luccarini, Craig | Baynes, Caroline | Harrington, Patricia | Kang, Daehee | Choi, Ji-Yeob | Hartman, Mikael | Chia, Kee Seng | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Sangrajrang, Suleeporn | Brennan, Paul | Slager, Susan | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hou, Ming-Feng | Swerdlow, Anthony | Orr, Nick | Simard, Jacques | Hall, Per | Pharoah, Paul D. P. | Easton, Douglas F. | Chanock, Stephen J. | Dunning, Alison M. | Figueroa, Jonine D.
PLoS ONE  2016;11(8):e0160316.
The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799–121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000–120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08–1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
doi:10.1371/journal.pone.0160316
PMCID: PMC4996485  PMID: 27556229
13.  Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent 
Guo, Yan | Warren Andersen, Shaneda | Shu, Xiao-Ou | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Garcia-Closas, Montserrat | Milne, Roger L. | Schmidt, Marjanka K. | Chang-Claude, Jenny | Dunning, Allison | Bojesen, Stig E. | Ahsan, Habibul | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bogdanova, Natalia V. | Bonanni, Bernardo | Børresen-Dale, Anne-Lise | Brand, Judith | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Casey, Graham | Chenevix-Trench, Georgia | Couch, Fergus J. | Cox, Angela | Cross, Simon S. | Czene, Kamila | Devilee, Peter | Dörk, Thilo | Dumont, Martine | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Fletcher, Olivia | Flyger, Henrik | Fostira, Florentia | Gammon, Marilie | Giles, Graham G. | Guénel, Pascal | Haiman, Christopher A. | Hamann, Ute | Hooning, Maartje J. | Hopper, John L. | Jakubowska, Anna | Jasmine, Farzana | Jenkins, Mark | John, Esther M. | Johnson, Nichola | Jones, Michael E. | Kabisch, Maria | Kibriya, Muhammad | Knight, Julia A. | Koppert, Linetta B. | Kosma, Veli-Matti | Kristensen, Vessela | Le Marchand, Loic | Lee, Eunjung | Li, Jingmei | Lindblom, Annika | Luben, Robert | Lubinski, Jan | Malone, Kathi E. | Mannermaa, Arto | Margolin, Sara | Marme, Frederik | McLean, Catriona | Meijers-Heijboer, Hanne | Meindl, Alfons | Neuhausen, Susan L. | Nevanlinna, Heli | Neven, Patrick | Olson, Janet E. | Perez, Jose I. A. | Perkins, Barbara | Peterlongo, Paolo | Phillips, Kelly-Anne | Pylkäs, Katri | Rudolph, Anja | Santella, Regina | Sawyer, Elinor J. | Schmutzler, Rita K. | Seynaeve, Caroline | Shah, Mitul | Shrubsole, Martha J. | Southey, Melissa C. | Swerdlow, Anthony J. | Toland, Amanda E. | Tomlinson, Ian | Torres, Diana | Truong, Thérèse | Ursin, Giske | Van Der Luijt, Rob B. | Verhoef, Senno | Whittemore, Alice S. | Winqvist, Robert | Zhao, Hui | Zhao, Shilin | Hall, Per | Simard, Jacques | Kraft, Peter | Pharoah, Paul | Hunter, David | Easton, Douglas F. | Zheng, Wei
PLoS Medicine  2016;13(8):e1002105.
Background
Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.
Methods
We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.
Results
In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10−10). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10−8) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10−8). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10−7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
Conclusions
BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.
Using Mendelian randomization analysis, Wei Zheng and colleagues probe potentially causal associations between BMI and breast cancer risk in both pre- and postmenopausal women.
Author Summary
Why Was This Study Done?
Body mass index (BMI) has been linked to breast cancer risk in conventional population studies.
In these studies, high BMI is associated with reduced risk of breast cancer in premenopausal women but with increased risk in postmenopausal women. These changed risks may be caused by BMI or caused by environmental factors that are associated with BMI.
We sought to use a research tool from the genetics field to understand BMI’s causal role in breast cancer.
What Did the Researchers Do and Find?
We took advantage of previously identified genetic sequence variations that are associated with BMI in European populations and used these variants to predict BMI. These variants are set at birth and are not affected by environmental factors; thus, outcomes associated with high BMI as predicted by genetic variants are more likely to be caused by high BMI itself rather than by environmental factors that are associated with high BMI.
Using databases containing individual genetic sequences and breast cancer diagnoses in a European population, we tested whether genetically predicted BMI was associated with diagnosis of breast cancer in either pre- or postmenopausal women.
We found that genetically predicted high BMI was associated with decreased breast cancer risk, in both cancer databases. Unexpectedly, this was true for both pre- and postmenopausal women.
What Do These Findings Mean?
Our results from postmenopausal women contradict prior findings from population studies, which used measured, rather than genetically predicted, BMI.
BMI predicted using genetic variants identified to date may be more closely related to body weight in early life or midlife, which is negatively associated with risk of breast cancer. Measured high BMI later in life may be influenced by environmental factors that are associated with increased risk of breast cancer.
More research is needed on the interrelationship of genetic factors, environment, and BMI in the risk of breast cancer.
