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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.  Association of Breast Cancer Risk loci with Breast Cancer Survival 
The survival of breast cancer patients is largely influenced by tumor characteristics, such as TNM stage, tumor grade and hormone receptor status. However, there is growing evidence that inherited genetic variation might affect the disease prognosis and response to treatment. Several lines of evidence suggest that alleles influencing breast cancer risk might also be associated with breast cancer survival. We examined the associations between 35 breast cancer susceptibility loci and the disease over-all survival (OS) in 10,255 breast cancer patients from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3) of which 1,379 died, including 754 of breast cancer. We also conducted a meta-analysis of almost 35,000 patients and 5,000 deaths, combining results from BPC3 and the Breast Cancer Association Consortium (BCAC) and performed in silico analyses of SNPs with significant associations. In BPC3, the C allele of LSP1-rs3817198 was significantly associated with improved OS (HRper-allele=0.70; 95% CI: 0.58–0.85; Ptrend=2.84×10−4; HRheterozygotes=0.71; 95% CI: 0.55–0.92; HRhomozygotes=0.48; 95% CI: 0.31–0.76; P2DF=1.45×10−3). In silico, the C allele of LSP1-rs3817198 was predicted to increase expression of the tumor suppressor cyclin-dependent kinase inhibitor 1C (CDKN1C). In the meta-analysis, TNRC9-rs3803662 was significantly associated with increased death hazard (HRMETA =1.09; 95% CI: 1.04–1.15; Ptrend=6.6×10−4; HRheterozygotes=0.96 95% CI: 0.90–1.03; HRhomozygotes= 1.21; 95% CI: 1.09–1.35; P2DF=1.25×10−4). In conclusion, we show that there is little overlap between the breast cancer risk single nucleotide polymorphisms (SNPs) identified so far and the SNPs associated with breast cancer prognosis, with the possible exceptions of LSP1-rs3817198 and TNRC9-rs3803662.
doi:10.1002/ijc.29446
PMCID: PMC4615576  PMID: 25611573
breast cancer; SNP; survival; BPC3; meta-analysis
3.  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
4.  The PALB2 p.Leu939Trp mutation is not associated with breast cancer risk 
doi:10.1186/s13058-016-0762-9
PMCID: PMC5101669  PMID: 27829436
Breast cancer predisposition; Breast cancer genetic risk factor; PALB2 p.Leu939Trp; VUS
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  Reliability of DNA methylation measures from dried blood spots and mononuclear cells using the HumanMethylation450k BeadArray 
Scientific Reports  2016;6:30317.
The reliability of methylation measures from the widely used HumanMethylation450 (HM450K) microarray has not been assessed for DNA from dried blood spots (DBS) or peripheral blood mononuclear cells (PBMC), nor for combined data from different studies. Repeated HM450K methylation measures in DNA from DBS and PBMC samples were available from participants in six case-control studies nested within the Melbourne Collaborative Cohort Study. Reliability was assessed for individual CpGs by calculating the intraclass correlation coefficient (ICC) based on technical replicates (samples repeated in a single study; 126 PBMC, 136 DBS) and study duplicates (samples repeated across studies; 280 PBMC, 769 DBS) using mixed-effects models. Reliability based on technical replicates was moderate for PBMC (median ICC = 0.42), but lower for DBS (median ICC = 0.20). Study duplicates gave lower ICCs than technical replicates. CpGs that were either highly methylated or unmethylated generally had lower ICCs, which appeared to be mostly related to their lower variability. The ICCs for global methylation measures were high, typically greater than 0.70. The reliability of methylation measures determined by the HM450K microarray is wide-ranging and depends primarily on the variability in methylation at individual CpG sites. The power of association studies is low for a substantial proportion of CpGs in the HM450K assay.
doi:10.1038/srep30317
PMCID: PMC4960587  PMID: 27457678
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.  Psychosocial Factors and Survival of Young Women With Breast Cancer: A Population-Based Prospective Cohort Study 
Journal of Clinical Oncology  2008;26(28):4666-4671.
Purpose
Most women with early-stage breast cancer believe that psychosocial factors are an important influence over whether their cancer will recur. Studies of the issue have produced conflicting results.
