Author: "Doerk, T" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Doerk, T"' showing total 162 results

Start Over Author "Doerk, T"

162 results on '"Doerk, T"'

51. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

Author: Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, Lawrenson, K, Kar, SP, Adler, E, Tyrer, J, Hazelett, D, Anton-Culver, H, Bandera, EV, Beckmann, MW, Berchuck, A, Bogdanova, N, Brinton, L, Butzow, R, Campbell, I, Carty, K, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Doherty, JA, Doerk, T, Duerst, M, Eccles, D, Fasching, PA, Flanagan, J, Gentry-Maharaj, A, Glasspool, R, Goode, EL, Goodman, MT, Gronwald, J, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Huntsman, DG, Jensen, A, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Levine, DA, Li, Q, Lissowska, J, Lu, KH, Lubinski, J, Massuger, LFAG, McGuire, V, McNeish, I, Menon, U, Modugno, F, Monteiro, AN, Moysich, KB, Ness, RB, Nevanlinna, H, Paul, J, Pearce, CL, Pejovic, T, Permuth, JB, Phelan, C, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rossing, MA, Salvesen, HB, Schildkraut, JM, Sellers, TA, Sherman, M, Siddiqui, N, Sieh, W, Song, H, Southey, M, Terry, KL, Tworoger, SS, Walsh, C, Wentzensen, N, Whittemore, AS, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Freedman, ML, Gayther, SA, Pharoah, PDP, and Lawrenson, K
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery), and combined (9627 cases/30 845 controls; including additional individuals). RESULTS: The PAX8-target gene set was ranked 1/615 in the discovery (PGSEA<0.001; FDR=0.21), 7/615 in the replication (PGSEA=0.004; FDR=0.37), and 1/615 in the combined (PGSEA<0.001; FDR=0.21) studies. Adding other genes reported to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P<10-5 (including six with P<5 × 10-8). The pathway was also associated with differential gene expression after shRNA-mediated silencing of PAX8 in HeyA8 (PGSEA=0.025) and IGROV1 (PGSEA=0.004) SOC cells and several PAX8 targets near SOC risk loci demonstrated in vitro transcriptomic perturbation. CONCLUSIONS: Putative PAX8 target genes are enriched for common SOC risk variants. This finding from our agnostic evaluation is of particular interest given that PAX8 is well-established as a specific marker for the cell of origin of SOC.
Published: 2017

52. Genetic modifiers of CHEK2*1100delC-associated breast cancer risk

Author: Muranen, TA, Greco, D, Blomqvist, C, Aittomaki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE, Nordestgaard, BG, Schoemaker, M, Swerdlow, A, Garcia-Closas, M, Figueroa, J, Doerk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Peto, J, Silva, IDS, Couch, FJ, Olson, JE, Hillemans, P, Park-Simon, T-W, Brauch, H, Hamann, U, Burwinkel, B, Marme, F, Meindl, A, Schmutzler, RK, Cox, A, Cross, SS, Sawyer, EJ, Tomlinson, I, Lambrechts, D, Moisse, M, Lindblom, A, Margolin, S, Hollestelle, A, Martens, JWM, Fasching, PA, Beckmann, MW, Andrulis, IL, Knight, JA, Anton-Culver, H, Ziogas, A, Giles, GG, Milne, RL, Brenner, H, Arndt, V, Mannermaa, A, Kosma, V-M, Chang-Claude, J, Rudolph, A, Devilee, P, Seynaeve, C, Hopper, JL, Southey, MC, John, EM, Whittemore, AS, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Easton, DF, Schmidt, MK, Nevanlinna, H, Muranen, TA, Greco, D, Blomqvist, C, Aittomaki, K, Khan, S, Hogervorst, F, Verhoef, S, Pharoah, PDP, Dunning, AM, Shah, M, Luben, R, Bojesen, SE, Nordestgaard, BG, Schoemaker, M, Swerdlow, A, Garcia-Closas, M, Figueroa, J, Doerk, T, Bogdanova, NV, Hall, P, Li, J, Khusnutdinova, E, Bermisheva, M, Kristensen, V, Borresen-Dale, A-L, Peto, J, Silva, IDS, Couch, FJ, Olson, JE, Hillemans, P, Park-Simon, T-W, Brauch, H, Hamann, U, Burwinkel, B, Marme, F, Meindl, A, Schmutzler, RK, Cox, A, Cross, SS, Sawyer, EJ, Tomlinson, I, Lambrechts, D, Moisse, M, Lindblom, A, Margolin, S, Hollestelle, A, Martens, JWM, Fasching, PA, Beckmann, MW, Andrulis, IL, Knight, JA, Anton-Culver, H, Ziogas, A, Giles, GG, Milne, RL, Brenner, H, Arndt, V, Mannermaa, A, Kosma, V-M, Chang-Claude, J, Rudolph, A, Devilee, P, Seynaeve, C, Hopper, JL, Southey, MC, John, EM, Whittemore, AS, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Easton, DF, Schmidt, MK, and Nevanlinna, H
Abstract: PURPOSE: CHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC). METHODS: Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction. RESULTS: The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average. CONCLUSION: Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
Published: 2017

53. PALB2, CHEK2 and ATM rare variants and cancer risk:data from COGS

Author: Southey, M. C. (Melissa C.), Goldgar, D. E. (David E.), Winqvist, R. (Robert), Pylkäs, K. (Katri), Couch, F. (Fergus), Tischkowitz, M. (Marc), Foulkes, W. D. (William D.), Dennis, J. (Joe), Michailidou, K. (Kyriaki), van Rensburg, E. J. (Elizabeth J.), Heikkinen, T. (Tuomas), Nevanlinna, H. (Heli), Hopper, J. L. (John L.), Doerk, T. (Thilo), Claes, K. B. (Kathleen B. M.), Reis-Filho, J. (Jorge), Teo, Z. L. (Zhi Ling), Radice, P. (Paolo), Catucci, I. (Irene), Peterlongo, P. (Paolo), Tsimiklis, H. (Helen), Odefrey, F. A. (Fabrice A.), Dowty, J. G. (James G.), Schmidt, M. K. (Marjanka K.), Broeks, A. (Annegien), Hogervorst, F. B. (Frans B.), Verhoef, S. (Senno), Carpenter, J. (Jane), Clarke, C. (Christine), Scott, R. J. (Rodney J.), Fasching, P. A. (Peter A.), Haeberle, L. (Lothar), Ekici, A. B. (Arif B.), Beckmann, M. W. (Matthias W.), Peto, J. (Julian), dos-Santos-Silva, I. (Isabel), Fletcher, O. (Olivia), Johnson, N. (Nichola), Bolla, M. K. (Manjeet K.), Sawyer, E. J. (Elinor J.), Tomlinson, I. (Ian), Kerin, M. J. (Michael J.), Miller, N. (Nicola), Marme, F. (Federik), Burwinkel, B. (Barbara), Yang, R. (Rongxi), Guenel, P. (Pascal), Menegaux, F. (Florence), Sanchez, M. (Marie), Bojesen, S. (Stig), Nielsen, S. F. (Sune F.), Flyger, H. (Henrik), Benitez, J. (Javier), Pilar Zamora, M. (M.), Arias Perez, J. I. (Jose Ignacio), Menendez, P. (Primitiva), Anton-Culver, H. (Hoda), Neuhausen, S. (Susan), Ziogas, A. (Argyrios), Clarke, C. A. (Christina A.), Brenner, H. (Hermann), Arndt, V. (Volker), Stegmaier, C. (Christa), Brauch, H. (Hiltrud), Bruening, T. (Thomas), Ko, Y.-D. (Yon-Dschun), Muranen, T. A. (Taru A.), Aittomaki, K. (Kristiina), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia V.), Antonenkova, N. N. (Natalia N.), Lindblom, A. (Annika), Margolin, S. (Sara), Mannermaa, A. (Arto), Kataja, V. (Vesa), Kosma, V.-M. (Veli-Matti), Hartikainen, J. M. (Jaana M.), Spurdle, A. B. (Amanda B.), Wauters, E. (Els), Smeets, D. (Dominiek), Beuselinck, B. (Benoit), Floris, G. (Giuseppe), Chang-Claude, J. (Jenny), Rudolph, A. (Anja), Seibold, P. (Petra), Flesch-Janys, D. (Dieter), Olson, J. E. (Janet E.), Vachon, C. (Celine), Pankratz, V. S. (Vernon S.), McLean, C. (Catriona), Haiman, C. A. (Christopher A.), Henderson, B. E. (Brian E.), Schumacher, F. (Fredrick), Le Marchand, L. (Loic), Kristensen, V. (Vessela), Alnaes, G. G. (Grethe Grenaker), Zheng, W. (Wei), Hunter, D. J. (David J.), Lindstrom, S. (Sara), Hankinson, S. E. (Susan E.), Kraft, P. (Peter), Andrulis, I. (Irene), Knight, J. A. (Julia A.), Glendon, G. (Gord), Mulligan, A. M. (Anna Marie), Jukkola-Vuorinen, A. (Arja), Grip, M. (Mervi), Kauppila, S. (Saila), Devilee, P. (Peter), Tollenaar, R. A. (Robert A. E. M.), Seynaeve, C. (Caroline), Hollestelle, A. (Antoinette), Garcia-Closas, M. (Montserrat), Figueroa, J. (Jonine), Chanock, S. J. (Stephen J.), Lissowska, J. (Jolanta), Czene, K. (Kamila), Darabi, H. (Hatef), Eriksson, M. (Mikael), Eccles, D. M. (Diana M.), Rafiq, S. (Sajjad), Tapper, W. J. (William J.), Gerty, S. M. (Sue M.), Hooning, M. J. (Maartje J.), Martens, J. W. (John W. M.), Collee, J. M. (J. Margriet), Tilanus-Linthorst, M. (Madeleine), Hall, P. (Per), Li, J. (Jingmei), Brand, J. S. (Judith S.), Humphreys, K. (Keith), Cox, A. (Angela), Reed, M. W. (Malcolm W. R.), Luccarini, C. (Craig), Baynes, C. (Caroline), Dunning, A. M. (Alison M.), Hamann, U. (Ute), Torres, D. (Diana), Ulmer, H. U. (Hans Ulrich), Ruediger, T. (Thomas), Jakubowska, A. (Anna), Lubinski, J. (Jan), Jaworska, K. (Katarzyna), Durda, K. (Katarzyna), Slager, S. (Susan), Toland, A. E. (Amanda E.), Ambrosone, C. B. (Christine B.), Yannoukakos, D. (Drakoulis), Swerdlow, A. (Anthony), Ashworth, A. (Alan), Orr, N. (Nick), Jones, M. (Michael), Gonzalez-Neira, A. (Anna), Pita, G. (Guillermo), Rosario Alonso, M. (M.), Alvarez, N. (Nuria), Herrero, D. (Daniel), Tessier, D. C. (Daniel C.), Vincent, D. (Daniel), Bacot, F. (Francois), Simard, J. (Jacques), Dumont, M. (Martine), Soucy, P. (Penny), Eeles, R. (Rosalind), Muir, K. (Kenneth), Wiklund, F. (Fredrik), Gronberg, H. (Henrik), Schleutker, J. (Johanna), Nordestgaard, B. G. (Borge G.), Weischer, M. (Maren), Travis, R. C. (Ruth C.), Neal, D. (David), Donovan, J. L. (Jenny L.), Hamdy, F. C. (Freddie C.), Khaw, K.-T. (Kay-Tee), Stanford, J. L. (Janet L.), Blot, W. J. (William J.), Thibodeau, S. (Stephen), Schaid, D. J. (Daniel J.), Kelley, J. L. (Joseph L.), Maier, C. (Christiane), Kibel, A. S. (Adam S.), Cybulski, C. (Cezary), Cannon-Albright, L. (Lisa), Butterbach, K. (Katja), Park, J. (Jong), Kaneva, R. (Radka), Batra, J. (Jyotsna), Teixeira, M. R. (Manuel R.), Kote-Jarai, Z. (Zsofia), Al Olama, A. A. (Ali Amin), Benlloch, S. (Sara), Renner, S. P. (Stefan P.), Hartmann, A. (Arndt), Hein, A. (Alexander), Ruebner, M. (Matthias), Lambrechts, D. (Diether), Van Nieuwenhuysen, E. (Els), Vergote, I. (Ignace), Lambretchs, S. (Sandrina), Doherty, J. A. (Jennifer A.), Rossing, M. A. (Mary Anne), Nickels, S. (Stefan), Eilber, U. (Ursula), Wang-Gohrke, S. (Shan), Odunsi, K. (Kunle), Sucheston-Campbell, L. E. (Lara E.), Friel, G. (Grace), Lurie, G. (Galina), Killeen, J. L. (Jeffrey L.), Wilkens, L. R. (Lynne R.), Goodman, M. T. (Marc T.), Runnebaum, I. (Ingo), Hillemanns, P. A. (Peter A.), Pelttari, L. M. (Liisa M.), Butzow, R. (Ralf), Modugno, F. (Francesmary), Edwards, R. P. (Robert P.), Ness, R. B. (Roberta B.), Moysich, K. B. (Kirsten B.), du Bois, A. (Andreas), Heitz, F. (Florian), Harter, P. (Philipp), Kommoss, S. (Stefan), Karlan, B. Y. (Beth Y.), Walsh, C. (Christine), Lester, J. (Jenny), Jensen, A. (Allan), Kjaer, S. K. (Susanne Kruger), Hogdall, E. (Estrid), Peissel, B. (Bernard), Bonanni, B. (Bernardo), Bernard, L. (Loris), Goode, E. L. (Ellen L.), Fridley, B. L. (Brooke L.), Vierkant, R. A. (Robert A.), Cunningham, J. M. (Julie M.), Larson, M. C. (Melissa C.), Fogarty, Z. C. (Zachary C.), Kalli, K. R. (Kimberly R.), Liang, D. (Dong), Lu, K. H. (Karen H.), Hildebrandt, M. A. (Michelle A. T.), Wu, X. (Xifeng), Levine, D. A. (Douglas A.), Dao, F. (Fanny), Bisogna, M. (Maria), Berchuck, A. (Andrew), Iversen, E. S. (Edwin S.), Marks, J. R. (Jeffrey R.), Akushevich, L. (Lucy), Cramer, D. W. (Daniel W.), Schildkraut, J. (Joellen), Terry, K. L. (Kathryn L.), Poole, E. M. (Elizabeth M.), Stampfer, M. (Meir), Tworoger, S. S. (Shelley S.), Bandera, E. V. (Elisa V.), Orlow, I. (Irene), Olson, S. H. (Sara H.), Bjorge, L. (Line), Salvesen, H. B. (Helga B.), van Altena, A. M. (Anne M.), Aben, K. K. (Katja K. H.), Kiemeney, L. A. (Lambertus A.), Massuger, L. F. (Leon F. A. G.), Pejovic, T. (Tanja), Bean, Y. (Yukie), Brooks-Wilson, A. (Angela), Kelemen, L. E. (Linda E.), Cook, L. S. (Linda S.), Le, N. D. (Nhu D.), Grski, B. (Bohdan), Gronwald, J. (Jacek), Menkiszak, J. (Janusz), Hogdall, C. K. (Claus K.), Lundvall, L. (Lene), Nedergaard, L. (Lotte), Engelholm, S. A. (Svend Aage), Dicks, E. (Ed), Tyrer, J. (Jonathan), Campbell, I. (Ian), McNeish, I. (Iain), Paul, J. (James), Siddiqui, N. (Nadeem), Glasspool, R. (Rosalind), Whittemore, A. S. (Alice S.), Rothstein, J. H. (Joseph H.), McGuire, V. (Valerie), Sieh, W. (Weiva), Cai, H. (Hui), Shu, X.-O. (Xiao-Ou), Teten, R. T. (Rachel T.), Sutphen, R. (Rebecca), McLaughlin, J. R. (John R.), Narod, S. A. (Steven A.), Phelan, C. M. (Catherine M.), Monteiro, A. N. (Alvaro N.), Fenstermacher, D. (David), Lin, H.-Y. (Hui-Yi), Permuth, J. B. (Jennifer B.), Sellers, T. A. (Thomas A.), Chen, Y. A. (Y. Ann), Tsai, Y.-Y. (Ya-Yu), Chen, Z. (Zhihua), Gentry-Maharaj, A. (Aleksandra), Gayther, S. A. (Simon A.), Ramus, S. J. (Susan J.), Menon, U. (Usha), Wu, A. H. (Anna H.), Pearce, C. L. (Celeste L.), Van den Berg, D. (David), Pike, M. C. (Malcolm C.), Dansonka-Mieszkowska, A. (Agnieszka), Plisiecka-Halasa, J. (Joanna), Moes-Sosnowska, J. (Joanna), Kupryjanczyk, J. (Jolanta), Pharoah, P. D. (Paul D. P.), Song, H. (Honglin), Winship, I. (Ingrid), Chenevix-Trench, G. (Georgia), Giles, G. G. (Graham G.), Tavtigian, S. V. (Sean V.), Easton, D. F. (Doug F.), and Milne, R. L. (Roger L.)
Subjects: skin and connective tissue diseases
Abstract: 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.
Published: 2016