doi:10.1371/journal.pmed.1002105
PMCID: PMC4995025  PMID: 27551723
14.  Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus 
Zeng, Chenjie | Guo, Xingyi | Long, Jirong | Kuchenbaecker, Karoline B. | Droit, Arnaud | Michailidou, Kyriaki | Ghoussaini, Maya | Kar, Siddhartha | Freeman, Adam | Hopper, John L. | Milne, Roger L. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Agata, Simona | Ahmed, Shahana | Aittomäki, Kristiina | Andrulis, Irene L. | Anton-Culver, Hoda | Antonenkova, Natalia N. | Arason, Adalgeir | Arndt, Volker | Arun, Banu K. | Arver, Brita | Bacot, Francois | Barrowdale, Daniel | Baynes, Caroline | Beeghly-Fadiel, Alicia | Benitez, Javier | Bermisheva, Marina | Blomqvist, Carl | Blot, William J. | Bogdanova, Natalia V. | Bojesen, Stig E. | Bonanni, Bernardo | Borresen-Dale, Anne-Lise | Brand, Judith S. | Brauch, Hiltrud | Brennan, Paul | Brenner, Hermann | Broeks, Annegien | Brüning, Thomas | Burwinkel, Barbara | Buys, Saundra S. | Cai, Qiuyin | Caldes, Trinidad | Campbell, Ian | Carpenter, Jane | Chang-Claude, Jenny | Choi, Ji-Yeob | Claes, Kathleen B. M. | Clarke, Christine | Cox, Angela | Cross, Simon S. | Czene, Kamila | Daly, Mary B. | de la Hoya, Miguel | De Leeneer, Kim | Devilee, Peter | Diez, Orland | Domchek, Susan M. | Doody, Michele | Dorfling, Cecilia M. | Dörk, Thilo | dos-Santos-Silva, Isabel | Dumont, Martine | Dwek, Miriam | Dworniczak, Bernd | Egan, Kathleen | Eilber, Ursula | Einbeigi, Zakaria | Ejlertsen, Bent | Ellis, Steve | Frost, Debra | Lalloo, Fiona | Fasching, Peter A. | Figueroa, Jonine | Flyger, Henrik | Friedlander, Michael | Friedman, Eitan | Gambino, Gaetana | Gao, Yu-Tang | Garber, Judy | García-Closas, Montserrat | Gehrig, Andrea | Damiola, Francesca | Lesueur, Fabienne | Mazoyer, Sylvie | Stoppa-Lyonnet, Dominique | Giles, Graham G. | Godwin, Andrew K. | Goldgar, David E. | González-Neira, Anna | Greene, Mark H. | Guénel, Pascal | Haeberle, Lothar | Haiman, Christopher A. | Hallberg, Emily | Hamann, Ute | Hansen, Thomas V. O. | Hart, Steven | Hartikainen, Jaana M. | Hartman, Mikael | Hassan, Norhashimah | Healey, Sue | Hogervorst, Frans B. L. | Verhoef, Senno | Hendricks, Carolyn B. | Hillemanns, Peter | Hollestelle, Antoinette | Hulick, Peter J. | Hunter, David J. | Imyanitov, Evgeny N. | Isaacs, Claudine | Ito, Hidemi | Jakubowska, Anna | Janavicius, Ramunas | Jaworska-Bieniek, Katarzyna | Jensen, Uffe Birk | John, Esther M. | Joly Beauparlant, Charles | Jones, Michael | Kabisch, Maria | Kang, Daehee | Karlan, Beth Y. | Kauppila, Saila | Kerin, Michael J. | Khan, Sofia | Khusnutdinova, Elza | Knight, Julia A. | Konstantopoulou, Irene | Kraft, Peter | Kwong, Ava | Laitman, Yael | Lambrechts, Diether | Lazaro, Conxi | Le Marchand, Loic | Lee, Chuen Neng | Lee, Min Hyuk | Lester, Jenny | Li, Jingmei | Liljegren, Annelie | Lindblom, Annika | Lophatananon, Artitaya | Lubinski, Jan | Mai, Phuong L. | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Matsuo, Keitaro | McGuffog, Lesley | Meindl, Alfons | Menegaux, Florence | Montagna, Marco | Muir, Kenneth | Mulligan, Anna Marie | Nathanson, Katherine L. | Neuhausen, Susan L. | Nevanlinna, Heli | Newcomb, Polly A. | Nord, Silje | Nussbaum, Robert L. | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olswold, Curtis | Osorio, Ana | Papi, Laura | Park-Simon, Tjoung-Won | Paulsson-Karlsson, Ylva | Peeters, Stephanie | Peissel, Bernard | Peterlongo, Paolo | Peto, Julian | Pfeiler, Georg | Phelan, Catherine M. | Presneau, Nadege | Radice, Paolo | Rahman, Nazneen | Ramus, Susan J. | Rashid, Muhammad Usman | Rennert, Gad | Rhiem, Kerstin | Rudolph, Anja | Salani, Ritu | Sangrajrang, Suleeporn | Sawyer, Elinor J. | Schmidt, Marjanka K | Schmutzler, Rita K. | Schoemaker, Minouk J. | Schürmann, Peter | Seynaeve, Caroline | Shen, Chen-Yang | Shrubsole, Martha J. | Shu, Xiao-Ou | Sigurdson, Alice | Singer, Christian F. | Slager, Susan | Soucy, Penny | Southey, Melissa | Steinemann, Doris | Swerdlow, Anthony | Szabo, Csilla I. | Tchatchou, Sandrine | Teixeira, Manuel R. | Teo, Soo H. | Terry, Mary Beth | Tessier, Daniel C. | Teulé, Alex | Thomassen, Mads | Tihomirova, Laima | Tischkowitz, Marc | Toland, Amanda E. | Tung, Nadine | Turnbull, Clare | van den Ouweland, Ans M. W. | van Rensburg, Elizabeth J. | ven den Berg, David | Vijai, Joseph | Wang-Gohrke, Shan | Weitzel, Jeffrey N. | Whittemore, Alice S. | Winqvist, Robert | Wong, Tien Y. | Wu, Anna H. | Yannoukakos, Drakoulis | Yu, Jyh-Cherng | Pharoah, Paul D. P. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison M. | Simard, Jacques | Couch, Fergus J. | Antoniou, Antonis C. | Easton, Douglas F. | Zheng, Wei
Background
Multiple recent genome-wide association studies (GWAS) have identified a single nucleotide polymorphism (SNP), rs10771399, at 12p11 that is associated with breast cancer risk.
Method
We performed a fine-scale mapping study of a 700 kb region including 441 genotyped and more than 1300 imputed genetic variants in 48,155 cases and 43,612 controls of European descent, 6269 cases and 6624 controls of East Asian descent and 1116 cases and 932 controls of African descent in the Breast Cancer Association Consortium (BCAC; http://bcac.ccge.medschl.cam.ac.uk/), and in 15,252 BRCA1 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Stepwise regression analyses were performed to identify independent association signals. Data from the Encyclopedia of DNA Elements project (ENCODE) and the Cancer Genome Atlas (TCGA) were used for functional annotation.
Results
Analysis of data from European descendants found evidence for four independent association signals at 12p11, represented by rs7297051 (odds ratio (OR) = 1.09, 95 % confidence interval (CI) = 1.06–1.12; P = 3 × 10-9), rs805510 (OR = 1.08, 95 % CI = 1.04–1.12, P = 2 × 10-5), and rs1871152 (OR = 1.04, 95 % CI = 1.02–1.06; P = 2 × 10-4) identified in the general populations, and rs113824616 (P = 7 × 10-5) identified in the meta-analysis of BCAC ER-negative cases and BRCA1 mutation carriers. SNPs rs7297051, rs805510 and rs113824616 were also associated with breast cancer risk at P < 0.05 in East Asians, but none of the associations were statistically significant in African descendants. Multiple candidate functional variants are located in putative enhancer sequences. Chromatin interaction data suggested that PTHLH was the likely target gene of these enhancers. Of the six variants with the strongest evidence of potential functionality, rs11049453 was statistically significantly associated with the expression of PTHLH and its nearby gene CCDC91 at P < 0.05.