Patients and Methods
A population-based sample of 708 Australian women diagnosed before age 60 years with nonmetastatic breast cancer was observed for a median of 8.2 years. Depression and anxiety, coping style, and social support were assessed at a median of 11 months after diagnosis. Hazard ratios for distant disease-free survival (DDFS) and overall survival (OS) associated with psychosocial factors were estimated separately using Cox proportional hazards survival models, with and without adjustment for known prognostic factors.
Results
Distant recurrence occurred in 209 (33%) of 638 assessable patients, and 170 (24%) of 708 patients died during the follow-up period. There were no statistically significant associations between any of the measured psychosocial factors and DDFS or OS from the adjusted analyses. From unadjusted analyses, associations between greater anxious preoccupation and poorer DDFS and OS were observed (P = .02). These associations were no longer evident after adjustment for established prognostic factors; greater anxious preoccupation was associated with younger age at diagnosis (P = .03), higher tumor grade (P = .02), and greater number of involved axillary nodes (P = .008).
Conclusion
The findings do not support the measured psychosocial factors being an important influence on breast cancer outcomes. Interventions for adverse psychosocial factors are warranted to improve quality of life but should not be expected to improve survival.
doi:10.1200/JCO.2007.14.8718
PMCID: PMC2653129  PMID: 18824713
16.  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
17.  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
18.  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
19.  Tamoxifen and Risk of Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers 
Journal of Clinical Oncology  2013;31(25):3091-3099.
Purpose
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
Methods
Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
Results
Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
Conclusion
This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
doi:10.1200/JCO.2012.47.8313
PMCID: PMC3753701  PMID: 23918944
20.  Anti-Müllerian hormone serum concentrations of women with germline BRCA1 or BRCA2 mutations 
Human Reproduction (Oxford, England)  2016;31(5):1126-1132.
STUDY QUESTION
Do women with BRCA1 or BRCA2 mutations have reduced ovarian reserve, as measured by circulating anti-Müllerian hormone (AMH) concentration?
SUMMARY ANSWER
Women with a germline mutation in BRCA1 have reduced ovarian reserve as measured by AMH.
WHAT IS KNOWN ALREADY
The DNA repair enzymes encoded by BRCA1 and BRCA2 are implicated in reproductive aging. Circulating AMH is a biomarker of ovarian reserve and hence reproductive lifespan.
STUDY DESIGN, SIZE, DURATION
This was a cross-sectional study of AMH concentrations of 693 women at the time of enrolment into the Kathleen Cuningham Foundation Consortium for research in the Familial Breast Cancer (kConFab) cohort study (recruitment from 19 August 1997 until 18 September 2012). AMH was measured on stored plasma samples between November 2014 and January 2015 using an electrochemiluminescence immunoassay platform.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Eligible women were from families segregating BRCA1 or BRCA2 mutations and had known mutation status. Participants were aged 25–45 years, had no personal history of cancer, retained both ovaries and were not pregnant or breastfeeding at the time of plasma storage. Circulating AMH was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Associations between plasma AMH concentration and carrier status were tested by linear regression, adjusted for age at plasma storage, oral contraceptive use, body mass index and cigarette smoking.
MAIN RESULTS AND THE ROLE OF CHANCE
Mean AMH concentration was negatively associated with age (P < 0.001). Mutation carriers were younger at blood draw than non-carriers (P ≤ 0.031). BRCA1 mutation carriers had, on average, 25% (95% CI: 5%–41%, P = 0.02) lower AMH concentrations than non-carriers and were more likely to have AMH concentrations in the lowest quartile for age (OR 1.84, 95% CI: 1.11–303, P = 0.02). There was no evidence of an association between AMH concentration and BRCA2 mutation status (P = 0.94).
LIMITATIONS, REASONS FOR CAUTION
AMH does not directly measure the primordial follicle pool. The clinical implications of the lower AMH concentrations seen in BRCA1 mutation carriers cannot be assessed by this study design.
WIDER IMPLICATIONS OF THE FINDINGS
Women with a germline mutation in BRCA1 may have reduced ovarian reserve. This is consistent with other smaller studies in the literature and has potential implications for fertility and reproductive lifespan.