54. Corrigendum: Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, Y-Y, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brooks-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, Vergote, I, Amant, F, Lambrechts, D, Despierre, E, Fasching, PA, Beckmann, MW, Thiel, FC, Ekici, AB, Chen, X, Australian Ovarian Cancer Study Group, Johnatty, SE, Webb, PM, Beesley, J, Chanock, S, Garcia-Closas, M, Sellers, T, Easton, DF, Berchuck, A, Chenevix-Trench, G, Pharoah, PDP, and Gayther, SA
Subjects: Australian Ovarian Cancer Study Group
Published: 2016

55. Abstract P5-10-09: Prospective cross-sectional-study on participation in mammography screening according to immigration background and education status

Author: Kuehnle, E, primary, Oeztuerk, T, additional, Siggelkow, W, additional, Luebbe, K, additional, Moser, A, additional, Noeding, S, additional, John, J, additional, Noesselt, T, additional, Busch, C, additional, Arfsten, M, additional, Lemster, S, additional, Hillemans, P, additional, Doerk, T, additional, and Park-Simon, T-W, additional
Published: 2017
Full Text: View/download PDF

56. Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci

Author: Al Olama, A.A., Benlloch, S., Antoniou, A.C., Giles, G.G., Severi, G., Neal, D.E., Hamdy, F.C., Donovan, J.L., Muir, K., Schleutker, J., Henderson, B.E., Haiman, C.A., Schumacher, F.R., Pashayan, N., Pharoah, P.D.P., Ostrander, E.A., Stanford, J.L., Batra, J., Clements, J.A., Chambers, S.K., Weischer, M., Nordestgaard, B.G., Ingles, S.A., Sorensen, K.D., Orntoft, T.F., Park, J.Y., Cybulski, C., Maier, C., Doerk, T., Dickinson, J.L., Cannon-Albright, L., Brenner, H., Rebbeck, T.R., Zeigler-Johnson, C., Habuchi, T., Thibodeau, S.N., Cooney, K.A., Chappuis, P.O., Hutter, P., Kaneva, R.P., Foulkes, W.D., Zeegers, M.P., Lu, Y-J., Zhang, H-W., Stephenson, R., Cox, A., Southey, M.C., Spurdle, A.B., FitzGerald, L., Leongamornlert, D., Saunders, E., Tymrakiewicz, M., Guy, M., Dadaev, T., Little, S.J., Govindasami, K., Sawyer, E., Wilkinson, R., Herkommer, K., Hopper, J.L., Lophatonanon, A., Rinckleb, A.E., Kote-Jarai, Z., Eeles, R.A., Easton, D.F., Surgeons, B.A.U., Collaborators, U.K.P.S., Consortium, PRACTICAL., Amin Al Olama, Ali [0000-0002-7178-3431], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, Male, Genotype, Genetic Variation, Prostatic Neoplasms, Middle Aged, urologic and male genital diseases, Risk Assessment, Risk Factors, Odds Ratio, Humans, Genetic Predisposition to Disease, Alleles, Aged, Genome-Wide Association Study
Abstract: BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. RESULTS: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). CONCLUSIONS: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. IMPACT: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
Published: 2015

57. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author: Painter, J.N., O'Mara, T.A., Batra, J., Cheng, T., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Kaufmann, S., Hillman, K.M., Walpole, C., Moya, L., Pollock, P., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Magdalena Echeverry De Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Santos, E., Teixeira, M.R., Carvajal-Carmona, L., Shu, X-O., Long, J., Zheng, W., Xiang, Y-B., Montgomery, G.W., Webb, P.M., Scott, R.J., McEvoy, M., Attia, J., Holliday, E., Martin, N.G., Nyholt, D.R., Henders, A.K., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Ashton, K., Proietto, T., Otton, G., Tzortzatos, G., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., French, J.D., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Edwards, S.L., Thompson, D.J., Spurdle, A.B., Canc, N.S.E., Consortium, CHIBCHA, Canc, ANE, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Thompson, Deborah [0000-0003-1465-5799], and Apollo - University of Cambridge Repository
Subjects: Genotype, Chromosome Mapping, Computational Biology, Genetic Variation, Polymorphism, Single Nucleotide, Linkage Disequilibrium, White People, Endometrial Neoplasms, Epigenesis, Genetic, Haplotypes, Genetic Loci, Risk Factors, Case-Control Studies, Cell Line, Tumor, Databases, Genetic, Humans, Female, RNA, Messenger, Promoter Regions, Genetic, Alleles, Genome-Wide Association Study, Hepatocyte Nuclear Factor 1-beta
Abstract: Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1,184 genotyped and imputed SNPs in 6,608 Caucasian cases and 37,925 controls, and 895 Asian cases and 1,968 controls, revealed the best signal of association for SNP rs11263763 (P=8.4×10(-14), OR=0.86, 95% CI=0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumour samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high to moderate LD as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression. ispartof: Human Molecular Genetics vol:24 issue:5 pages:1478-92 ispartof: location:England status: published
Published: 2015

58. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author: Carvajal-Carmona, L.G., O'Mara, T.A., Painter, J.N.., Lose, F.A., Dennis, J., Michailidou, K., Tyrer, J.P., Ahmed, S., Ferguson, K., Healey, C.S., Pooley, K., Beesley, J., Cheng, T., Jones, A., Howarth, K., Martin, L., Gorman, M., Hodgson, S., Wentzensen, N., Fasching, P.A., Hein, A., Beckmann, M.W., Renner, S.P., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I., Lambrechts, D., Coenegrachts, L., Schrauwen, S., Amant, F., Winterhoff, B., Dowdy, S.C., Goode, E.L., Teoman, A., Salvesen, H.B., Trovik, J., Njolstad, T.S., Werner, H.M.J., Scott, R.J., Ashton, K., Proietto, T., Otton, G., Wersaell, O., Mints, M., Tham, E., Hall, P., Czene, K., Liu, J., Li, J., Hopper, J.L., Southey, M.C., Ekici, A.B., Ruebner, M., Johnson, N., Peto, J., Burwinkel, B., Marme, F., Brenner, H., Dieffenbach, A.K., Meindl, A., Brauch, H., Lindblom, A., Depreeuw, J., Moisse, M., Chang-Claude, J., Rudolph, A., Couch, F.J., Olson, J.E., Giles, G.G., Bruinsma, F., Cunningham, J.M., Fridley, B.L., Borresen-Dale, A.-L., Kristensen, V.N., Cox, A., Swerdlow, A.J., Orr, N., Bolla, M.K., Wang, Q., Weber, R.P., Chen, Z., Shah, M., Pharoah, P.D.P., Dunning, A.M., Tomlinson, I., Easton, D.F., Spurdle, A.B., Thompson, D.J., NSECG, ANECS, RENDOCAS, AOCS, Network, GENICA, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Pooley, Karen [0000-0002-1274-9460], Wang, Jean [0000-0002-9139-0627], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: National Study of Endometrial Cancer Genetics Group, Australian Ovarian Cancer Study, Polymorphism, Single Nucleotide, Chromosomes, Promoter Regions, Paediatrics and Reproductive Medicine, Databases, Uterine Cancer, Genetic, Complementary and Alternative Medicine, Risk Factors, Models, Australian National Endometrial Cancer Study Group, Genetics, 2.1 Biological and endogenous factors, Humans, Genetic Testing, Aetiology, Polymorphism, Promoter Regions, Genetic, Telomerase, Cancer, Genetics & Heredity, Neoplastic, Models, Genetic, Nucleic Acid, RENDOCAS, Prevention, Human Genome, Membrane Proteins, Single Nucleotide, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Gene Expression Regulation, Haplotypes, Genetic Loci, Chromosomes, Human, Pair 5, Female, GENICA Network, Pair 5, Databases, Nucleic Acid, Human
Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility. ispartof: Human Genetics vol:134 issue:2 pages:231-45 ispartof: location:Germany status: published
Published: 2015

59. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author: Cheng, T.H.T., Thompson, D., Painter, J., O'Mara, T., Gorman, M., Martin, L., Palles, C., Jones, A., Buchanan, D.D., Win, A.K., Hopper, J., Jenkins, M., Lindor, N.M., Newcomb, P.A., Gallinger, S., Conti, D., Schumacher, F., Casey, G., Giles, G.G., Pharoah, P., Peto, J., Cox, A., Swerdlow, A., Couch, F., Cunningham, J.M., Goode, E.L., Winham, S.J., Lambrechts, D., Fasching, P., Burwinkel, B., Brenner, H., Brauch, H., Chang-Claude, J., Salvesen, H.B., Kristensen, V., Darabi, H., Li, J., Liu, T., Lindblom, A., Hall, P., Echeverry de Polanco, M., Sans, M., Carracedo, A., Castellvi-Bel, S., Rojas-Martinez, A., Jr, A.S., Teixeira, M.R., Dunning, A.M., Dennis, J., Otton, G., Proietto, T., Holliday, E., Attia, J., Ashton, K., Scott, R.J., McEvoy, M., Dowdy, S.C., Fridley, B.L., Werner, H.M.J., Trovik, J., Njolstad, T.S., Tham, E., Mints, M., Runnebaum, I., Hillemanns, P., Doerk, T., Amant, F., Schrauwen, S., Hein, A., Beckmann, M.W., Ekici, A., Czene, K., Meindl, A., Bolla, M.K., Michailidou, K., Tyrer, J.P., Wang, Q., Ahmed, S., Healey, C.S., Shah, M., Annibali, D., Depreeuw, J., Al-Tassan, N.A., Harris, R., Meyer, B.F., Whiffin, N., Hosking, F.J., Kinnersley, B., Farrington, S.M., Timofeeva, M., Tenesa, A., Campbell, H., Haile, R.W., Hodgson, S., Carvajal-Carmona, L., Cheadle, J.P., Easton, D., Dunlop, M., Houlston, R., Spurdle, A., Tomlinson, I., and Other departments
Subjects: Male, CARCINOMA, MICROSATELLITE INSTABILITY, DNA-POLYMERASE, LOCI, MTHFR C677T, VARIANTS, LYNCH-SYNDROME, Article, BREAST-CANCER, Humans, Genetic Predisposition to Disease, Alleles, Adaptor Proteins, Signal Transducing, RISK, Homeodomain Proteins, Science & Technology, Polymorphism, Genetic, MUTATIONS, Intracellular Signaling Peptides and Proteins, Proteins, Endometrial Neoplasms, Neoplasm Proteins, Multidisciplinary Sciences, Repressor Proteins, Science & Technology - Other Topics, Female, Colorectal Neoplasms, Genome-Wide Association Study
Abstract: High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers. ispartof: Scientific Reports vol:5 pages:17369- ispartof: location:England status: published
Published: 2015