Conclusion
This study identified four independent association signals at 12p11 and revealed potentially functional variants, providing additional insights into the underlying biological mechanism(s) for the association observed between variants at 12p11 and breast cancer risk.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0718-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0718-0
PMCID: PMC4962376  PMID: 27459855
Fine-scale mapping; Genetic risk factor; PTHLH; CCDC91; Breast cancer; BRAC1 mutation carriers
15.  RAD51B in Familial Breast Cancer 
Pelttari, Liisa M. | Khan, Sofia | Vuorela, Mikko | Kiiski, Johanna I. | Vilske, Sara | Nevanlinna, Viivi | Ranta, Salla | Schleutker, Johanna | Winqvist, Robert | Kallioniemi, Anne | Dörk, Thilo | Bogdanova, Natalia V. | Figueroa, Jonine | Pharoah, Paul D. P. | Schmidt, Marjanka K. | Dunning, Alison M. | García-Closas, Montserrat | Bolla, Manjeet K. | Dennis, Joe | Michailidou, Kyriaki | Wang, Qin | Hopper, John L. | Southey, Melissa C. | Rosenberg, Efraim H. | Fasching, Peter A. | Beckmann, Matthias W. | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Surowy, Harald | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Nordestgaard, Børge G. | Benitez, Javier | González-Neira, Anna | Neuhausen, Susan L. | Anton-Culver, Hoda | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Brüning, Thomas | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Hartikainen, Jaana M. | Chenevix-Trench, Georgia | Van Dyck, Laurien | Janssen, Hilde | Chang-Claude, Jenny | Rudolph, Anja | Radice, Paolo | Peterlongo, Paolo | Hallberg, Emily | Olson, Janet E. | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Dumont, Martine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | Devilee, Peter | Seynaeve, Caroline | Hooning, Maartje J. | Collée, Margriet | Cox, Angela | Cross, Simon S. | Shah, Mitul | Luben, Robert N. | Hamann, Ute | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Couch, Fergus J. | Yannoukakos, Drakoulis | Orr, Nick | Swerdlow, Anthony | Darabi, Hatef | Li, Jingmei | Czene, Kamila | Hall, Per | Easton, Douglas F. | Mattson, Johanna | Blomqvist, Carl | Aittomäki, Kristiina | Nevanlinna, Heli
PLoS ONE  2016;11(5):e0153788.
Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk.
doi:10.1371/journal.pone.0153788
PMCID: PMC4858276  PMID: 27149063
16.  Large-scale genomic analyses link reproductive ageing to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair 
Day, Felix R. | Ruth, Katherine S. | Thompson, Deborah J. | Lunetta, Kathryn L. | Pervjakova, Natalia | Chasman, Daniel I. | Stolk, Lisette | Finucane, Hilary K. | Sulem, Patrick | Bulik-Sullivan, Brendan | Esko, Tõnu | Johnson, Andrew D. | Elks, Cathy E. | Franceschini, Nora | He, Chunyan | Altmaier, Elisabeth | Brody, Jennifer A. | Franke, Lude L. | Huffman, Jennifer E. | Keller, Margaux F. | McArdle, Patrick F. | Nutile, Teresa | Porcu, Eleonora | Robino, Antonietta | Rose, Lynda M. | Schick, Ursula M. | Smith, Jennifer A. | Teumer, Alexander | Traglia, Michela | Vuckovic, Dragana | Yao, Jie | Zhao, Wei | Albrecht, Eva | Amin, Najaf | Corre, Tanguy | Hottenga, Jouke-Jan | Mangino, Massimo | Smith, Albert V. | Tanaka, Toshiko | Abecasis, Goncalo | Andrulis, Irene L. | Anton-Culver, Hoda | Antoniou, Antonis C. | Arndt, Volker | Arnold, Alice M. | Barbieri, Caterina | Beckmann, Matthias W. | Beeghly-Fadiel, Alicia | Benitez, Javier | Bernstein, Leslie | Bielinski, Suzette J. | Blomqvist, Carl | Boerwinkle, Eric | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Borresen-Dale, Anne-Lise | Boutin, Thibaud S | Brauch, Hiltrud | Brenner, Hermann | Brüning, Thomas | Burwinkel, Barbara | Campbell, Archie | Campbell, Harry | Chanock, Stephen J. | Chapman, J. Ross | Chen, Yii-Der Ida | Chenevix-Trench, Georgia | Couch, Fergus J. | Coviello, Andrea D. | Cox, Angela | Czene, Kamila | Darabi, Hatef | De Vivo, Immaculata | Demerath, Ellen W. | Dennis, Joe | Devilee, Peter | Dörk, Thilo | dos-Santos-Silva, Isabel | Dunning, Alison M. | Eicher, John D. | Fasching, Peter A. | Faul, Jessica D. | Figueroa, Jonine | Flesch-Janys, Dieter | Gandin, Ilaria | Garcia, Melissa E. | García-Closas, Montserrat | Giles, Graham G. | Girotto, Giorgia G. | Goldberg, Mark S. | González-Neira, Anna | Goodarzi, Mark O. | Grove, Megan L. | Gudbjartsson, Daniel F. | Guénel, Pascal | Guo, Xiuqing | Haiman, Christopher A. | Hall, Per | Hamann, Ute | Henderson, Brian E. | Hocking, Lynne J. | Hofman, Albert | Homuth, Georg | Hooning, Maartje J. | Hopper, John L. | Hu, Frank B. | Huang, Jinyan | Humphreys, Keith | Hunter, David J. | Jakubowska, Anna | Jones, Samuel E. | Kabisch, Maria | Karasik, David | Knight, Julia A. | Kolcic, Ivana | Kooperberg, Charles | Kosma, Veli-Matti | Kriebel, Jennifer | Kristensen, Vessela | Lambrechts, Diether | Langenberg, Claudia | Li, Jingmei | Li, Xin | Lindström, Sara | Liu, Yongmei | Luan, Jian’an | Lubinski, Jan | Mägi, Reedik | Mannermaa, Arto | Manz, Judith | Margolin, Sara | Marten, Jonathan | Martin, Nicholas G. | Masciullo, Corrado | Meindl, Alfons | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L. | Müller-Nurasyid, Martina | Nalls, Michael | Neale, Ben M. | Nevanlinna, Heli | Neven, Patrick | Newman, Anne B. | Nordestgaard, Børge G. | Olson, Janet E. | Padmanabhan, Sandosh | Peterlongo, Paolo | Peters, Ulrike | Petersmann, Astrid | Peto, Julian | Pharoah, Paul D.P. | Pirastu, Nicola N. | Pirie, Ailith | Pistis, Giorgio | Polasek, Ozren | Porteous, David | Psaty, Bruce M. | Pylkäs, Katri | Radice, Paolo | Raffel, Leslie J. | Rivadeneira, Fernando | Rudan, Igor | Rudolph, Anja | Ruggiero, Daniela | Sala, Cinzia F. | Sanna, Serena | Sawyer, Elinor J. | Schlessinger, David | Schmidt, Marjanka K. | Schmidt, Frank | Schmutzler, Rita K. | Schoemaker, Minouk J. | Scott, Robert A. | Seynaeve, Caroline M. | Simard, Jacques | Sorice, Rossella | Southey, Melissa C. | Stöckl, Doris | Strauch, Konstantin | Swerdlow, Anthony | Taylor, Kent D. | Thorsteinsdottir, Unnur | Toland, Amanda E. | Tomlinson, Ian | Truong, Thérèse | Tryggvadottir, Laufey | Turner, Stephen T. | Vozzi, Diego | Wang, Qin | Wellons, Melissa | Willemsen, Gonneke | Wilson, James F. | Winqvist, Robert | Wolffenbuttel, Bruce B.H.R. | Wright, Alan F. | Yannoukakos, Drakoulis | Zemunik, Tatijana | Zheng, Wei | Zygmunt, Marek | Bergmann, Sven | Boomsma, Dorret I. | Buring, Julie E. | Ferrucci, Luigi | Montgomery, Grant W. | Gudnason, Vilmundur | Spector, Tim D. | van Duijn, Cornelia M | Alizadeh, Behrooz Z. | Ciullo, Marina | Crisponi, Laura | Easton, Douglas F. | Gasparini, Paolo P. | Gieger, Christian | Harris, Tamara B. | Hayward, Caroline | Kardia, Sharon L.R. | Kraft, Peter | McKnight, Barbara | Metspalu, Andres | Morrison, Alanna C. | Reiner, Alex P. | Ridker, Paul M. | Rotter, Jerome I. | Toniolo, Daniela | Uitterlinden, André G. | Ulivi, Sheila | Völzke, Henry | Wareham, Nicholas J. | Weir, David R. | Yerges-Armstrong, Laura M. | Price, Alkes L. | Stefansson, Kari | Visser, Jenny A. | Ong, Ken K. | Chang-Claude, Jenny | Murabito, Joanne M. | Perry, John R.B. | Murray, Anna
Nature genetics  2015;47(11):1294-1303.
Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ~70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.
doi:10.1038/ng.3412
PMCID: PMC4661791  PMID: 26414677
17.  Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer 
Couch, Fergus J. | Kuchenbaecker, Karoline B. | Michailidou, Kyriaki | Mendoza-Fandino, Gustavo A. | Nord, Silje | Lilyquist, Janna | Olswold, Curtis | Hallberg, Emily | Agata, Simona | Ahsan, Habibul | Aittomäki, Kristiina | Ambrosone, Christine | Andrulis, Irene L. | Anton-Culver, Hoda | Arndt, Volker | Arun, Banu K. | Arver, Brita | Barile, Monica | Barkardottir, Rosa B. | Barrowdale, Daniel | Beckmann, Lars | Beckmann, Matthias W. | Benitez, Javier | Blank, Stephanie V. | Blomqvist, Carl | Bogdanova, Natalia V. | Bojesen, Stig E. | Bolla, Manjeet K. | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Burwinkel, Barbara | Buys, Saundra S. | Caldes, Trinidad | Caligo, Maria A. | Canzian, Federico | Carpenter, Jane | Chang-Claude, Jenny | Chanock, Stephen J. | Chung, Wendy K. | Claes, Kathleen B. M. | Cox, Angela | Cross, Simon S. | Cunningham, Julie M. | Czene, Kamila | Daly, Mary B. | Damiola, Francesca | Darabi, Hatef | de la Hoya, Miguel | Devilee, Peter | Diez, Orland | Ding, Yuan C. | Dolcetti, Riccardo | Domchek, Susan M. | Dorfling, Cecilia M. | dos-Santos-Silva, Isabel | Dumont, Martine | Dunning, Alison M. | Eccles, Diana M. | Ehrencrona, Hans | Ekici, Arif B. | Eliassen, Heather | Ellis, Steve | Fasching, Peter A. | Figueroa, Jonine | Flesch-Janys, Dieter | Försti, Asta | Fostira, Florentia | Foulkes, William D. | Friebel, Tara | Friedman, Eitan | Frost, Debra | Gabrielson, Marike | Gammon, Marilie D. | Ganz, Patricia A. | Gapstur, Susan M. | Garber, Judy | Gaudet, Mia M. | Gayther, Simon A. | Gerdes, Anne-Marie | Ghoussaini, Maya | Giles, Graham G. | Glendon, Gord | Godwin, Andrew K. | Goldberg, Mark S. | Goldgar, David E. | González-Neira, Anna | Greene, Mark H. | Gronwald, Jacek | Guénel, Pascal | Gunter, Marc | Haeberle, Lothar | Haiman, Christopher A. | Hamann, Ute | Hansen, Thomas V. O. | Hart, Steven | Healey, Sue | Heikkinen, Tuomas | Henderson, Brian E. | Herzog, Josef | Hogervorst, Frans B. L. | Hollestelle, Antoinette | Hooning, Maartje J. | Hoover, Robert N. | Hopper, John L. | Humphreys, Keith | Hunter, David J. | Huzarski, Tomasz | Imyanitov, Evgeny N. | Isaacs, Claudine | Jakubowska, Anna | James, Paul | Janavicius, Ramunas | Jensen, Uffe Birk | John, Esther M. | Jones, Michael | Kabisch, Maria | Kar, Siddhartha | Karlan, Beth Y. | Khan, Sofia | Khaw, Kay-Tee | Kibriya, Muhammad G. | Knight, Julia A. | Ko, Yon-Dschun | Konstantopoulou, Irene | Kosma, Veli-Matti | Kristensen, Vessela | Kwong, Ava | Laitman, Yael | Lambrechts, Diether | Lazaro, Conxi | Lee, Eunjung | Le Marchand, Loic | Lester, Jenny | Lindblom, Annika | Lindor, Noralane | Lindstrom, Sara | Liu, Jianjun | Long, Jirong | Lubinski, Jan | Mai, Phuong L. | Makalic, Enes | Malone, Kathleen E. | Mannermaa, Arto | Manoukian, Siranoush | Margolin, Sara | Marme, Frederik | Martens, John W. M. | McGuffog, Lesley | Meindl, Alfons | Miller, Austin | Milne, Roger L. | Miron, Penelope | Montagna, Marco | Mazoyer, Sylvie | Mulligan, Anna M. | Muranen, Taru A. | Nathanson, Katherine L. | Neuhausen, Susan L. | Nevanlinna, Heli | Nordestgaard, Børge G. | Nussbaum, Robert L. | Offit, Kenneth | Olah, Edith | Olopade, Olufunmilayo I. | Olson, Janet E. | Osorio, Ana | Park, Sue K. | Peeters, Petra H. | Peissel, Bernard | Peterlongo, Paolo | Peto, Julian | Phelan, Catherine M. | Pilarski, Robert | Poppe, Bruce | Pylkäs, Katri | Radice, Paolo | Rahman, Nazneen | Rantala, Johanna | Rappaport, Christine | Rennert, Gad | Richardson, Andrea | Robson, Mark | Romieu, Isabelle | Rudolph, Anja | Rutgers, Emiel J. | Sanchez, Maria-Jose | Santella, Regina M. | Sawyer, Elinor J. | Schmidt, Daniel F. | Schmidt, Marjanka K. | Schmutzler, Rita K. | Schumacher, Fredrick | Scott, Rodney | Senter, Leigha | Sharma, Priyanka | Simard, Jacques | Singer, Christian F. | Sinilnikova, Olga M. | Soucy, Penny | Southey, Melissa | Steinemann, Doris | Stenmark-Askmalm, Marie | Stoppa-Lyonnet, Dominique | Swerdlow, Anthony | Szabo, Csilla I. | Tamimi, Rulla | Tapper, William | Teixeira, Manuel R. | Teo, Soo-Hwang | Terry, Mary B. | Thomassen, Mads | Thompson, Deborah | Tihomirova, Laima | Toland, Amanda E. | Tollenaar, Robert A. E. M. | Tomlinson, Ian | Truong, Thérèse | Tsimiklis, Helen | Teulé, Alex | Tumino, Rosario | Tung, Nadine | Turnbull, Clare | Ursin, Giski | van Deurzen, Carolien H. M. | van Rensburg, Elizabeth J. | Varon-Mateeva, Raymonda | Wang, Zhaoming | Wang-Gohrke, Shan | Weiderpass, Elisabete | Weitzel, Jeffrey N. | Whittemore, Alice | Wildiers, Hans | Winqvist, Robert | Yang, Xiaohong R. | Yannoukakos, Drakoulis | Yao, Song | Zamora, M Pilar | Zheng, Wei | Hall, Per | Kraft, Peter | Vachon, Celine | Slager, Susan | Chenevix-Trench, Georgia | Pharoah, Paul D. P. | Monteiro, Alvaro A. N. | García-Closas, Montserrat | Easton, Douglas F. | Antoniou, Antonis C.
Nature Communications  2016;7:11375.
Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Oestrogen negative breast cancer is associated with a poor prognosis. In this study, the authors perform a meta-analysis of 11 breast cancer genome-wide association studies and identify four new loci associated with oestrogen negative breast cancer risk. These findings may aid in stratifying patients in the clinic.
doi:10.1038/ncomms11375
PMCID: PMC4853421  PMID: 27117709
18.  High‐throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium 
Abstract
Automated methods are needed to facilitate high‐throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large‐scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37–0.87) and study (kappa range = 0.39–0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p‐value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000–4,500 cells: kappa = 0.78) than those with lower counts (50–500 cells: kappa = 0.41; p‐value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre‐ and post‐analytical quality control procedures are necessary in order to ensure satisfactory performance.
doi:10.1002/cjp2.42
PMCID: PMC4958735  PMID: 27499923
breast cancer; automated algorithm; tissue microarrays; Ki67; immunohistochemistry
19.  An investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors 
Rudolph, Anja | Milne, Roger L. | Truong, Thérèse | Knight, Julia A. | Seibold, Petra | Flesch-Janys, Dieter | Behrens, Sabine | Eilber, Ursula | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Dunning, Alison M. | Shah, Mitul | Munday, Hannah R. | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Olson, Janet | Vachon, Celine M. | Hallberg, Emily | Castelao, J. Esteban | Carracedo, Angel | Torres, Maria | Li, Jingmei | Humphreys, Keith | Cordina-Duverger, Emilie | Menegaux, Florence | Flyger, Henrik | Nordestgaard, Børge G. | Nielsen, Sune F. | Yesilyurt, Betul T. | Floris, Giuseppe | Leunen, Karin | Engelhardt, Ellen G. | Broeks, Annegien | Rutgers, Emiel J. | Glendon, Gord | Mulligan, Anna Marie | Cross, Simon | Reed, Malcolm | Gonzalez-Neira, Anna | Perez, José Ignacio Arias | Provenzano, Elena | Apicella, Carmel | Southey, Melissa C. | Spurdle, Amanda | Investigators, kConFab | Group, AOCS | Häberle, Lothar | Beckmann, Matthias W. | Ekici, Arif B. | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | McLean, Catriona | Baglietto, Laura | Chanock, Stephen J. | Lissowska, Jolanta | Sherman, Mark E. | Brüning, Thomas | Hamann, Ute | Ko, Yon-Dschun | Orr, Nick | Schoemaker, Minouk | Ashworth, Alan | Kosma, Veli-Matti | Kataja, Vesa | Hartikainen, Jaana M. | Mannermaa, Arto | Swerdlow, Anthony | Giles, Graham G. | Brenner, Hermann | Fasching, Peter A. | Chenevix-Trench, Georgia | Hopper, John | Benítez, Javier | Cox, Angela | Andrulis, Irene L. | Lambrechts, Diether | Gago-Dominguez, Manuela | Couch, Fergus | Czene, Kamila | Bojesen, Stig E. | Easton, Doug F. | Schmidt, Marjanka K. | Guénel, Pascal | Hall, Per | Pharoah, Paul D. P. | Garcia-Closas, Montserrat | Chang-Claude, Jenny
A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC.
Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator.
Six SNPs showed interactions with associated p-values (pint) <1.1×10−3. None of the observed interactions was significant after accounting for multiple testing. The Bayesian False Discovery Probability was used to rank the findings, which indicated three interactions as being noteworthy at 1% prior probability of interaction. SNP rs6828523 was associated with increased ER-negative BC risk in women ≥170cm (OR=1.22, p=0.017), but inversely associated with ER-negative BC risk in women <160cm (OR=0.83, p=0.039, pint=1.9×10−4). The inverse association between rs4808801 and overall BC risk was stronger for women who had had four or more pregnancies (OR=0.85, p=2.0×10−4), and absent in women who had had just one (OR=0.96, p=0.19, pint = 6.1×10−4). SNP rs11242675 was inversely associated with overall BC risk in never/former smokers (OR=0.93, p=2.8×10−5), but no association was observed in current smokers (OR=1.07, p=0.14, pint = 3.4×10−4).