STUDY FUNDING/COMPETING INTEREST(S)
kConFab is supported by a grant from the Australian National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. K.A.P. is an Australian National Breast Cancer Foundation Practitioner Fellow. J.L.H. is a NHMRC Senior Principal Research Fellow. M.H. is a NHMRC Practitioner Fellow. R.A.A. reports personal fees from Roche Diagnostics & Beckman Coulter outside the submitted work and C.S. reports other earnings from Melbourne IVF outside the submitted work. The remaining authors have nothing to declare and no conflicts of interest.
doi:10.1093/humrep/dew044
PMCID: PMC4840025  PMID: 27094481
BRCA1; BRCA2; anti-Müllerian hormone; ovarian reserve; fertility; DNA repair; reproduction
21.  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
22.  Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia 
Berndt, Sonja I. | Camp, Nicola J. | Skibola, Christine F. | Vijai, Joseph | Wang, Zhaoming | Gu, Jian | Nieters, Alexandra | Kelly, Rachel S. | Smedby, Karin E. | Monnereau, Alain | Cozen, Wendy | Cox, Angela | Wang, Sophia S. | Lan, Qing | Teras, Lauren R. | Machado, Moara | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Vajdic, Claire M. | Cocco, Pierluigi | Zhang, Yawei | Giles, Graham G. | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Montalvan, Rebecca | Burdett, Laurie | Hutchinson, Amy | Ye, Yuanqing | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Cunningham, Julie M. | Allmer, Cristine | Hjalgrim, Henrik | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Diver, W Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Arnett, Donna K. | Zhi, Degui | Leach, Justin M. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Sala, Núria | Casabonne, Delphine | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Chaffee, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R. | Strom, Sara S. | Leis, Jose F. | Weinberg, J. Brice | Caporaso, Neil E. | Norman, Aaron D. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María- Dolores | Vermeulen, Roel C. H. | Travis, Ruth C. | Southey, Melissa C. | Milne, Roger L. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R. | Villano, Danylo J. | Maria, Ann | Spinelli, John J. | Gascoyne, Randy D. | Connors, Joseph M. | Bertrand, Kimberly A. | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Ma, Baoshan | Huang, Jinyan | Crouch, Simon | Park, Ju-Hyun | Chatterjee, Nilanjan | North, Kari E. | Snowden, John A. | Wright, Josh | Fraumeni, Joseph F. | Offit, Kenneth | Wu, Xifeng | de Sanjose, Silvia | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature Communications  2016;7:10933.
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
doi:10.1038/ncomms10933
PMCID: PMC4786871  PMID: 26956414
23.  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
24.  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
25.  Common Genetic Variation in Circadian Rhythm Genes and Risk of Epithelial Ovarian Cancer (EOC) 
Jim, Heather S.L. | Lin, Hui-Yi | Tyrer, Jonathan P. | Lawrenson, Kate | Dennis, Joe | Chornokur, Ganna | Chen, Zhihua | Chen, Ann Y. | Permuth-Wey, Jennifer | Aben, Katja KH. | Anton-Culver, Hoda | Antonenkova, Natalia | Bruinsma, Fiona | Bandera, Elisa V. | Bean, Yukie T. | Beckmann, Matthias W. | Bisogna, Maria | Bjorge, Line | Bogdanova, Natalia | Brinton, Louise A. | Brooks-Wilson, Angela | Bunker, Clareann H. | Butzow, Ralf | Campbell, Ian G. | Carty, Karen | Chang-Claude, Jenny | Cook, Linda S. | Cramer, Daniel W. | Cunningham, Julie M. | Cybulski, Cezary | Dansonka-Mieszkowska, Agnieszka | du Bois, Andreas | Despierre, Evelyn | Sieh, Weiva | Doherty, Jennifer A. | Dörk, Thilo | Dürst, Matthias | Easton, Douglas F. | Eccles, Diana M. | Edwards, Robert P. | Ekici, Arif B. | Fasching, Peter A. | Fridley, Brooke L. | Gao, Yu-Tang | Gentry-Maharaj, Aleksandra | Giles, Graham G. | Glasspool, Rosalind | Goodman, Marc T. | Gronwald, Jacek | Harter, Philipp | Hasmad, Hanis N. | Hein, Alexander | Heitz, Florian | Hildebrandt, Michelle A.T. | Hillemanns, Peter | Hogdall, Claus K. | Hogdall, Estrid | Hosono, Satoyo | Iversen, Edwin S. | Jakubowska, Anna | Jensen, Allan | Ji, Bu-Tian | Karlan, Beth Y. | Kellar, Melissa | Kiemeney, Lambertus A. | Krakstad, Camilla | Kjaer, Susanne K. | Kupryjanczyk, Jolanta | Vierkant, Robert A. | Lambrechts, Diether | Lambrechts, Sandrina | Le, Nhu D. | Lee, Alice W. | Lele, Shashi | Leminen, Arto | Lester, Jenny | Levine, Douglas A. | Liang, Dong | Lim, Boon Kiong | Lissowska, Jolanta | Lu, Karen | Lubinski, Jan | Lundvall, Lene | Massuger, Leon F.A.G. | Matsuo, Keitaro | McGuire, Valerie | McLaughlin, John R. | McNeish, Ian | Menon, Usha | Milne, Roger L. | Modugno, Francesmary | Thomsen, Lotte | Moysich, Kirsten B. | Ness, Roberta B. | Nevanlinna, Heli | Eilber, Ursula | Odunsi, Kunle | Olson, Sara H. | Orlow, Irene | Orsulic, Sandra | Palmieri Weber, Rachel | Paul, James | Pearce, Celeste L. | Pejovic, Tanja | Pelttari, Liisa M. | Pike, Malcolm C. | Poole, Elizabeth M. | Schernhammer, Eva | Risch, Harvey A. | Rosen, Barry | Rossing, Mary Anne | Rothstein, Joseph H. | Rudolph, Anja | Runnebaum, Ingo B. | Rzepecka, Iwona K. | Salvesen, Helga B. | Schwaab, Ira | Shu, Xiao-Ou | Shvetsov, Yurii B. | Siddiqui, Nadeem | Song, Honglin | Southey, Melissa C. | Spiewankiewicz, Beata | Sucheston-Campbell, Lara | Teo, Soo-Hwang | Terry, Kathryn L. | Thompson, Pamela J. | Tangen, Ingvild L. | Tworoger, Shelley S. | van Altena, Anne M. | Vergote, Ignace | Walsh, Christine S. | Wang-Gohrke, Shan | Wentzensen, Nicolas | Whittemore, Alice S. | Wicklund, Kristine G. | Wilkens, Lynne R. | Wu, Anna H. | Wu, Xifeng | Woo, Yin-Ling | Yang, Hannah | Zheng, Wei | Ziogas, Argyrios | Amankwah, Ernest | Berchuck, Andrew | Schildkraut, Joellen M. | Kelemen, Linda E. | Ramus, Susan J. | Monteiro, Alvaro N.A. | Goode, Ellen L. | Narod, Steven A. | Gayther, Simon A. | Pharoah, Paul D. P. | Sellers, Thomas A. | Phelan, Catherine M.
Disruption in circadian gene expression, whether due to genetic variation or environmental factors (e.g., light at night, shiftwork), is associated with increased incidence of breast, prostate, gastrointestinal and hematologic cancers and gliomas. Circadian genes are highly expressed in the ovaries where they regulate ovulation; circadian disruption is associated with several ovarian cancer risk factors (e.g., endometriosis). However, no studies have examined variation in germline circadian genes as predictors of ovarian cancer risk and invasiveness. The goal of the current study was to examine single nucleotide polymorphisms (SNPs) in circadian genes BMAL1, CRY2, CSNK1E, NPAS2, PER3, REV1 and TIMELESS and downstream transcription factors KLF10 and SENP3 as predictors of risk of epithelial ovarian cancer (EOC) and histopathologic subtypes. The study included a test set of 3,761 EOC cases and 2,722 controls and a validation set of 44,308 samples including 18,174 (10,316 serous) cases and 26,134 controls from 43 studies participating in the Ovarian Cancer Association Consortium (OCAC). Analysis of genotype data from 36 genotyped SNPs and 4600 imputed SNPs indicated that the most significant association was rs117104877 in BMAL1 (OR = 0.79, 95% CI = 0.68–0.90, p = 5.59 × 10−4]. Functional analysis revealed a significant down regulation of BMAL1 expression following cMYC overexpression and increasing transformation in ovarian surface epithelial (OSE) cells as well as alternative splicing of BMAL1 exons in ovarian and granulosa cells. These results suggest that variation in circadian genes, and specifically BMAL1, may be associated with risk of ovarian cancer, likely through disruption of hormonal pathways.
PMCID: PMC4722961  PMID: 26807442

Results 1-25 (92)