60. Genetic predisposition to ductal carcinoma in situ of the breast

Author: Petridis, C, Brook, MN, Shah, V, Kohut, K, Gorman, P, Caneppele, M, Levi, D, Papouli, E, Orr, N, Cox, A, Cross, SS, dos-Santos-Silva, I, Peto, J, Swerdlow, A, Schoemaker, MJ, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Benitez, J, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Li, J, Figueroa, J, Kristensen, V, Borresen-Dale, A-L, Soucy, P, Simard, J, Milne, RL, Giles, GG, Margolin, S, Lindblom, A, Bruening, T, Brauch, H, Southey, MC, Hopper, JL, Doerk, T, Bogdanova, NV, Kabisch, M, Hamann, U, Schmutzler, RK, Meindl, A, Brenner, H, Arndt, V, Winqvist, R, Pylkas, K, Fasching, PA, Beckmann, MW, Lubinski, J, Jakubowska, A, Mulligan, AM, Andrulis, IL, Tollenaar, RAEM, Devilee, P, Le Marchand, L, Haiman, CA, Mannermaa, A, Kosma, V-M, Radice, P, Peterlongo, P, Marme, F, Burwinkel, B, van Deurzen, CHM, Hollestelle, A, Miller, N, Kerin, MJ, Lambrechts, D, Floris, G, Wesseling, J, Flyger, H, Bojesen, SE, Yao, S, Ambrosone, CB, Chenevix-Trench, G, Truong, T, Guenel, P, Rudolph, A, Chang-Claude, J, Nevanlinna, H, Blomqvist, C, Czene, K, Brand, JS, Olson, JE, Couch, FJ, Dunning, AM, Hall, P, Easton, DF, Pharoah, PDP, Pinder, SE, Schmidt, MK, Tomlinson, I, Roylance, R, Garcia-Closas, M, Sawyer, EJ, Petridis, C, Brook, MN, Shah, V, Kohut, K, Gorman, P, Caneppele, M, Levi, D, Papouli, E, Orr, N, Cox, A, Cross, SS, dos-Santos-Silva, I, Peto, J, Swerdlow, A, Schoemaker, MJ, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Benitez, J, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Li, J, Figueroa, J, Kristensen, V, Borresen-Dale, A-L, Soucy, P, Simard, J, Milne, RL, Giles, GG, Margolin, S, Lindblom, A, Bruening, T, Brauch, H, Southey, MC, Hopper, JL, Doerk, T, Bogdanova, NV, Kabisch, M, Hamann, U, Schmutzler, RK, Meindl, A, Brenner, H, Arndt, V, Winqvist, R, Pylkas, K, Fasching, PA, Beckmann, MW, Lubinski, J, Jakubowska, A, Mulligan, AM, Andrulis, IL, Tollenaar, RAEM, Devilee, P, Le Marchand, L, Haiman, CA, Mannermaa, A, Kosma, V-M, Radice, P, Peterlongo, P, Marme, F, Burwinkel, B, van Deurzen, CHM, Hollestelle, A, Miller, N, Kerin, MJ, Lambrechts, D, Floris, G, Wesseling, J, Flyger, H, Bojesen, SE, Yao, S, Ambrosone, CB, Chenevix-Trench, G, Truong, T, Guenel, P, Rudolph, A, Chang-Claude, J, Nevanlinna, H, Blomqvist, C, Czene, K, Brand, JS, Olson, JE, Couch, FJ, Dunning, AM, Hall, P, Easton, DF, Pharoah, PDP, Pinder, SE, Schmidt, MK, Tomlinson, I, Roylance, R, Garcia-Closas, M, and Sawyer, EJ
Abstract: 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.
Published: 2016

61. RAD51B in Familial Breast Cancer

Author: Brusgaard, K, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Doerk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, Garcia-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guenel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, Gonzalez-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Bruening, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Dumont, M, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Grip, M, Andrulis, IL, Glendon, G, Devilee, P, Seynaeve, C, Hooning, MJ, Collee, M, Cox, A, Cross, SS, Shah, M, Luben, RN, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Couch, FJ, Yannoukakos, D, Orr, N, Swerdlow, A, Darabi, H, Li, J, Czene, K, Hall, P, Easton, DF, Mattson, J, Blomqvist, C, Aittomaki, K, Nevanlinna, H, Brusgaard, K, Pelttari, LM, Khan, S, Vuorela, M, Kiiski, JI, Vilske, S, Nevanlinna, V, Ranta, S, Schleutker, J, Winqvist, R, Kallioniemi, A, Doerk, T, Bogdanova, NV, Figueroa, J, Pharoah, PDP, Schmidt, MK, Dunning, AM, Garcia-Closas, M, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Hopper, JL, Southey, MC, Rosenberg, EH, Fasching, PA, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Surowy, H, Guenel, P, Truong, T, Bojesen, SE, Nordestgaard, BG, Benitez, J, Gonzalez-Neira, A, Neuhausen, SL, Anton-Culver, H, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Bruening, T, Lindblom, A, Margolin, S, Mannermaa, A, Hartikainen, JM, Chenevix-Trench, G, Van Dyck, L, Janssen, H, Chang-Claude, J, Rudolph, A, Radice, P, Peterlongo, P, Hallberg, E, Olson, JE, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Dumont, M, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Grip, M, Andrulis, IL, Glendon, G, Devilee, P, Seynaeve, C, Hooning, MJ, Collee, M, Cox, A, Cross, SS, Shah, M, Luben, RN, Hamann, U, Torres, D, Jakubowska, A, Lubinski, J, Couch, FJ, Yannoukakos, D, Orr, N, Swerdlow, A, Darabi, H, Li, J, Czene, K, Hall, P, Easton, DF, Mattson, J, Blomqvist, C, Aittomaki, K, and Nevanlinna, H
Abstract: 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.
Published: 2016

62. Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21

Author: Hamdi, Y, Soucy, P, Adoue, V, Michailidou, K, Canisius, S, Lemacon, A, Droit, A, Andrulis, IL, Anton-Culver, H, Arndt, V, Baynes, C, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Chang-Claude, J, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Dennis, J, Devilee, P, Doerk, T, Dos-Santos-Silva, I, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Grenaker-Alnaes, G, Guenel, P, Haeberle, L, Haiman, CA, Hamann, U, Hallberg, E, Hooning, MJ, Hopper, JL, Jakubowska, A, Jones, M, Kabisch, M, Kataja, V, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Maranian, M, Margolin, S, Marme, F, Milne, RL, Neuhausen, SL, Nevanlinna, H, Neven, P, Olswold, C, Peto, J, Plaseska-Karanfilska, D, Pylkaes, K, Radice, P, Rudolph, A, Sawyer, EJ, Schmidt, MK, Shu, X-O, Southey, MC, Swerdlow, A, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Vachon, C, Van Den Ouweland, AMW, Wang, Q, Winqvist, R, Zheng, W, Benitez, J, Chenevix-Trench, G, Dunning, AM, Pharoah, PDP, Kristensen, V, Hall, P, Easton, DF, Pastinen, T, Nord, S, Simard, J, Hamdi, Y, Soucy, P, Adoue, V, Michailidou, K, Canisius, S, Lemacon, A, Droit, A, Andrulis, IL, Anton-Culver, H, Arndt, V, Baynes, C, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brenner, H, Broeks, A, Burwinkel, B, Chang-Claude, J, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Dennis, J, Devilee, P, Doerk, T, Dos-Santos-Silva, I, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Grenaker-Alnaes, G, Guenel, P, Haeberle, L, Haiman, CA, Hamann, U, Hallberg, E, Hooning, MJ, Hopper, JL, Jakubowska, A, Jones, M, Kabisch, M, Kataja, V, Lambrechts, D, Le Marchand, L, Lindblom, A, Lubinski, J, Mannermaa, A, Maranian, M, Margolin, S, Marme, F, Milne, RL, Neuhausen, SL, Nevanlinna, H, Neven, P, Olswold, C, Peto, J, Plaseska-Karanfilska, D, Pylkaes, K, Radice, P, Rudolph, A, Sawyer, EJ, Schmidt, MK, Shu, X-O, Southey, MC, Swerdlow, A, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Vachon, C, Van Den Ouweland, AMW, Wang, Q, Winqvist, R, Zheng, W, Benitez, J, Chenevix-Trench, G, Dunning, AM, Pharoah, PDP, Kristensen, V, Hall, P, Easton, DF, Pastinen, T, Nord, S, and Simard, J
Abstract: There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
Published: 2016

63. Fine scale mapping of the 17q22 breast cancer locus using dense SNPs, genotyped within the Collaborative Oncological Gene-Environment Study (COGs)

Author: Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, Dunning, AM, Darabi, H, Beesley, J, Droit, A, Kar, S, Nord, S, Marjaneh, MM, Soucy, P, Michailidou, K, Ghoussaini, M, Wahl, HF, Bolla, MK, Wang, Q, Dennis, J, Alonso, MR, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Benitez, J, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Chang-Claude, J, Choi, J-Y, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Easton, DF, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Galle, E, Garcia-Closas, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hallberg, E, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Ito, H, Jakubowska, A, Johnson, N, Kang, D, Khan, S, Kosma, V-M, Kriege, M, Kristensen, V, Lambrechts, D, Le Marchand, L, Lee, SC, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Mayes, R, Mckay, J, Meindl, A, Milne, RL, Muir, K, Neuhausen, SL, Nevanlinna, H, Olswold, C, Orr, N, Peterlongo, P, Pita, G, Pylkaes, K, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Surowy, H, Swerdlow, A, Teo, SH, Tessier, DC, Tomlinson, I, Torres, D, Truong, T, Vachon, CM, Vincent, D, Winqvist, R, Wu, AH, Wu, P-E, Yip, CH, Zheng, W, Pharoah, PDP, Hall, P, Edwards, SL, Simard, J, French, JD, Chenevix-Trench, G, and Dunning, AM
Abstract: 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), r(2) = 0.73 with lead SNP) and rs1156287 (OR = 0.93, P = 3.41 × 10(-11), r(2) = 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.
Published: 2016

64. Inherited variants affecting RNA editing may contribute to ovarian cancer susceptibility: results from a large-scale collaboration

Author: Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Doerk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, Jensen, A, Giles, G, Hildebrandt, M, Liang, D, Lu, KH, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Cramer, DW, Terry, KL, Tworoger, SS, Poole, EM, Bandera, EV, Fridley, B, Cunningham, J, Winham, SJ, Olson, SH, Orlow, I, Bjorge, L, Kiemeney, LA, Massuger, L, Pejovic, T, Moffitt, M, Le, N, Cook, LS, Brooks-Wilson, A, Kelemen, LE, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Yang, H, Hogdall, E, Hogdall, C, Lundvall, L, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, McNeish, I, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Phelan, CM, Risch, H, Narod, S, McLaughlin, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, S, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Schildkraut, JM, Cheng, JQ, Goode, EL, Sellers, TA, Permuth, JB, Reid, B, Earp, M, Chen, YA, Monteiro, ANA, Chen, Z, Chenevix-Trench, G, Fasching, PA, Beckmann, MW, Lambrechts, D, Vanderstichele, A, Van Niewenhuyse, E, Vergote, I, Rossing, MA, Doherty, JA, Chang-Claude, J, Moysich, K, Odunsi, K, Goodman, MT, Shvetsov, YB, Wilkens, LR, Thompson, PJ, Doerk, T, Bogdanova, N, Butzow, R, Nevanlinna, H, Pelttari, L, Leminen, A, Modugno, F, Edwards, RP, Ness, RB, Kelley, J, Heitz, F, Karlan, B, Lester, J, Kjaer, SK, Jensen, A, Giles, G, Hildebrandt, M, Liang, D, Lu, KH, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Cramer, DW, Terry, KL, Tworoger, SS, Poole, EM, Bandera, EV, Fridley, B, Cunningham, J, Winham, SJ, Olson, SH, Orlow, I, Bjorge, L, Kiemeney, LA, Massuger, L, Pejovic, T, Moffitt, M, Le, N, Cook, LS, Brooks-Wilson, A, Kelemen, LE, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Yang, H, Hogdall, E, Hogdall, C, Lundvall, L, Pharoah, PDP, Song, H, Campbell, I, Eccles, D, McNeish, I, Whittemore, A, McGuire, V, Sieh, W, Rothstein, J, Phelan, CM, Risch, H, Narod, S, McLaughlin, J, Anton-Culver, H, Ziogas, A, Menon, U, Gayther, S, Ramus, SJ, Gentry-Maharaj, A, Pearce, CL, Wu, AH, Kupryjanczyk, J, Dansonka-Mieszkowska, A, Schildkraut, JM, Cheng, JQ, Goode, EL, and Sellers, TA
Abstract: RNA editing in mammals is a form of post-transcriptional modification in which adenosine is converted to inosine by the adenosine deaminases acting on RNA (ADAR) family of enzymes. Based on evidence of altered ADAR expression in epithelial ovarian cancers (EOC), we hypothesized that single nucleotide polymorphisms (SNPs) in ADAR genes modify EOC susceptibility, potentially by altering ovarian tissue gene expression. Using directly genotyped and imputed data from 10,891 invasive EOC cases and 21,693 controls, we evaluated the associations of 5,303 SNPs in ADAD1, ADAR, ADAR2, ADAR3, and SND1. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI), with adjustment for European ancestry. We conducted gene-level analyses using the Admixture Maximum Likelihood (AML) test and the Sequence-Kernel Association test for common and rare variants (SKAT-CR). Association analysis revealed top risk-associated SNP rs77027562 (OR (95% CI)= 1.39 (1.17-1.64), P=1.0x10-4) in ADAR3 and rs185455523 in SND1 (OR (95% CI)= 0.68 (0.56-0.83), P=2.0x10-4). When restricting to serous histology (n=6,500), the magnitude of association strengthened for rs185455523 (OR=0.60, P=1.0x10-4). Gene-level analyses revealed that variation in ADAR was associated (P<0.05) with EOC susceptibility, with PAML=0.022 and PSKAT-CR=0.020. Expression quantitative trait locus analysis in EOC tissue revealed significant associations (P<0.05) with ADAR expression for several SNPs in ADAR, including rs1127313 (G/A), a SNP in the 3' untranslated region. In summary, germline variation involving RNA editing genes may influence EOC susceptibility, warranting further investigation of inherited and acquired alterations affecting RNA editing.
Published: 2016

65. rs2735383, located at a microRNA binding site in the 3′UTR of NBS1, is not associated with breast cancer risk