In conclusion, recently identified breast cancer susceptibility loci are not strongly modified by established risk factors and the observed potential interactions require confirmation in independent studies.
doi:10.1002/ijc.29188
PMCID: PMC4289418  PMID: 25227710
gene-environment interaction; breast cancer; risk factor; genetic susceptibility
20.  Genetic predisposition to ductal carcinoma in situ of the breast 
Petridis, Christos | Brook, Mark N. | Shah, Vandna | Kohut, Kelly | Gorman, Patricia | Caneppele, Michele | Levi, Dina | Papouli, Efterpi | Orr, Nick | Cox, Angela | Cross, Simon S. | dos-Santos-Silva, Isabel | Peto, Julian | Swerdlow, Anthony | Schoemaker, Minouk J. | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Michailidou, Kyriaki | Benitez, Javier | González-Neira, Anna | Tessier, Daniel C. | Vincent, Daniel | Li, Jingmei | Figueroa, Jonine | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Soucy, Penny | Simard, Jacques | Milne, Roger L. | Giles, Graham G. | Margolin, Sara | Lindblom, Annika | Brüning, Thomas | Brauch, Hiltrud | Southey, Melissa C. | Hopper, John L. | Dörk, Thilo | Bogdanova, Natalia V. | Kabisch, Maria | Hamann, Ute | Schmutzler, Rita K. | Meindl, Alfons | Brenner, Hermann | Arndt, Volker | Winqvist, Robert | Pylkäs, Katri | Fasching, Peter A. | Beckmann, Matthias W. | Lubinski, Jan | Jakubowska, Anna | Mulligan, Anna Marie | Andrulis, Irene L. | Tollenaar, Rob A. E. M. | Devilee, Peter | Le Marchand, Loic | Haiman, Christopher A. | Mannermaa, Arto | Kosma, Veli-Matti | Radice, Paolo | Peterlongo, Paolo | Marme, Frederik | Burwinkel, Barbara | van Deurzen, Carolien H. M. | Hollestelle, Antoinette | Miller, Nicola | Kerin, Michael J. | Lambrechts, Diether | Floris, Giuseppe | Wesseling, Jelle | Flyger, Henrik | Bojesen, Stig E. | Yao, Song | Ambrosone, Christine B. | Chenevix-Trench, Georgia | Truong, Thérèse | Guénel, Pascal | Rudolph, Anja | Chang-Claude, Jenny | Nevanlinna, Heli | Blomqvist, Carl | Czene, Kamila | Brand, Judith S. | Olson, Janet E. | Couch, Fergus J. | Dunning, Alison M. | Hall, Per | Easton, Douglas F. | Pharoah, Paul D. P. | Pinder, Sarah E. | Schmidt, Marjanka K | Tomlinson, Ian | Roylance, Rebecca | García-Closas, Montserrat | Sawyer, Elinor J.
Background
Ductal carcinoma in situ (DCIS) is a non-invasive form of breast cancer. It is often associated with invasive ductal carcinoma (IDC), and is considered to be a non-obligate precursor of IDC. It is not clear to what extent these two forms of cancer share low-risk susceptibility loci, or whether there are differences in the strength of association for shared loci.
Methods
To identify genetic polymorphisms that predispose to DCIS, we pooled data from 38 studies comprising 5,067 cases of DCIS, 24,584 cases of IDC and 37,467 controls, all genotyped using the iCOGS chip.
Results
Most (67 %) of the 76 known breast cancer predisposition loci showed an association with DCIS in the same direction as previously reported for invasive breast cancer. Case-only analysis showed no evidence for differences between associations for IDC and DCIS after considering multiple testing.
Analysis by estrogen receptor (ER) status confirmed that loci associated with ER positive IDC were also associated with ER positive DCIS. Analysis of DCIS by grade suggested that two independent SNPs at 11q13.3 near CCND1 were specific to low/intermediate grade DCIS (rs75915166, rs554219). These associations with grade remained after adjusting for ER status and were also found in IDC.
We found no novel DCIS-specific loci at a genome wide significance level of P < 5.0x10-8.
Conclusion
In conclusion, this study provides the strongest evidence to date of a shared genetic susceptibility for IDC and DCIS. Studies with larger numbers of DCIS are needed to determine if IDC or DCIS specific loci exist.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0675-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0675-7
PMCID: PMC4756509  PMID: 26884359
Ductal carcinoma in situ; Association study; Genetic predisposition; Common variants
21.  Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer 
Kabisch, Maria | Lorenzo Bermejo, Justo | Dünnebier, Thomas | Ying, Shibo | Michailidou, Kyriaki | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Shah, Mitul | Perkins, Barbara J. | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Lambrechts, Diether | Neven, Patrick | Peeters, Stephanie | Weltens, Caroline | Couch, Fergus J. | Olson, Janet E. | Wang, Xianshu | Purrington, Kristen | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Peto, Julian | dos-Santos-Silva, Isabel | Johnson, Nichola | Fletcher, Olivia | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Hogervorst, Frans B.L. | Li, Jingmei | Brand, Judith S. | Humphreys, Keith | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Sanchez, Marie | Burwinkel, Barbara | Marmé, Frederik | Yang, Rongxi | Bugert, Peter | González-Neira, Anna | Benitez, Javier | Pilar Zamora, M. | Arias Perez, Jose I. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J. | Hollestelle, Antoinette | Kriege, Mieke | Koppert, Linetta B. | Hopper, John L. | Southey, Melissa C. | Tsimiklis, Helen | Apicella, Carmel | Slettedahl, Seth | Toland, Amanda E. | Vachon, Celine | Yannoukakos, Drakoulis | Giles, Graham G. | Milne, Roger L. | McLean, Catriona | Fasching, Peter A. | Ruebner, Matthias | Ekici, Arif B. | Beckmann, Matthias W. | Brenner, Hermann | Dieffenbach, Aida K. | Arndt, Volker | Stegmaier, Christa | Ashworth, Alan | Orr, Nicholas | Schoemaker, Minouk J. | Swerdlow, Anthony | García-Closas, Montserrat | Figueroa, Jonine | Chanock, Stephen J. | Lissowska, Jolanta | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Radice, Paolo | Peterlongo, Paolo | Scuvera, Giulietta | Fortuzzi, Stefano | Bogdanova, Natalia | Dörk, Thilo | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Zheng, Wei | Shrubsole, Martha J. | Cai, Qiuyin | Torres, Diana | Anton-Culver, Hoda | Kristensen, Vessela | Bacot, François | Tessier, Daniel C. | Vincent, Daniel | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Simard, Jacques | Chenevix-Trench, Georgia | Hall, Per | Pharoah, Paul D.P. | Dunning, Alison M. | Easton, Douglas F. | Hamann, Ute
Carcinogenesis  2015;36(2):256-271.
Summary
This is the first study investigating the contribution of inherited variants in core genes of the chromosomal passenger complex to breast cancer susceptibility. It was found that several INCENP variants are associated with the risk of ER-negative breast cancer in the European population.
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92–0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83–0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3ʹ untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00–1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02–1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04–1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.
doi:10.1093/carcin/bgu326
PMCID: PMC4335262  PMID: 25586992
22.  Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk 
Lin, Wei-Yu | Camp, Nicola J. | Ghoussaini, Maya | Beesley, Jonathan | Michailidou, Kyriaki | Hopper, John L. | Apicella, Carmel | Southey, Melissa C. | Stone, Jennifer | Schmidt, Marjanka K. | Broeks, Annegien | Van't Veer, Laura J. | Th Rutgers, Emiel J. | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Fasching, Peter A. | Haeberle, Lothar | Ekici, Arif B. | Beckmann, Matthias W. | Peto, Julian | Dos-Santos-Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Bolla, Manjeet K. | Wang, Qin | Dennis, Joe | Sawyer, Elinor J. | Cheng, Timothy | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Marmé, Frederik | Surowy, Harald M. | Burwinkel, Barbara | Guénel, Pascal | Truong, Thérèse | Menegaux, Florence | Mulot, Claire | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, M. Pilar | Arias Perez, Jose Ignacio | Menéndez, Primitiva | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Álvarez, Nuria | Herrero, Daniel | Anton-Culver, Hoda | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Meindl, Alfons | Lichtner, Peter | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Tessier, Daniel C. | Vincent, Daniel | Bacot, Francois | Nevanlinna, Heli | Aittomäki, Kristiina | Blomqvist, Carl | Khan, Sofia | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Horio, Akiyo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Dörk, Thilo | Lindblom, Annika | Margolin, Sara | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Neven, Patrick | Wauters, Els | Wildiers, Hans | Lambrechts, Diether | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Purrington, Kristen | Giles, Graham G. | Milne, Roger L. | Mclean, Catriona | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Teo, Soo Hwang | Yip, Cheng Har | Hassan, Norhashimah | Vithana, Eranga Nishanthie | Kristensen, Vessela | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Van Asperen, Christi J. | García-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Czene, Kamila | Darabi, Hatef | Eriksson, Mikael | Brand, Judith S. | Hooning, Maartje J. | Hollestelle, Antoinette | Van Den Ouweland, Ans M.W. | Jager, Agnes | Li, Jingmei | Liu, Jianjun | Humphreys, Keith | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Cross, Simon S. | Reed, Malcolm W. R. | Blot, William | Signorello, Lisa B. | Cai, Qiuyin | Pharoah, Paul D.P. | Perkins, Barbara | Shah, Mitul | Blows, Fiona M. | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Hartman, Mikael | Miao, Hui | Chia, Kee Seng | Putti, Thomas Choudary | Hamann, Ute | Luccarini, Craig | Baynes, Caroline | Ahmed, Shahana | Maranian, Mel | Healey, Catherine S. | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | Mckay, James | Slager, Susan | Toland, Amanda E. | Yannoukakos, Drakoulis | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-ling | Ashworth, Alan | Jones, Michael | Orr, Nick | Swerdlow, Anthony J | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel F. | Bui, Quang M. | Chanock, Stephen J. | Hunter, David J. | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Muranen, Taru A. | Heikkinen, Tuomas | Irwanto, Astrid | Rahman, Nazneen | Turnbull, Clare A. | Waisfisz, Quinten | Meijers-Heijboer, Hanne E. J. | Adank, Muriel A. | Van Der Luijt, Rob B. | Hall, Per | Chenevix-Trench, Georgia | Dunning, Alison | Easton, Douglas F. | Cox, Angela
Human Molecular Genetics  2014;24(1):285-298.
Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03–1.07), P = 1 × 10−5. Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10−6), yielding a combined OR (95% CI) of 1.06 (1.04–1.08), P = 1 × 10−9. Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
doi:10.1093/hmg/ddu431
PMCID: PMC4334820  PMID: 25168388
23.  A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients 
BMC Cancer  2015;15:978.
Background
Personalized therapy considering clinical and genetic patient characteristics will further improve breast cancer survival. Two widely used treatments, chemotherapy and radiotherapy, can induce oxidative DNA damage and, if not repaired, cell death. Since base excision repair (BER) activity is specific for oxidative DNA damage, we hypothesized that germline genetic variation in this pathway will affect breast cancer-specific survival depending on treatment.
Methods
We assessed in 1,408 postmenopausal breast cancer patients from the German MARIE study whether cancer specific survival after adjuvant chemotherapy, anthracycline chemotherapy, and radiotherapy is modulated by 127 Single Nucleotide Polymorphisms (SNPs) in 21 BER genes. For SNPs with interaction terms showing p < 0.1 (likelihood ratio test) using multivariable Cox proportional hazard analyses, replication in 6,392 patients from nine studies of the Breast Cancer Association Consortium (BCAC) was performed.
Results
rs878156 in PARP2 showed a differential effect by chemotherapy (p = 0.093) and was replicated in BCAC studies (p = 0.009; combined analysis p = 0.002). Compared to non-carriers, carriers of the variant G allele (minor allele frequency = 0.07) showed better survival after chemotherapy (combined allelic hazard ratio (HR) = 0.75, 95 % 0.53–1.07) and poorer survival when not treated with chemotherapy (HR = 1.42, 95 % 1.08–1.85). A similar effect modification by rs878156 was observed for anthracycline-based chemotherapy in both MARIE and BCAC, with improved survival in carriers (combined allelic HR = 0.73, 95 % CI 0.40–1.32). None of the SNPs showed significant differential effects by radiotherapy.
Conclusions
Our data suggest for the first time that a SNP in PARP2, rs878156, may together with other genetic variants modulate cancer specific survival in breast cancer patients depending on chemotherapy. These germline SNPs could contribute towards the design of predictive tests for breast cancer patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1957-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-015-1957-7
PMCID: PMC4682235  PMID: 26674097
Survival; Genetic variation; Chemotherapy; Radiotherapy; Anthracyclines
24.  Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium 
Lei, Jieping | Rudolph, Anja | Moysich, Kirsten B. | Behrens, Sabine | Goode, Ellen L. | Bolla, Manjeet K. | Dennis, Joe | Dunning, Alison M. | Easton, Douglas F. | Wang, Qin | Benitez, Javier | Hopper, John L. | Southey, Melissa C. | Schmidt, Marjanka K. | Broeks, Annegien | Fasching, Peter A. | Haeberle, Lothar | Peto, Julian | dos-Santos-Silva, Isabel | Sawyer, Elinor J. | Tomlinson, Ian | Burwinkel, Barbara | Marmé, Frederik | Guénel, Pascal | Truong, Thérèse | Bojesen, Stig E. | Flyger, Henrik | Nielsen, Sune F. | Nordestgaard, Børge G. | González-Neira, Anna | Menéndez, Primitiva | Anton-Culver, Hoda | Neuhausen, Susan L. | Brenner, Hermann | Arndt, Volker | Meindl, Alfons | Schmutzler, Rita K. | Brauch, Hiltrud | Hamann, Ute | Nevanlinna, Heli | Fagerholm, Rainer | Dörk, Thilo | Bogdanova, Natalia V. | Mannermaa, Arto | Hartikainen, Jaana M. | Van Dijck, Laurien | Smeets, Ann | Flesch-Janys, Dieter | Eilber, Ursula | Radice, Paolo | Peterlongo, Paolo | Couch, Fergus J. | Hallberg, Emily | Giles, Graham G. | Milne, Roger L. | Haiman, Christopher A. | Schumacher, Fredrick | Simard, Jacques | Goldberg, Mark S. | Kristensen, Vessela | Borresen-Dale, Anne-Lise | Zheng, Wei | Beeghly-Fadiel, Alicia | Winqvist, Robert | Grip, Mervi | Andrulis, Irene L. | Glendon, Gord | García-Closas, Montserrat | Figueroa, Jonine | Czene, Kamila | Brand, Judith S. | Darabi, Hatef | Eriksson, Mikael | Hall, Per | Li, Jingmei | Cox, Angela | Cross, Simon S. | Pharoah, Paul D. P. | Shah, Mitul | Kabisch, Maria | Torres, Diana | Jakubowska, Anna | Lubinski, Jan | Ademuyiwa, Foluso | Ambrosone, Christine B. | Swerdlow, Anthony | Jones, Michael | Chang-Claude, Jenny
Human Genetics  2015;135:137-154.
Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03–1.08; p value = 1.4 × 10−6). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10−3 and 7.0 × 10−3, respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10−3, 4.5 × 10−4 and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3,IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-015-1616-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-015-1616-8
PMCID: PMC4698282  PMID: 26621531
25.  Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade 
Purrington, Kristen S. | Slettedahl, Seth | Bolla, Manjeet K. | Michailidou, Kyriaki | Czene, Kamila | Nevanlinna, Heli | Bojesen, Stig E. | Andrulis, Irene L. | Cox, Angela | Hall, Per | Carpenter, Jane | Yannoukakos, Drakoulis | Haiman, Christopher A. | Fasching, Peter A. | Mannermaa, Arto | Winqvist, Robert | Brenner, Hermann | Lindblom, Annika | Chenevix-Trench, Georgia | Benitez, Javier | Swerdlow, Anthony | Kristensen, Vessela | Guénel, Pascal | Meindl, Alfons | Darabi, Hatef | Eriksson, Mikael | Fagerholm, Rainer | Aittomäki, Kristiina | Blomqvist, Carl | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Wang, Xianshu | Olswold, Curtis | Olson, Janet E. | Mulligan, Anna Marie | Knight, Julia A. | Tchatchou, Sandrine | Reed, Malcolm W.R. | Cross, Simon S. | Liu, Jianjun | Li, Jingmei | Humphreys, Keith | Clarke, Christine | Scott, Rodney | Fostira, Florentia | Fountzilas, George | Konstantopoulou, Irene | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Ekici, Arif B. | Hartmann, Arndt | Beckmann, Matthias W. | Hartikainen, Jaana M. | Kosma, Veli-Matti | Kataja, Vesa | Jukkola-Vuorinen, Arja | Pylkäs, Katri | Kauppila, Saila | Dieffenbach, Aida Karina | Stegmaier, Christa | Arndt, Volker | Margolin, Sara | Balleine, Rosemary | Arias Perez, Jose Ignacio | Pilar Zamora, M. | Menéndez, Primitiva | Ashworth, Alan | Jones, Michael | Orr, Nick | Arveux, Patrick | Kerbrat, Pierre | Truong, Thérèse | Bugert, Peter | Toland, Amanda E. | Ambrosone, Christine B. | Labrèche, France | Goldberg, Mark S. | Dumont, Martine | Ziogas, Argyrios | Lee, Eunjung | Dite, Gillian S. | Apicella, Carmel | Southey, Melissa C. | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Ficarazzi, Filomena | Barile, Monica | Peterlongo, Paolo | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Brüning, Thomas | Ko, Yon-Dschun | Van Deurzen, Carolien H.M. | Martens, John W.M. | Kriege, Mieke | Figueroa, Jonine D. | Chanock, Stephen J. | Lissowska, Jolanta | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Schneeweiss, Andreas | Tapper, William J. | Gerty, Susan M. | Durcan, Lorraine | Mclean, Catriona | Milne, Roger L. | Baglietto, Laura | dos Santos Silva, Isabel | Fletcher, Olivia | Johnson, Nichola | Van'T Veer, Laura J. | Cornelissen, Sten | Försti, Asta | Torres, Diana | Rüdiger, Thomas | Rudolph, Anja | Flesch-Janys, Dieter | Nickels, Stefan | Weltens, Caroline | Floris, Giuseppe | Moisse, Matthieu | Dennis, Joe | Wang, Qin | Dunning, Alison M. | Shah, Mitul | Brown, Judith | Simard, Jacques | Anton-Culver, Hoda | Neuhausen, Susan L. | Hopper, John L. | Bogdanova, Natalia | Dörk, Thilo | Zheng, Wei | Radice, Paolo | Jakubowska, Anna | Lubinski, Jan | Devillee, Peter | Brauch, Hiltrud | Hooning, Maartje | García-Closas, Montserrat | Sawyer, Elinor | Burwinkel, Barbara | Marmee, Frederick | Eccles, Diana M. | Giles, Graham G. | Peto, Julian | Schmidt, Marjanka | Broeks, Annegien | Hamann, Ute | Chang-Claude, Jenny | Lambrechts, Diether | Pharoah, Paul D.P. | Easton, Douglas | Pankratz, V. Shane | Slager, Susan | Vachon, Celine M. | Couch, Fergus J.
Human Molecular Genetics  2014;23(22):6034-6046.
Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16–1.33, P = 4.2 × 10−10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04–1.11, P = 8.7 × 10−6) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07–1.23, P = 7.9 × 10−5) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10−3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
doi:10.1093/hmg/ddu300
PMCID: PMC4204763  PMID: 24927736

Results 1-25 (92)