Author: Liu, J, Loncar, I, Collee, JM, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Andrulis, IL, Barile, M, Beckmann, MW, Behrens, S, Benitez, J, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Burwinkel, B, Chang-Claude, J, Chen, S-T, Chenevix-Trench, G, Cheng, CY, Choi, J-Y, Couch, FJ, Cox, A, Cross, SS, Cuk, K, Czene, K, Doerk, T, Dos-Santos-Silva, I, Fasching, PA, Figueroa, J, Flyger, H, Garcia-Closas, M, Giles, GG, Glendon, G, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hamann, U, Hart, SN, Hartman, M, Hatse, S, Hopper, JL, Ito, H, Jakubowska, A, Kabisch, M, Kang, D, Kosma, V-M, Kristensen, VN, Le Marchand, L, Lee, E, Li, J, Lophatananon, A, Lubinski, J, Mannermaa, A, Matsuo, K, Milne, RL, Neuhausen, SL, Nevanlinna, H, Orr, N, Perez, JIA, Peto, J, Putti, TC, Pylkas, K, Radice, P, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schneeweiss, A, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Simard, J, Southey, MC, Swerdlow, A, Teo, SH, Tessier, DC, Thanasitthichai, S, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Vachon, C, Winqvist, R, Wu, AH, Yannoukakos, D, Zheng, W, Hall, P, Dunning, AM, Easton, DF, Hooning, MJ, van den Ouweland, AMW, Martens, JWM, Hollestelle, A, Liu, J, Loncar, I, Collee, JM, Bolla, MK, Dennis, J, Michailidou, K, Wang, Q, Andrulis, IL, Barile, M, Beckmann, MW, Behrens, S, Benitez, J, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Burwinkel, B, Chang-Claude, J, Chen, S-T, Chenevix-Trench, G, Cheng, CY, Choi, J-Y, Couch, FJ, Cox, A, Cross, SS, Cuk, K, Czene, K, Doerk, T, Dos-Santos-Silva, I, Fasching, PA, Figueroa, J, Flyger, H, Garcia-Closas, M, Giles, GG, Glendon, G, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hamann, U, Hart, SN, Hartman, M, Hatse, S, Hopper, JL, Ito, H, Jakubowska, A, Kabisch, M, Kang, D, Kosma, V-M, Kristensen, VN, Le Marchand, L, Lee, E, Li, J, Lophatananon, A, Lubinski, J, Mannermaa, A, Matsuo, K, Milne, RL, Neuhausen, SL, Nevanlinna, H, Orr, N, Perez, JIA, Peto, J, Putti, TC, Pylkas, K, Radice, P, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schneeweiss, A, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Simard, J, Southey, MC, Swerdlow, A, Teo, SH, Tessier, DC, Thanasitthichai, S, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Vachon, C, Winqvist, R, Wu, AH, Yannoukakos, D, Zheng, W, Hall, P, Dunning, AM, Easton, DF, Hooning, MJ, van den Ouweland, AMW, Martens, JWM, and Hollestelle, A
Abstract: 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.
Published: 2016

66. Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus

Author: Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, J-Y, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Doerk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Foretova, L, Fostira, F, Foulkes, WD, Fridley, BL, Friedman, E, Frost, D, Gambino, G, Ganz, PA, Garber, J, Garcia-Closas, M, Gentry-Maharaj, A, Ghoussaini, M, Giles, GG, Glasspool, R, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Goode, EL, Goodman, MT, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hallberg, E, Hamann, U, Hansen, TVO, Harrington, PA, Hartman, M, Hassan, N, Healey, S, Heitz, F, Herzog, J, Hogdall, E, Hogdall, CK, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Hulick, PJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jensen, A, John, EM, Johnson, N, Kabisch, M, Kang, D, Kapuscinski, M, Karlan, BY, Khan, S, Kiemeney, LA, Kjaer, SK, Knight, JA, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kupryjanczyk, J, Kwong, A, de la Hoya, M, Laitman, Y, Lambrechts, D, Le, N, De Leeneer, K, Lester, J, Levine, DA, Li, J, Lindblom, A, Long, J, Lophatananon, A, Loud, JT, Lu, K, Lubinski, J, Mannermaa, A, Manoukian, S, Le Marchand, L, Margolin, S, Marme, F, Massuger, LFAG, Matsuo, K, Mazoyer, S, McGuffog, L, McLean, C, McNeish, I, Meindl, A, Menon, U, Mensenkamp, AR, Milne, RL, Montagna, M, Moysich, KB, Muir, K, Mulligan, AM, Nathanson, KL, Ness, RB, Neuhausen, SL, Nevanlinna, H, Nord, S, Nussbaum, RL, Odunsi, K, Offit, K, Olah, E, Olopade, OI, Olson, JE, Olswold, C, O'Malley, D, Orlow, I, Orr, N, Osorio, A, Park, SK, Pearce, CL, Pejovic, T, Peterlongo, P, Pfeiler, G, Phelan, CM, Poole, EM, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rhenius, V, Rhiem, K, Risch, HA, Rodriguez, G, Rossing, MA, Rudolph, A, Salvesen, HB, Sangrajrang, S, Sawyer, EJ, Schildkraut, JM, Schmidt, MK, Schmutzler, RK, Sellers, TA, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Sieh, W, Singer, CF, Sinilnikova, OM, Slager, S, Song, H, Soucy, P, Southey, MC, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Sutter, C, Swerdlow, A, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Tung, N, Tworoger, SS, Vachon, C, van den Ouweland, AMW, van Doorn, HC, van Rensburg, EJ, Van't Veer, LJ, Vanderstichele, A, Vergote, I, Vijai, J, Wang, Q, Wang-Gohrke, S, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wildiers, H, Winqvist, R, Wu, AH, Yannoukakos, D, Yoon, S-Y, Yu, J-C, Zheng, W, Zheng, Y, Khanna, KK, Simard, J, Monteiro, AN, French, JD, Couch, FJ, Freedman, ML, Easton, DF, Dunning, AM, Pharoah, PD, Edwards, SL, Chenevix-Trench, G, Antoniou, AC, Gayther, SA, Lawrenson, K, Kar, S, McCue, K, Kuchenbaeker, K, Michailidou, K, Tyrer, J, Beesley, J, Ramus, SJ, Li, Q, Delgado, MK, Lee, JM, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arun, BK, Arver, B, Bandera, EV, Barile, M, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Benitez, J, Berchuck, A, Bisogna, M, Bjorge, L, Blomqvist, C, Blot, W, Bogdanova, N, Bojesen, A, Bojesen, SE, Bolla, MK, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brennan, P, Brenner, H, Bruinsma, F, Brunet, J, Buhari, SA, Burwinkel, B, Butzow, R, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Canniotto, R, Chang-Claude, J, Chiquette, J, Choi, J-Y, Claes, KBM, Cook, LS, Cox, A, Cramer, DW, Cross, SS, Cybulski, C, Czene, K, Daly, MB, Damiola, F, Dansonka-Mieszkowska, A, Darabi, H, Dennis, J, Devilee, P, Diez, O, Doherty, JA, Domchek, SM, Dorfling, CM, Doerk, T, Dumont, M, Ehrencrona, H, Ejlertsen, B, Ellis, S, Engel, C, Lee, E, Evans, DG, Fasching, PA, Feliubadalo, L, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Foretova, L, Fostira, F, Foulkes, WD, Fridley, BL, Friedman, E, Frost, D, Gambino, G, Ganz, PA, Garber, J, Garcia-Closas, M, Gentry-Maharaj, A, Ghoussaini, M, Giles, GG, Glasspool, R, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Goode, EL, Goodman, MT, Greene, MH, Gronwald, J, Guenel, P, Haiman, CA, Hall, P, Hallberg, E, Hamann, U, Hansen, TVO, Harrington, PA, Hartman, M, Hassan, N, Healey, S, Heitz, F, Herzog, J, Hogdall, E, Hogdall, CK, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Hulick, PJ, Huzarski, T, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jensen, A, John, EM, Johnson, N, Kabisch, M, Kang, D, Kapuscinski, M, Karlan, BY, Khan, S, Kiemeney, LA, Kjaer, SK, Knight, JA, Konstantopoulou, I, Kosma, V-M, Kristensen, V, Kupryjanczyk, J, Kwong, A, de la Hoya, M, Laitman, Y, Lambrechts, D, Le, N, De Leeneer, K, Lester, J, Levine, DA, Li, J, Lindblom, A, Long, J, Lophatananon, A, Loud, JT, Lu, K, Lubinski, J, Mannermaa, A, Manoukian, S, Le Marchand, L, Margolin, S, Marme, F, Massuger, LFAG, Matsuo, K, Mazoyer, S, McGuffog, L, McLean, C, McNeish, I, Meindl, A, Menon, U, Mensenkamp, AR, Milne, RL, Montagna, M, Moysich, KB, Muir, K, Mulligan, AM, Nathanson, KL, Ness, RB, Neuhausen, SL, Nevanlinna, H, Nord, S, Nussbaum, RL, Odunsi, K, Offit, K, Olah, E, Olopade, OI, Olson, JE, Olswold, C, O'Malley, D, Orlow, I, Orr, N, Osorio, A, Park, SK, Pearce, CL, Pejovic, T, Peterlongo, P, Pfeiler, G, Phelan, CM, Poole, EM, Pylkas, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rhenius, V, Rhiem, K, Risch, HA, Rodriguez, G, Rossing, MA, Rudolph, A, Salvesen, HB, Sangrajrang, S, Sawyer, EJ, Schildkraut, JM, Schmidt, MK, Schmutzler, RK, Sellers, TA, Seynaeve, C, Shah, M, Shen, C-Y, Shu, X-O, Sieh, W, Singer, CF, Sinilnikova, OM, Slager, S, Song, H, Soucy, P, Southey, MC, Stenmark-Askmalm, M, Stoppa-Lyonnet, D, Sutter, C, Swerdlow, A, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, Thomassen, M, Tibiletti, MG, Tihomirova, L, Tognazzo, S, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Tseng, C-C, Tung, N, Tworoger, SS, Vachon, C, van den Ouweland, AMW, van Doorn, HC, van Rensburg, EJ, Van't Veer, LJ, Vanderstichele, A, Vergote, I, Vijai, J, Wang, Q, Wang-Gohrke, S, Weitzel, JN, Wentzensen, N, Whittemore, AS, Wildiers, H, Winqvist, R, Wu, AH, Yannoukakos, D, Yoon, S-Y, Yu, J-C, Zheng, W, Zheng, Y, Khanna, KK, Simard, J, Monteiro, AN, French, JD, Couch, FJ, Freedman, ML, Easton, DF, Dunning, AM, Pharoah, PD, Edwards, SL, Chenevix-Trench, G, Antoniou, AC, and Gayther, SA
Abstract: 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.
Published: 2016

67. Identification of independent association signals and putative functional variants for breast cancer risk through fine-scale mapping of the 12p11 locus

Author: Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, Zheng, W, Zeng, C, Guo, X, Long, J, Kuchenbaecker, KB, Droit, A, Michailidou, K, Ghoussaini, M, Kar, S, Freeman, A, Hopper, JL, Milne, RL, Bolla, MK, Wang, Q, Dennis, J, Agata, S, Ahmed, S, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arason, A, Arndt, V, Arun, BK, Arver, B, Bacot, F, Barrowdale, D, Baynes, C, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Blomqvist, C, Blot, WJ, Bogdanova, NV, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brand, JS, Brauch, H, Brennan, P, Brenner, H, Broeks, A, Bruening, T, Burwinkel, B, Buys, SS, Cai, Q, Caldes, T, Campbell, I, Carpenter, J, Chang-Claude, J, Choi, J-Y, Claes, KBM, Clarke, C, Cox, A, Cross, SS, Czene, K, Daly, MB, de la Hoya, M, De Leeneer, K, Devilee, P, Diez, O, Domchek, SM, Doody, M, Dorfling, CM, Doerk, T, dos-Santos-Silva, I, Dumont, M, Dwek, M, Dworniczak, B, Egan, K, Eilber, U, Einbeigi, Z, Ejlertsen, B, Ellis, S, Frost, D, Lalloo, F, Fasching, PA, Figueroa, J, Flyger, H, Friedlander, M, Friedman, E, Gambino, G, Gao, Y-T, Garber, J, Garcia-Closas, M, Gehrig, A, Damiola, F, Lesueur, F, Mazoyer, S, Stoppa-Lyonnet, D, Giles, GG, Godwin, AK, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Haiman, CA, Hallberg, E, Hamann, U, Hansen, TVO, Hart, S, Hartikainen, JM, Hartman, M, Hassan, N, Healey, S, Hogervorst, FBL, Verhoef, S, Hendricks, CB, Hillemanns, P, Hollestelle, A, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Isaacs, C, Ito, H, Jakubowska, A, Janavicius, R, Jaworska-Bieniek, K, Jensen, UB, John, EM, Beauparlant, CJ, Jones, M, Kabisch, M, Kang, D, Karlan, BY, Kauppila, S, Kerin, MJ, Khan, S, Khusnutdinova, E, Knight, JA, Konstantopoulou, I, Kraft, P, Kwong, A, Laitman, Y, Lambrechts, D, Lazaro, C, Le Marchand, L, Lee, CN, Lee, MH, Lester, J, Li, J, Liljegren, A, Lindblom, A, Lophatananon, A, Lubinski, J, Mai, PL, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McGuffog, L, Meindl, A, Menegaux, F, Montagna, M, Muir, K, Mulligan, AM, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Newcomb, PA, Nord, S, Nussbaum, RL, Offit, K, Olah, E, Olopade, OI, Olswold, C, Osorio, A, Papi, L, Park-Simon, T-W, Paulsson-Karlsson, Y, Peeters, S, Peissel, B, Peterlongo, P, Peto, J, Pfeiler, G, Phelan, CM, Presneau, N, Radice, P, Rahman, N, Ramus, SJ, Rashid, MU, Rennert, G, Rhiem, K, Rudolph, A, Salani, R, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schuermann, P, Seynaeve, C, Shen, C-Y, Shrubsole, MJ, Shu, X-O, Sigurdson, A, Singer, CF, Slager, S, Soucy, P, Southey, M, Steinemann, D, Swerdlow, A, Szabo, CI, Tchatchou, S, Teixeira, MR, Teo, SH, Terry, MB, Tessier, DC, Teule, A, Thomassen, M, Tihomirova, L, Tischkowitz, M, Toland, AE, Tung, N, Turnbull, C, van den Ouweland, AMW, van Rensburg, EJ, ven den Berg, D, Vijai, J, Wang-Gohrke, S, Weitzel, JN, Whittemore, AS, Winqvist, R, Wong, TY, Wu, AH, Yannoukakos, D, Yu, J-C, Pharoah, PDP, Hall, P, Chenevix-Trench, G, Dunning, AM, Simard, J, Couch, FJ, Antoniou, AC, Easton, DF, and Zheng, W
Abstract: 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
Published: 2016

68. Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer

Author: Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, Moysich, KB, Hampras, SS, Sucheston-Campbell, LE, Cannioto, R, Chang-Claude, J, Modugno, F, Doerk, T, Hillemanns, P, Preus, L, Knutson, KL, Wallace, PK, Hong, C-C, Friel, G, Davis, W, Nesline, M, Pearce, CL, Kelemen, LE, Goodman, MT, Bandera, EV, Terry, KL, Schoof, N, Eng, KH, Clay, A, Singh, PK, Joseph, JM, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Despierre, E, Dicks, E, Doherty, JA, du Bois, A, Duerst, M, Easton, D, Eccles, D, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hogdall, C, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Klapdor, R, Kolomeyevskaya, N, Krakstad, C, Kjaer, SK, Kruszka, B, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Liu, S, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Moes-Sosnowska, J, Narod, SA, Nedergaard, L, Nevanlinna, H, Nickels, S, Olson, SH, Orlow, I, Weber, RP, Paul, J, Pejovic, T, Pelttari, LM, Perkins, B, Permuth-Wey, J, Pike, MC, Plisiecka-Halasa, J, Poole, EM, Risch, HA, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schmitt, K, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Tangen, IL, Teo, S-H, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Tyrer, J, van Altena, AM, Vergote, I, Vierkant, RA, Walsh, C, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Y-L, Yang, H, Zheng, W, Ziogas, A, Gayther, SA, Ramus, SJ, Sellers, TA, Schildkraut, JM, Phelan, CM, Berchuck, A, Chenevix-Trench, G, Cunningham, JM, Pharoah, PP, Ness, RB, Odunsi, K, Goode, EL, and Moysich, KB
Abstract: BACKGROUND: Regulatory T (Treg) cells, a subset of CD4+ T lymphocytes, are mediators of immunosuppression in cancer, and, thus, variants in genes encoding Treg cell immune molecules could be associated with ovarian cancer. METHODS: In a population of 15,596 epithelial ovarian cancer (EOC) cases and 23,236 controls, we measured genetic associations of 1,351 SNPs in Treg cell pathway genes with odds of ovarian cancer and tested pathway and gene-level associations, overall and by histotype, for the 25 genes, using the admixture likelihood (AML) method. The most significant single SNP associations were tested for correlation with expression levels in 44 ovarian cancer patients. RESULTS: The most significant global associations for all genes in the pathway were seen in endometrioid ( p = 0.082) and clear cell ( p = 0.083), with the most significant gene level association seen with TGFBR2 ( p = 0.001) and clear cell EOC. Gene associations with histotypes at p < 0.05 included: IL12 ( p = 0.005 and p = 0.008, serous and high-grade serous, respectively), IL8RA ( p = 0.035, endometrioid and mucinous), LGALS1 ( p = 0.03, mucinous), STAT5B ( p = 0.022, clear cell), TGFBR1 ( p = 0.021 endometrioid) and TGFBR2 ( p = 0.017 and p = 0.025, endometrioid and mucinous, respectively). CONCLUSIONS: Common inherited gene variation in Treg cell pathways shows some evidence of germline genetic contribution to odds of EOC that varies by histologic subtype and may be associated with mRNA expression of immune-complex receptor in EOC patients.
Published: 2016

69. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing

Author: Easton, DF, Lesueur, F, Decker, B, Michailidou, K, Li, J, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Dennis, J, Ahmad, J, Thompson, ER, Damiola, F, Pertesi, M, Voegele, C, Mebirouk, N, Robinot, N, Durand, G, Forey, N, Luben, RN, Ahmed, S, Aittomaki, K, Anton-Culver, H, Arndt, V, Baynes, C, Beckman, MW, Benitez, J, Van Den Berg, D, Blot, WJ, Bogdanova, NV, Bojesen, SE, Brenner, H, Chang-Claude, J, Chia, KS, Choi, J-Y, Conroy, DM, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Fostira, F, Garcia-Closas, M, Giles, GG, Glendon, G, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hall, P, Hart, SN, Hartman, M, Hooning, MJ, Hsiung, C-N, Ito, H, Jakubowska, A, James, PA, John, EM, Johnson, N, Jones, M, Kabisch, M, Kang, D, Kosma, V-M, Kristensen, V, Lambrechts, D, Li, N, Lindblom, A, Long, J, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Meindl, A, Mitchell, G, Muir, K, Nevelsteen, I, van den Ouweland, A, Peterlongo, P, Phuah, SY, Pylkas, K, Rowley, SM, Sangrajrang, S, Schmutzler, RK, Shen, C-Y, Shu, X-O, Southey, MC, Surowy, H, Swerdlow, A, Teo, SH, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Vachon, C, Verhoef, S, Wong-Brown, M, Zheng, W, Zheng, Y, Nevanlinna, H, Scott, RJ, Andrulis, IL, Wu, AH, Hopper, JL, Couch, FJ, Winqvist, R, Burwinkel, B, Sawyer, EJ, Schmidt, MK, Rudolph, A, Doerk, T, Brauch, H, Hamann, U, Neuhausen, SL, Milne, RL, Fletcher, O, Pharoah, PDP, Campbell, IG, Dunning, AM, Le Calvez-Kelm, F, Goldgar, DE, Tavtigian, SV, Chenevix-Trench, G, Easton, DF, Lesueur, F, Decker, B, Michailidou, K, Li, J, Allen, J, Luccarini, C, Pooley, KA, Shah, M, Bolla, MK, Wang, Q, Dennis, J, Ahmad, J, Thompson, ER, Damiola, F, Pertesi, M, Voegele, C, Mebirouk, N, Robinot, N, Durand, G, Forey, N, Luben, RN, Ahmed, S, Aittomaki, K, Anton-Culver, H, Arndt, V, Baynes, C, Beckman, MW, Benitez, J, Van Den Berg, D, Blot, WJ, Bogdanova, NV, Bojesen, SE, Brenner, H, Chang-Claude, J, Chia, KS, Choi, J-Y, Conroy, DM, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Eriksson, M, Fasching, PA, Figueroa, J, Flyger, H, Fostira, F, Garcia-Closas, M, Giles, GG, Glendon, G, Gonzalez-Neira, A, Guenel, P, Haiman, CA, Hall, P, Hart, SN, Hartman, M, Hooning, MJ, Hsiung, C-N, Ito, H, Jakubowska, A, James, PA, John, EM, Johnson, N, Jones, M, Kabisch, M, Kang, D, Kosma, V-M, Kristensen, V, Lambrechts, D, Li, N, Lindblom, A, Long, J, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Matsuo, K, Meindl, A, Mitchell, G, Muir, K, Nevelsteen, I, van den Ouweland, A, Peterlongo, P, Phuah, SY, Pylkas, K, Rowley, SM, Sangrajrang, S, Schmutzler, RK, Shen, C-Y, Shu, X-O, Southey, MC, Surowy, H, Swerdlow, A, Teo, SH, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Vachon, C, Verhoef, S, Wong-Brown, M, Zheng, W, Zheng, Y, Nevanlinna, H, Scott, RJ, Andrulis, IL, Wu, AH, Hopper, JL, Couch, FJ, Winqvist, R, Burwinkel, B, Sawyer, EJ, Schmidt, MK, Rudolph, A, Doerk, T, Brauch, H, Hamann, U, Neuhausen, SL, Milne, RL, Fletcher, O, Pharoah, PDP, Campbell, IG, Dunning, AM, Le Calvez-Kelm, F, Goldgar, DE, Tavtigian, SV, and Chenevix-Trench, G
Abstract: 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.
Published: 2016

70. Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium

Author: Lei, J, Rudolph, A, Moysich, KB, Behrens, S, Goode, EL, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Wang, Q, Benitez, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Fasching, PA, Haeberle, L, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Nielsen, SF, Nordestgaard, BG, Gonzalez-Neira, A, Menendez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Fagerholm, R, Doerk, T, Bogdanova, NV, Mannermaa, A, Hartikainen, JM, Van Dijck, L, Smeets, A, Flesch-Janys, D, Eilber, U, Radice, P, Peterlongo, P, Couch, FJ, Hallberg, E, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Goldberg, MS, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Winqvist, R, Grip, M, Andrulis, IL, Glendon, G, Garcia-Closas, M, Figueroa, J, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hall, P, Li, J, Cox, A, Cross, SS, Pharoah, PDP, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Ademuyiwa, F, Ambrosone, CB, Swerdlow, A, Jones, M, Chang-Claude, J, Lei, J, Rudolph, A, Moysich, KB, Behrens, S, Goode, EL, Bolla, MK, Dennis, J, Dunning, AM, Easton, DF, Wang, Q, Benitez, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Fasching, PA, Haeberle, L, Peto, J, dos-Santos-Silva, I, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Nielsen, SF, Nordestgaard, BG, Gonzalez-Neira, A, Menendez, P, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Fagerholm, R, Doerk, T, Bogdanova, NV, Mannermaa, A, Hartikainen, JM, Van Dijck, L, Smeets, A, Flesch-Janys, D, Eilber, U, Radice, P, Peterlongo, P, Couch, FJ, Hallberg, E, Giles, GG, Milne, RL, Haiman, CA, Schumacher, F, Simard, J, Goldberg, MS, Kristensen, V, Borresen-Dale, A-L, Zheng, W, Beeghly-Fadiel, A, Winqvist, R, Grip, M, Andrulis, IL, Glendon, G, Garcia-Closas, M, Figueroa, J, Czene, K, Brand, JS, Darabi, H, Eriksson, M, Hall, P, Li, J, Cox, A, Cross, SS, Pharoah, PDP, Shah, M, Kabisch, M, Torres, D, Jakubowska, A, Lubinski, J, Ademuyiwa, F, Ambrosone, CB, Swerdlow, A, Jones, M, and Chang-Claude, J
Abstract: Immunosuppression plays a pivotal role in assisting tumors to evade immune destruction and promoting tumor development. We hypothesized that genetic variation in the immunosuppression pathway genes may be implicated in breast cancer tumorigenesis. We included 42,510 female breast cancer cases and 40,577 controls of European ancestry from 37 studies in the Breast Cancer Association Consortium (2015) with available genotype data for 3595 single nucleotide polymorphisms (SNPs) in 133 candidate genes. Associations between genotyped SNPs and overall breast cancer risk, and secondarily according to estrogen receptor (ER) status, were assessed using multiple logistic regression models. Gene-level associations were assessed based on principal component analysis. Gene expression analyses were conducted using RNA sequencing level 3 data from The Cancer Genome Atlas for 989 breast tumor samples and 113 matched normal tissue samples. SNP rs1905339 (A>G) in the STAT3 region was associated with an increased breast cancer risk (per allele odds ratio 1.05, 95 % confidence interval 1.03-1.08; p value = 1.4 × 10(-6)). The association did not differ significantly by ER status. On the gene level, in addition to TGFBR2 and CCND1, IL5 and GM-CSF showed the strongest associations with overall breast cancer risk (p value = 1.0 × 10(-3) and 7.0 × 10(-3), respectively). Furthermore, STAT3 and IL5 but not GM-CSF were differentially expressed between breast tumor tissue and normal tissue (p value = 2.5 × 10(-3), 4.5 × 10(-4) and 0.63, respectively). Our data provide evidence that the immunosuppression pathway genes STAT3, IL5, and GM-CSF may be novel susceptibility loci for breast cancer in women of European ancestry.
Published: 2016

71. Five endometrial cancer risk loci identified through genome-wide association analysis

Author: Cheng, THT, Thompson, DJ, O'Mara, TA, Painter, JN, Glubb, DM, Flach, S, Lewis, A, French, JD, Freeman-Mills, L, Church, D, Gorman, M, Martin, L, Hodgson, S, Webb, PM, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Henders, AK, Martin, NG, Montgomery, GW, Nyholt, DR, Ahmed, S, Healey, CS, Shah, M, Dennis, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Doerk, T, Duerst, M, Hillemanns, P, Runnebaum, I, Amant, F, Schrauwen, S, Zhao, H, Lambrechts, D, Depreeuw, J, Dowdy, SC, Goode, EL, Fridley, BL, Winham, SJ, Njolstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, K, Otton, G, Proietto, T, Liu, T, Mints, M, Tham, E, Li, MJ, Yip, SH, Wang, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Dunlop, M, Houlston, R, Palles, C, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Cunningham, JM, Pharoah, PDP, Dunning, AM, Edwards, SL, Easton, DF, Tomlinson, I, Spurdle, AB, Cheng, THT, Thompson, DJ, O'Mara, TA, Painter, JN, Glubb, DM, Flach, S, Lewis, A, French, JD, Freeman-Mills, L, Church, D, Gorman, M, Martin, L, Hodgson, S, Webb, PM, Attia, J, Holliday, EG, McEvoy, M, Scott, RJ, Henders, AK, Martin, NG, Montgomery, GW, Nyholt, DR, Ahmed, S, Healey, CS, Shah, M, Dennis, J, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Hall, P, Czene, K, Darabi, H, Li, J, Doerk, T, Duerst, M, Hillemanns, P, Runnebaum, I, Amant, F, Schrauwen, S, Zhao, H, Lambrechts, D, Depreeuw, J, Dowdy, SC, Goode, EL, Fridley, BL, Winham, SJ, Njolstad, TS, Salvesen, HB, Trovik, J, Werner, HMJ, Ashton, K, Otton, G, Proietto, T, Liu, T, Mints, M, Tham, E, Li, MJ, Yip, SH, Wang, J, Bolla, MK, Michailidou, K, Wang, Q, Tyrer, JP, Dunlop, M, Houlston, R, Palles, C, Hopper, JL, Peto, J, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Cunningham, JM, Pharoah, PDP, Dunning, AM, Edwards, SL, Easton, DF, Tomlinson, I, and Spurdle, AB
Abstract: We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
Published: 2016

72. Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

Author: Beck, AH, Guo, Y, Andersen, SW, Shu, X-O, Michailidou, K, Bolla, MK, Wang, Q, Garcia-Closas, M, Milne, RL, Schmidt, MK, Chang-Claude, J, Dunning, A, Bojesen, SE, Ahsan, H, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bogdanova, NV, Bonanni, B, Borresen-Dale, A-L, Brand, J, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Casey, G, Chenevix-Trench, G, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Dumont, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fostira, F, Gammon, M, Giles, GG, Guenel, P, Haiman, CA, Hamann, U, Hooning, MJ, Hopper, JL, Jakubowska, A, Jasmine, F, Jenkins, M, John, EM, Johnson, N, Jones, ME, Kabisch, M, Kibriya, M, Knight, JA, Koppert, LB, Kosma, V-M, Kristensen, V, Le Marchand, L, Lee, E, Li, J, Lindblom, A, Luben, R, Lubinski, J, Malone, KE, Mannermaa, A, Margolin, S, Marme, F, McLean, C, Meijers-Heijboer, H, Meindl, A, Neuhausen, SL, Nevanlinna, H, Neven, P, Olson, JE, Perez, JIA, Perkins, B, Peterlongo, P, Phillips, K-A, Pylkas, K, Rudolph, A, Santella, R, Sawyer, EJ, Schmutzler, RK, Seynaeve, C, Shah, M, Shrubsole, MJ, Southey, MC, Swerdlow, AJ, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Ursin, G, Van Der Luijt, RB, Verhoef, S, Whittemore, AS, Winqvist, R, Zhao, H, Zhao, S, Hall, P, Simard, J, Kraft, P, Pharoah, P, Hunter, D, Easton, DF, Zheng, W, Beck, AH, Guo, Y, Andersen, SW, Shu, X-O, Michailidou, K, Bolla, MK, Wang, Q, Garcia-Closas, M, Milne, RL, Schmidt, MK, Chang-Claude, J, Dunning, A, Bojesen, SE, Ahsan, H, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bogdanova, NV, Bonanni, B, Borresen-Dale, A-L, Brand, J, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Casey, G, Chenevix-Trench, G, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Doerk, T, Dumont, M, Fasching, PA, Figueroa, J, Flesch-Janys, D, Fletcher, O, Flyger, H, Fostira, F, Gammon, M, Giles, GG, Guenel, P, Haiman, CA, Hamann, U, Hooning, MJ, Hopper, JL, Jakubowska, A, Jasmine, F, Jenkins, M, John, EM, Johnson, N, Jones, ME, Kabisch, M, Kibriya, M, Knight, JA, Koppert, LB, Kosma, V-M, Kristensen, V, Le Marchand, L, Lee, E, Li, J, Lindblom, A, Luben, R, Lubinski, J, Malone, KE, Mannermaa, A, Margolin, S, Marme, F, McLean, C, Meijers-Heijboer, H, Meindl, A, Neuhausen, SL, Nevanlinna, H, Neven, P, Olson, JE, Perez, JIA, Perkins, B, Peterlongo, P, Phillips, K-A, Pylkas, K, Rudolph, A, Santella, R, Sawyer, EJ, Schmutzler, RK, Seynaeve, C, Shah, M, Shrubsole, MJ, Southey, MC, Swerdlow, AJ, Toland, AE, Tomlinson, I, Torres, D, Truong, T, Ursin, G, Van Der Luijt, RB, Verhoef, S, Whittemore, AS, Winqvist, R, Zhao, H, Zhao, S, Hall, P, Simard, J, Kraft, P, Pharoah, P, Hunter, D, Easton, DF, and Zheng, W
Abstract: 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 wit
Published: 2016

73. PALB2, CHEK2 and ATM rare variants and cancer risk: data from COGS

Author: Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, Milne, RL, Southey, MC, Goldgar, DE, Winqvist, R, Pylkas, K, Couch, F, Tischkowitz, M, Foulkes, WD, Dennis, J, Michailidou, K, van Rensburg, EJ, Heikkinen, T, Nevanlinna, H, Hopper, JL, Doerk, T, Claes, KBM, Reis-Filho, J, Teo, ZL, Radice, P, Catucci, I, Peterlongo, P, Tsimiklis, H, Odefrey, FA, Dowty, JG, Schmidt, MK, Broeks, A, Hogervorst, FB, Verhoef, S, Carpenter, J, Clarke, C, Scott, RJ, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Peto, J, dos-Santos-Silva, I, Fletcher, O, Johnson, N, Bolla, MK, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Marme, F, Burwinkel, B, Yang, R, Guenel, P, Therese, T, Menegaux, F, Sanchez, M, Bojesen, S, Nielsen, SF, Flyger, H, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Anton-Culver, H, Neuhausen, S, Ziogas, A, Clarke, CA, Brenner, H, Arndt, V, Stegmaier, C, Brauch, H, Bruening, T, Ko, Y-D, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Spurdle, AB, Wauters, E, Smeets, D, Beuselinck, B, Floris, G, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Olson, JE, Vachon, C, Pankratz, VS, McLean, C, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Kristensen, V, Alnaes, GG, Zheng, W, Hunter, DJ, Lindstrom, S, Hankinson, SE, Kraft, P, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Jukkola-Vuorinen, A, Grip, M, Kauppila, S, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Hollestelle, A, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Czene, K, Darabi, H, Eriksson, M, Eccles, DM, Rafiq, S, Tapper, WJ, Gerty, SM, Hooning, MJ, Martens, JWM, Collee, JM, Tilanus-Linthorst, M, Hall, P, Li, J, Brand, JS, Humphreys, K, Cox, A, Reed, MWR, Luccarini, C, Baynes, C, Dunning, AM, Hamann, U, Torres, D, Ulmer, HU, Ruediger, T, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Simard, J, Dumont, M, Soucy, P, Eeles, R, Muir, K, Wiklund, F, Gronberg, H, Schleutker, J, Nordestgaard, BG, Weischer, M, Travis, RC, Neal, D, Donovan, JL, Hamdy, FC, Khaw, K-T, Stanford, JL, Blot, WJ, Thibodeau, S, Schaid, DJ, Kelley, JL, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Butterbach, K, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Renner, SP, Hartmann, A, Hein, A, Ruebner, M, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambretchs, S, Doherty, JA, Rossing, MA, Nickels, S, Eilber, U, Wang-Gohrke, S, Odunsi, K, Sucheston-Campbell, LE, Friel, G, Lurie, G, Killeen, JL, Wilkens, LR, Goodman, MT, Runnebaum, I, Hillemanns, PA, Pelttari, LM, Butzow, R, Modugno, F, Edwards, RP, Ness, RB, Moysich, KB, du Bois, A, Heitz, F, Harter, P, Kommoss, S, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, E, Peissel, B, Bonanni, B, Bernard, L, Goode, EL, Fridley, BL, Vierkant, RA, Cunningham, JM, Larson, MC, Fogarty, ZC, Kalli, KR, Liang, D, Lu, KH, Hildebrandt, MAT, Wu, X, Levine, DA, Dao, F, Bisogna, M, Berchuck, A, Iversen, ES, Marks, JR, Akushevich, L, Cramer, DW, Schildkraut, J, Terry, KL, Poole, EM, Stampfer, M, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Bjorge, L, Salvesen, HB, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, Y, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Grski, B, Gronwald, J, Menkiszak, J, Hogdall, CK, Lundvall, L, Nedergaard, L, Engelholm, SA, Dicks, E, Tyrer, J, Campbell, I, McNeish, I, Paul, J, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Cai, H, Shu, X-O, Teten, RT, Sutphen, R, McLaughlin, JR, Narod, SA, Phelan, CM, Monteiro, AN, Fenstermacher, D, Lin, H-Y, Permuth, JB, Sellers, TA, Chen, YA, Tsai, Y-Y, Chen, Z, Gentry-Maharaj, A, Gayther, SA, Ramus, SJ, Menon, U, Wu, AH, Pearce, CL, Van den Berg, D, Pike, MC, Dansonka-Mieszkowska, A, Plisiecka-Halasa, J, Moes-Sosnowska, J, Kupryjanczyk, J, Pharoah, PDP, Song, H, Winship, I, Chenevix-Trench, G, Giles, GG, Tavtigian, SV, Easton, DF, and Milne, RL
Abstract: 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.
Published: 2016

74. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Author: Johnson, N., Dudbridge, F., Orr, N., Gibson, L., Jones, M.E., Schoemaker, M.J., Folkerd, E.J., Haynes, B.P., Hopper, J.L., Southey, M.C., Dite, G.S., Apicella, C., Schmidt, M.K., Broeks, A., Van't Veer, L.J., Atsma, F., Muir, K., Lophatananon, A., Fasching, P.A., Beckmann, M.W., Ekici, A.B., Renner, S.P., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Burwinkel, B., Marme, F., Schneeweiss, A., Sohn, C., Guenel, P., Truong, T., Cordina, E., Menegaux, F., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Milne, R., Zamora, M.P., Arias Perez, J.I., Benitez, J., Bernstein, L., Anton-Culver, H., Ziogas, A., Dur, C.C., Brenner, H., Mueller, H., Arndt, V., Dieffenbach, A.K., Meindl, A., Heil, J., Bartram, C.R., Schmutzler, R.K., Brauch, H., Justenhoven, C., Ko, Y-D., Nevanlinna, H., Muranen, T.A., Aittomaeki, K., Blomqvist, C., Matsuo, K., Doerk, T., Bogdanova, NV., Antonenkova, N.N., Lindblom, A., Mannermaa, A., Kataja, V., Kosma, V-M., Hartikainen, J.M., Chenevix-Trench, G., Beesley, J., Wu, A.H., Van den Berg, D., Tseng, C-C., Lambrechts, D., Smeets, D., Neven, P., Wildiers, H., Chang-Claude, J., Rudolph, A., Nickels, S., Flesch-Janys, D., Radice, P., Peterlongo, P., Bonanni, B., Pensotti, V., Couch, F.J., Olson, J.E., Wang, X., Fredericksen, Z., Pankratz, V.S., Giles, G.G., Severi, G., Baglietto, L., Haiman, C., Simard, J., Goldberg, M.S., Labreche, F., Dumont, M., Soucy, P., Teo, S., Yip, C.H., Phuah, S.Y., Cornes, B.K., Kristensen, V.N., Alnaes, G.G., Borresen-Dale, A-L., Zheng, W., Winqvist, R., Pylkaes, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L, Knight, J.A., Glendon, G., Mulligan, A.M., Devillee, P., Figueroa, J., Chanock, S.J., Lissowska, J., Sherman, M.E., Hall, P., Schoof, N., Hooning, M., Hollestelle, A., Oldenburg, R.A., Tilanus-Linthorst, M., Liu, J., Cox, A., Brock, I.W., Reed, M.W.R., Cross, S.S., Blot, W., Signorello, L.B., Pharoah, P.D.P., Dunning, A.M., Shah, M., Kang, D., Noh, D-Y., Park, S.K., Choi, J-Y., Hartman, M., Miao, H., Lim, W.Y., Tang, A., Hamann, U., Foersti, A., Ruediger, T., Ulmer, H.U., Jakubowska, A., Lubinski, J., Jaworska-Bieniek, K., Durda, K., Sangrajrang, S., Gaborieau, V., Brennan, P., Mckay, J., Slager, S., Toland, A.E., Vachon, C., Yannoukakos, D., Shen, C-Y., Yu, J-C., Huang, C-S., Hou, M-F., Gonzalez-Neira, A., Tessier, D.C., Vincent, D., Bacot, F., Luccarini, C., Dennis, J., Michailidou, K., Bolla, M.K., Wang, J., Easton, D.F., Garcia-Closas, M., Dowsett, M., Ashworth, A., Swerdlow, A.J., Peto, J., Silva, I.D.S., Fletcher, O., Breast, G.E.I., Investigators, K., Grp, AOCS, Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Adult, Menarche, Genotype, Age Factors, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, White People, Premenopause, Risk Factors, Cytochrome P-450 CYP3A, Humans, Female, Genetic Predisposition to Disease, Age of Onset, Reproductive History, Genetic Association Studies, Aged
Abstract: Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to\ud the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and\ud a modest reduction in risk of breast cancer in women age ≤50 years.\ud Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of\ud 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping\ud of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine\ud whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.\ud Results: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found\ud no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were\ud OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (Ptrend = 0.02). There was\ud no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche\ud in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast\ud cancer risk differed according to age at menarche (Phet = 0.02); the rare allele of rs10235235 was associated with a\ud reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94;\ud ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06,\ud 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 0.29).\ud Conclusions: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both\ud breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche\ud and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Published: 2014

75. Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Author: Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, J-J, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Boutin, TS, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Campbell, A, Campbell, H, Chanock, SJ, Chapman, JR, Chen, Y-DI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, De Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, Garcia-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonzalez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guenel, P, Guo, X, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, A, Homuth, G, Hooning, MJ, Hopper, JL, Hu, FB, Huang, J, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, V-M, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, J, Li, X, Lindstroem, S, Liu, Y, Luan, J, Lubinski, J, Maegi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Mueller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkas, K, Radice, P, Raffel, LJ, Rivadeneira, F, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK, Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, CM, Simard, J, Sorice, R, Southey, MC, Stoeckl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q, Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, van Duijn, CM, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, AG, Ulivi, S, Voelzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, JA, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB, Murray, A, Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, Huffman, JE, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, J-J, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, A-L, Boutin, TS, Brauch, H, Brenner, H, Bruening, T, Burwinkel, B, Campbell, A, Campbell, H, Chanock, SJ, Chapman, JR, Chen, Y-DI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, De Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, Garcia-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonzalez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guenel, P, Guo, X, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, A, Homuth, G, Hooning, MJ, Hopper, JL, Hu, FB, Huang, J, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, V-M, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, J, Li, X, Lindstroem, S, Liu, Y, Luan, J, Lubinski, J, Maegi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Mueller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkas, K, Radice, P, Raffel, LJ, Rivadeneira, F, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK, Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, CM, Simard, J, Sorice, R, Southey, MC, Stoeckl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q, Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, van Duijn, CM, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, AG, Ulivi, S, Voelzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, JA, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB, and Murray, A
Abstract: 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 regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Published: 2015

76. Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk

Author: Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, Spurdle, AB, Painter, JN, O'Mara, TA, Batra, J, Cheng, T, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Kaufmann, S, Hillman, KM, Walpole, C, Moya, L, Pollock, P, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Magdalena Echeverry De Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Santos, E, Teixeira, MR, Carvajal-Carmona, L, Shu, X-O, Long, J, Zheng, W, Xiang, Y-B, Montgomery, GW, Webb, PM, Scott, RJ, McEvoy, M, Attia, J, Holliday, E, Martin, NG, Nyholt, DR, Henders, AK, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Tzortzatos, G, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, French, JD, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Edwards, SL, Thompson, DJ, and Spurdle, AB
Abstract: Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.
Published: 2015

77. Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Author: Guo, X, Long, J, Zeng, C, Michailidou, K, Ghoussaini, M, Bolla, MK, Wang, Q, Milne, RL, Shu, X-O, Cai, Q, Beesley, J, Kar, SP, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Blot, W, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Brinton, L, Broeks, A, Bruening, T, Burwinkel, B, Cai, H, Canisius, S, Chang-Claude, J, Choi, J-Y, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Droit, A, Doerk, T, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Gaborieau, V, Garcia-Closas, M, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Hsiung, C-N, Ito, H, Jakubowska, A, Johnson, N, Kabisch, M, Kang, D, Khan, S, Knight, JA, Kosma, V-M, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McLean, CA, Meindl, A, Muir, K, Neuhausen, SL, Nevanlinna, H, Nord, S, Olson, JE, Orr, N, Peterlongo, P, Putti, TC, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shen, C-Y, Shi, J, Shrubsole, MJ, Southey, MC, Swerdlow, A, Teo, SH, Thienpont, B, Toland, AE, Tollenaar, RAEM, Tomlinson, IPM, Truong, T, Tseng, C-C, van den Ouweland, A, Wen, W, Winqvist, R, Wu, A, Yip, CH, Zamora, MP, Zheng, Y, Hall, P, Pharoah, PDP, Simard, J, Chenevix-Trench, G, Dunning, AM, Easton, DF, Zheng, W, Guo, X, Long, J, Zeng, C, Michailidou, K, Ghoussaini, M, Bolla, MK, Wang, Q, Milne, RL, Shu, X-O, Cai, Q, Beesley, J, Kar, SP, Andrulis, IL, Anton-Culver, H, Arndt, V, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Blot, W, Bogdanova, N, Bojesen, SE, Brauch, H, Brenner, H, Brinton, L, Broeks, A, Bruening, T, Burwinkel, B, Cai, H, Canisius, S, Chang-Claude, J, Choi, J-Y, Couch, FJ, Cox, A, Cross, SS, Czene, K, Darabi, H, Devilee, P, Droit, A, Doerk, T, Fasching, PA, Fletcher, O, Flyger, H, Fostira, F, Gaborieau, V, Garcia-Closas, M, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hamann, U, Hartman, M, Hollestelle, A, Hopper, JL, Hsiung, C-N, Ito, H, Jakubowska, A, Johnson, N, Kabisch, M, Kang, D, Khan, S, Knight, JA, Kosma, V-M, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Marme, F, Matsuo, K, McLean, CA, Meindl, A, Muir, K, Neuhausen, SL, Nevanlinna, H, Nord, S, Olson, JE, Orr, N, Peterlongo, P, Putti, TC, Rudolph, A, Sangrajrang, S, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shen, C-Y, Shi, J, Shrubsole, MJ, Southey, MC, Swerdlow, A, Teo, SH, Thienpont, B, Toland, AE, Tollenaar, RAEM, Tomlinson, IPM, Truong, T, Tseng, C-C, van den Ouweland, A, Wen, W, Winqvist, R, Wu, A, Yip, CH, Zamora, MP, Zheng, Y, Hall, P, Pharoah, PDP, Simard, J, Chenevix-Trench, G, Dunning, AM, Easton, DF, and Zheng, W
Abstract: 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% confidence interval (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 (r(2) ≥ 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.
Published: 2015

78. Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer

Author: Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guenel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Gonzalez-Neira, A, Benitez, J, Zamora, MP, Arias Perez, JI, Shu, X-O, Lu, W, Gao, Y-T, Cai, H, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NAM, Tan, G-H, Hooning, MJ, Hollestelle, A, Martens, JWM, Collee, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, C-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Kristensen, VN, Nord, S, Alnaes, GIG, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, K-T, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, J-M, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Bruening, T, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Doerk, T, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Simard, J, Pharoah, PPDP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, Easton, DF, Michailidou, K, Beesley, J, Lindstrom, S, Canisius, S, Dennis, J, Lush, MJ, Maranian, MJ, Bolla, MK, Wang, Q, Shah, M, Perkins, BJ, Czene, K, Eriksson, M, Darabi, H, Brand, JS, Bojesen, SE, Nordestgaard, BG, Flyger, H, Nielsen, SF, Rahman, N, Turnbull, C, Fletcher, O, Peto, J, Gibson, L, dos-Santos-Silva, I, Chang-Claude, J, Flesch-Janys, D, Rudolph, A, Eilber, U, Behrens, S, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Khan, S, Aaltonen, K, Ahsan, H, Kibriya, MG, Whittemore, AS, John, EM, Malone, KE, Gammon, MD, Santella, RM, Ursin, G, Makalic, E, Schmidt, DF, Casey, G, Hunter, DJ, Gapstur, SM, Gaudet, MM, Diver, WR, Haiman, CA, Schumacher, F, Henderson, BE, Le Marchand, L, Berg, CD, Chanock, SJ, Figueroa, J, Hoover, RN, Lambrechts, D, Neven, P, Wildiers, H, van Limbergen, E, Schmidt, MK, Broeks, A, Verhoef, S, Cornelissen, S, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Waisfisz, Q, Meijers-Heijboer, H, Adank, MA, van der Luijt, RB, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Yoo, K-Y, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Guenel, P, Truong, T, Mulot, C, Sanchez, M, Burwinkel, B, Marme, F, Surowy, H, Sohn, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Gonzalez-Neira, A, Benitez, J, Zamora, MP, Arias Perez, JI, Shu, X-O, Lu, W, Gao, Y-T, Cai, H, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Taib, NAM, Tan, G-H, Hooning, MJ, Hollestelle, A, Martens, JWM, Collee, JM, Blot, W, Signorello, LB, Cai, Q, Hopper, JL, Southey, MC, Tsimiklis, H, Apicella, C, Shen, C-Y, Hsiung, C-N, Wu, P-E, Hou, M-F, Kristensen, VN, Nord, S, Alnaes, GIG, Giles, GG, Milne, RL, McLean, C, Canzian, F, Trichopoulos, D, Peeters, P, Lund, E, Sund, M, Khaw, K-T, Gunter, MJ, Palli, D, Mortensen, LM, Dossus, L, Huerta, J-M, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Chia, KS, Chan, CW, Fasching, PA, Hein, A, Beckmann, MW, Haeberle, L, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Ashworth, A, Orr, N, Schoemaker, MJ, Swerdlow, AJ, Brinton, L, Garcia-Closas, M, Zheng, W, Halverson, SL, Shrubsole, M, Long, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Brauch, H, Hamann, U, Bruening, T, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Bogdanova, NV, Doerk, T, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska, K, Huzarski, T, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Kabisch, M, Torres, D, Neuhausen, SL, Anton-Culver, H, Luccarini, C, Baynes, C, Ahmed, S, Healey, CS, Tessier, DC, Vincent, D, Bacot, F, Pita, G, Rosario Alonso, M, Alvarez, N, Herrero, D, Simard, J, Pharoah, PPDP, Kraft, P, Dunning, AM, Chenevix-Trench, G, Hall, P, and Easton, DF
Abstract: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
Published: 2015

79. Identification of six new susceptibility loci for invasive epithelial ovarian cancer

Author: Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, Chenevix-Trench, G, Kuchenbaecker, KB, Ramus, SJ, Tyrer, J, Lee, A, Shen, HC, Beesley, J, Lawrenson, K, McGuffog, L, Healey, S, Lee, JM, Spindler, TJ, Lin, YG, Pejovic, T, Bean, Y, Li, Q, Coetzee, S, Hazelett, D, Miron, A, Southey, M, Terry, MB, Goldgar, DE, Buys, SS, Janavicius, R, Dorfling, CM, van Rensburg, EJ, Neuhausen, SL, Ding, YC, Hansen, TVO, Jonson, L, Gerdes, A-M, Ejlertsen, B, Barrowdale, D, Dennis, J, Benitez, J, Osorio, A, Garcia, MJ, Komenaka, I, Weitzel, JN, Ganschow, P, Peterlongo, P, Bernard, L, Viel, A, Bonanni, B, Peissel, B, Manoukian, S, Radice, P, Papi, L, Ottini, L, Fostira, F, Konstantopoulou, I, Garber, J, Frost, D, Perkins, J, Platte, R, Ellis, S, Godwin, AK, Schmutzler, RK, Meindl, A, Engel, C, Sutter, C, Sinilnikova, OM, Damiola, F, Mazoyer, S, Stoppa-Lyonnet, D, Claes, K, De Leeneer, K, Kirk, J, Rodriguez, GC, Piedmonte, M, O'Malley, DM, de la Hoya, M, Caldes, T, Aittomaeki, K, Nevanlinna, H, Collee, JM, Rookus, MA, Oosterwijk, JC, Tihomirova, L, Tung, N, Hamann, U, Isaccs, C, Tischkowitz, M, Imyanitov, EN, Caligo, MA, Campbell, IG, Hogervorst, FBL, Olah, E, Diez, O, Blanco, I, Brunet, J, Lazaroso, C, Angel Pujana, M, Jakubowska, A, Gronwald, J, Lubinski, J, Sukiennicki, G, Barkardottir, RB, Plante, M, Simard, J, Soucy, P, Montagna, M, Tognazzo, S, Teixeira, MR, Pankratz, VS, Wang, X, Lindor, N, Szabo, CI, Kauff, N, Vijai, J, Aghajanian, CA, Pfeiler, G, Berger, A, Singer, CF, Tea, M-K, Phelan, CM, Greene, MH, Mai, PL, Rennert, G, Mulligan, AM, Tchatchou, S, Andrulis, IL, Glendon, G, Toland, AE, Jensen, UB, Kruse, TA, Thomassen, M, Bojesen, A, Zidan, J, Friedman, E, Laitman, Y, Soller, M, Liljegren, A, Arver, B, Einbeigi, Z, Stenmark-Askmalm, M, Olopade, OI, Nussbaum, RL, Rebbeck, TR, Nathanson, KL, Domchek, SM, Lu, KH, Karlan, BY, Walsh, C, Lester, J, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Van Nieuwenhuysen, E, Vergote, I, Lambrechts, S, Dicks, E, Doherty, JA, Wicklund, KG, Rossing, MA, Rudolph, A, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Moysich, KB, Odunsi, K, Sucheston, L, Lele, S, Wilkens, LR, Goodman, MT, Thompson, PJ, Shvetsov, YB, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Pelttari, LM, Butzow, R, Modugno, F, Kelley, JL, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Matsuo, K, Hosono, S, Orsulic, S, Jensen, A, Kjaer, SK, Hogdall, E, Hasmad, HN, Azmi, MAN, Teo, S-H, Woo, Y-L, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Bruinsma, F, Giles, GG, Liang, D, Hildebrandt, MAT, Wu, X, Levine, DA, Bisogna, M, Berchuck, A, Iversen, ES, Schildkraut, JM, Concannon, P, Weber, RP, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Orlow, I, Olson, SH, Krakstad, C, Salvesen, HB, Tangen, IL, Bjorge, L, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Kellar, M, Brooks-Wilson, A, Kelemen, LE, Cook, LS, Le, ND, Cybulski, C, Yang, H, Lissowska, J, Brinton, LA, Wentzensen, N, Hogdall, C, Lundvall, L, Nedergaard, L, Baker, H, Song, H, Eccles, D, McNeish, I, Paul, J, Carty, K, Siddiqui, N, Glasspool, R, Whittemore, AS, Rothstein, JH, McGuire, V, Sieh, W, Ji, B-T, Zheng, W, Shu, X-O, Gao, Y-T, Rosen, B, Risch, HA, McLaughlin, JR, Narod, SA, Monteiro, AN, Chen, A, Lin, H-Y, Permuth-Wey, J, Sellers, TA, Tsai, Y-Y, Chen, Z, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Harrington, P, Lee, AW, Wu, AH, Pearce, CL, Coetzee, G, Pike, MC, Dansonka-Mieszkowska, A, Timorek, A, Rzepecka, IK, Kupryjanczyk, J, Freedman, M, Noushmehr, H, Easton, DF, Offit, K, Couch, FJ, Gayther, S, Pharoah, PP, Antoniou, AC, and Chenevix-Trench, G
Abstract: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
Published: 2015

80. Genome-wide significant risk associations for mucinous ovarian carcinoma

Author: Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Modugno, F, Moes-Sosnowska, J, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Adenan, NAM, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Tworoger, SS, van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Sawicki, W, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Freedman, ML, Chenevix-Trench, G, Pharoah, PDP, Gayther, SA, Berchuck, A, Kelemen, LE, Lawrenson, K, Tyrer, J, Li, Q, Lee, JM, Seo, J-H, Phelan, CM, Beesley, J, Chen, X, Spindler, TJ, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chen, YA, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Engelholm, SA, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, B-T, Karlan, BY, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Modugno, F, Moes-Sosnowska, J, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Adenan, NAM, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Tworoger, SS, van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Sawicki, W, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Sellers, TA, Freedman, ML, Chenevix-Trench, G, Pharoah, PDP, Gayther, SA, and Berchuck, A
Abstract: Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10(-8)), rs711830 at 2q31.1 (P = 7.5 × 10(-12)) and rs688187 at 19q13.2 (P = 6.8 × 10(-13)). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10(-4), false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.
Published: 2015

81. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Author: Lawrenson, K, Li, Q, Kar, S, Seo, J-H, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Doerk, T, Du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, B-T, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Azmi, MAN, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Sellers, TA, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Monteiro, A, Pharoah, PD, Gayther, SA, Freedman, ML, Grp, AOCS, Bowtell, D, Webb, PM, Defazio, A, Lawrenson, K, Li, Q, Kar, S, Seo, J-H, Tyrer, J, Spindler, TJ, Lee, J, Chen, Y, Karst, A, Drapkin, R, Aben, KKH, Anton-Culver, H, Antonenkova, N, Baker, H, Bandera, EV, Bean, Y, Beckmann, MW, Berchuck, A, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bruinsma, F, Butzow, R, Campbell, IG, Carty, K, Chang-Claude, J, Chenevix-Trench, G, Chen, A, Chen, Z, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, Dennis, J, Dicks, E, Doherty, JA, Doerk, T, Du Bois, A, Duerst, M, Eccles, D, Easton, DT, Edwards, RP, Eilber, U, Ekici, AB, Fasching, PA, Fridley, BL, Gao, Y-T, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goode, EL, Goodman, MT, Grownwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MAT, Hillemanns, P, Hogdall, E, Hogdall, C, Hosono, S, Iversen, ES, Jakubowska, A, James, P, Jensen, A, Ji, B-T, Karlan, BY, Kjaer, SK, Kelemen, LE, Kellar, M, Kelley, JL, Kiemeney, LA, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Nevanlinna, H, McNeish, I, Menon, U, Modugno, F, Moysich, KB, Narod, SA, Nedergaard, L, Ness, RB, Azmi, MAN, Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Phelan, CM, Pike, MC, Poole, EM, Ramus, SJ, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schildkraut, JM, Schwaab, I, Sellers, TA, Shu, X-O, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Sucheston, L, Tangen, IL, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tsai, Y-Y, Tworoger, SS, Van Altena, AM, Van Nieuwenhuysen, E, Vergote, I, Vierkant, RA, Wang-Gohrke, S, Walsh, C, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Woo, Y-L, Wu, X, Wu, AH, Yang, H, Zheng, W, Ziogas, A, Monteiro, A, Pharoah, PD, Gayther, SA, Freedman, ML, Grp, AOCS, Bowtell, D, Webb, PM, and Defazio, A
Abstract: Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.
Published: 2015

82. Candidate locus analysis of the TERT-CLPTM1L cancer risk region on chromosome 5p15 identifies multiple independent variants associated with endometrial cancer risk

Author: Carvajal-Carmona, LG, O'Mara, TA, Painter, JN, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Pooley, K, Beesley, J, Cheng, T, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Wentzensen, N, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Wersaell, O, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Spurdle, AB, Thompson, DJ, Carvajal-Carmona, LG, O'Mara, TA, Painter, JN, Lose, FA, Dennis, J, Michailidou, K, Tyrer, JP, Ahmed, S, Ferguson, K, Healey, CS, Pooley, K, Beesley, J, Cheng, T, Jones, A, Howarth, K, Martin, L, Gorman, M, Hodgson, S, Wentzensen, N, Fasching, PA, Hein, A, Beckmann, MW, Renner, SP, Doerk, T, Hillemanns, P, Duerst, M, Runnebaum, I, Lambrechts, D, Coenegrachts, L, Schrauwen, S, Amant, F, Winterhoff, B, Dowdy, SC, Goode, EL, Teoman, A, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Scott, RJ, Ashton, K, Proietto, T, Otton, G, Wersaell, O, Mints, M, Tham, E, Hall, P, Czene, K, Liu, J, Li, J, Hopper, JL, Southey, MC, Ekici, AB, Ruebner, M, Johnson, N, Peto, J, Burwinkel, B, Marme, F, Brenner, H, Dieffenbach, AK, Meindl, A, Brauch, H, Lindblom, A, Depreeuw, J, Moisse, M, Chang-Claude, J, Rudolph, A, Couch, FJ, Olson, JE, Giles, GG, Bruinsma, F, Cunningham, JM, Fridley, BL, Borresen-Dale, A-L, Kristensen, VN, Cox, A, Swerdlow, AJ, Orr, N, Bolla, MK, Wang, Q, Weber, RP, Chen, Z, Shah, M, Pharoah, PDP, Dunning, AM, Tomlinson, I, Easton, DF, Spurdle, AB, and Thompson, DJ
Abstract: Several studies have reported associations between multiple cancer types and single-nucleotide polymorphisms (SNPs) on chromosome 5p15, which harbours TERT and CLPTM1L, but no such association has been reported with endometrial cancer. To evaluate the role of genetic variants at the TERT-CLPTM1L region in endometrial cancer risk, we carried out comprehensive fine-mapping analyses of genotyped and imputed SNPs using a custom Illumina iSelect array which includes dense SNP coverage of this region. We examined 396 SNPs (113 genotyped, 283 imputed) in 4,401 endometrial cancer cases and 28,758 controls. Single-SNP and forward/backward logistic regression models suggested evidence for three variants independently associated with endometrial cancer risk (P = 4.9 × 10(-6) to P = 7.7 × 10(-5)). Only one falls into a haplotype previously associated with other cancer types (rs7705526, in TERT intron 1), and this SNP has been shown to alter TERT promoter activity. One of the novel associations (rs13174814) maps to a second region in the TERT promoter and the other (rs62329728) is in the promoter region of CLPTM1L; neither are correlated with previously reported cancer-associated SNPs. Using TCGA RNASeq data, we found significantly increased expression of both TERT and CLPTM1L in endometrial cancer tissue compared with normal tissue (TERT P = 1.5 × 10(-18), CLPTM1L P = 1.5 × 10(-19)). Our study thus reports a novel endometrial cancer risk locus and expands the spectrum of cancer types associated with genetic variation at 5p15, further highlighting the importance of this region for cancer susceptibility.
Published: 2015

83. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1

Author: Cheng, THT, Thompson, D, Painter, J, O'Mara, T, Gorman, M, Martin, L, Palles, C, Jones, A, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Giles, GG, Pharoah, P, Peto, J, Cox, A, Swerdlow, A, Couch, F, Cunningham, JM, Goode, EL, Winham, SJ, Lambrechts, D, Fasching, P, Burwinkel, B, Brenner, H, Brauch, H, Chang-Claude, J, Salvesen, HB, Kristensen, V, Darabi, H, Li, J, Liu, T, Lindblom, A, Hall, P, Echeverry de Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Aguiar, S, Teixeira, MR, Dunning, AM, Dennis, J, Otton, G, Proietto, T, Holliday, E, Attia, J, Ashton, K, Scott, RJ, McEvoy, M, Dowdy, SC, Fridley, BL, Werner, HMJ, Trovik, J, Njolstad, TS, Tham, E, Mints, M, Runnebaum, I, Hillemanns, P, Doerk, T, Amant, F, Schrauwen, S, Hein, A, Beckmann, MW, Ekici, A, Czene, K, Meindl, A, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, Ahmed, S, Healey, CS, Shah, M, Annibali, D, Depreeuw, J, Al-Tassan, NA, Harris, R, Meyer, BF, Whiffin, N, Hosking, FJ, Kinnersley, B, Farrington, SM, Timofeeva, M, Tenesa, A, Campbell, H, Haile, RW, Hodgson, S, Carvajal-Carmona, L, Cheadle, JP, Easton, D, Dunlop, M, Houlston, R, Spurdle, A, Tomlinson, I, Cheng, THT, Thompson, D, Painter, J, O'Mara, T, Gorman, M, Martin, L, Palles, C, Jones, A, Buchanan, DD, Win, AK, Hopper, J, Jenkins, M, Lindor, NM, Newcomb, PA, Gallinger, S, Conti, D, Schumacher, F, Casey, G, Giles, GG, Pharoah, P, Peto, J, Cox, A, Swerdlow, A, Couch, F, Cunningham, JM, Goode, EL, Winham, SJ, Lambrechts, D, Fasching, P, Burwinkel, B, Brenner, H, Brauch, H, Chang-Claude, J, Salvesen, HB, Kristensen, V, Darabi, H, Li, J, Liu, T, Lindblom, A, Hall, P, Echeverry de Polanco, M, Sans, M, Carracedo, A, Castellvi-Bel, S, Rojas-Martinez, A, Aguiar, S, Teixeira, MR, Dunning, AM, Dennis, J, Otton, G, Proietto, T, Holliday, E, Attia, J, Ashton, K, Scott, RJ, McEvoy, M, Dowdy, SC, Fridley, BL, Werner, HMJ, Trovik, J, Njolstad, TS, Tham, E, Mints, M, Runnebaum, I, Hillemanns, P, Doerk, T, Amant, F, Schrauwen, S, Hein, A, Beckmann, MW, Ekici, A, Czene, K, Meindl, A, Bolla, MK, Michailidou, K, Tyrer, JP, Wang, Q, Ahmed, S, Healey, CS, Shah, M, Annibali, D, Depreeuw, J, Al-Tassan, NA, Harris, R, Meyer, BF, Whiffin, N, Hosking, FJ, Kinnersley, B, Farrington, SM, Timofeeva, M, Tenesa, A, Campbell, H, Haile, RW, Hodgson, S, Carvajal-Carmona, L, Cheadle, JP, Easton, D, Dunlop, M, Houlston, R, Spurdle, A, and Tomlinson, I
Abstract: High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.
Published: 2015

84. Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants

Author: Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, Garcia-Closas, M, Mavaddat, N, Pharoah, PDP, Michailidou, K, Tyrer, J, Brook, MN, Bolla, MK, Wang, Q, Dennis, J, Dunning, AM, Shah, M, Luben, R, Brown, J, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Czene, K, Darabi, H, Eriksson, M, Peto, J, dos-Santos-Silva, I, Dudbridge, F, Johnson, N, Schmidt, MK, Broeks, A, Verhoef, S, Rutgers, EJ, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Figueroa, J, Chanock, SJ, Brinton, L, Lissowska, J, Couch, FJ, Olson, JE, Vachon, C, Pankratz, VS, Lambrechts, D, Wildiers, H, Van Ongeval, C, Van Limbergen, E, Kristensen, V, Alnaes, GG, Nord, S, Borresen-Dale, A-L, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Trentham-Dietz, A, Newcomb, P, Titus, L, Egan, KM, Hunter, DJ, Lindstrom, S, Tamimi, RM, Kraft, P, Rahman, N, Turnbull, C, Renwick, A, Seal, S, Li, J, Liu, J, Humphreys, K, Benitez, J, Zamora, MP, Perez, JIA, Menendez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Bogdanova, NV, Antonenkova, NN, Doerk, T, Anton-Culver, H, Neuhausen, SL, Ziogas, A, Bernstein, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, van Asperen, CJ, Cox, A, Cross, SS, Reed, MWR, Khusnutdinova, E, Bermisheva, M, Prokofyeva, D, Takhirova, Z, Meindl, A, Schmutzler, RK, Sutter, C, Yang, R, Schuermann, P, Bremer, M, Christiansen, H, Park-Simon, T-W, Hillemanns, P, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Radice, P, Peterlongo, P, Manoukian, S, Pensotti, V, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Brauch, H, Bruening, T, Ko, Y-D, Sigurdson, AJ, Doody, MM, Hamann, U, Torres, D, Ulmer, H-U, Foersti, A, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Chenevix-Trench, G, Balleine, R, Giles, GG, Milne, RL, McLean, C, Lindblom, A, Margolin, S, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Eilber, U, Wang-Gohrke, S, Hooning, MJ, Hollestelle, A, van den Ouweland, AMW, Koppert, LB, Carpenter, J, Clarke, C, Scott, R, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Brenner, H, Arndt, V, Stegmaier, C, Dieffenbach, AK, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Offit, K, Vijai, J, Robson, M, Rau-Murthy, R, Dwek, M, Swann, R, Perkins, KA, Goldberg, MS, Labreche, F, Dumont, M, Eccles, DM, Tapper, WJ, Rafiq, S, John, EM, Whittemore, AS, Slager, S, Yannoukakos, D, Toland, AE, Yao, S, Zheng, W, Halverson, SL, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Simard, J, Hall, P, Easton, DF, and Garcia-Closas, M
Abstract: BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
Published: 2015

85. Comparison of 6q25 Breast Cancer Hits from Asian and\ud European Genome Wide Association Studies in the\ud Breast Cancer Association Consortium (BCAC)

Author: Hein, R., Maranian, M., Hopper, J.L., Kapuscinski, M.K., Southey, M.C., Park, D.J., Schmidt, M.K., Broeks, A., Hogervorst, F.B.L., Bueno-de-Mesquit, H.B., Muir, K.R., Lophatananon, A., Rattanamongkongul, S., Puttawibul, P., Fasching, P.A., Hein, A., Ekici, A.B., Beckmann, M.W., Fletcher, O., Johnson, N., Silva, I.D.S., Peto, J., Sawyer, E., Tomlinson, I., Kerin, M., Miller, N., Marmee, F., Schneeweiss, A., Sohn, C., Burwinkel, B., Guenel, P., Cordina-Duverger, E., Menegaux, F., Truong, T., Bojesen, S.E., Nordestgaard, B.G., Flyger, H., Milne, R.L., Arias Perez, J.I., Pilar Zamora, M., Benitez, J., Anton-Culver, H., Ziogas, A., Bernstein, L., Clarke, C.A., Brenner, H., Mueller, H., Arndt, V., Stegmaier, C., Rahman, N., Seal, S., Turnbull, C., Renwick, A., Meindl, A., Schott, S., Bartram, C.R., Schmutzler, R.K., Brauch, H., Hamann, U., Ko, Y-D., Wang-Gohrke, S., Doerk, T., Schuermann, P., Karstens, J.H., Hillemanns, P., Nevanlinna, H., Heikkinen, T., Aittomaki, K., Blomqvist, C., Bogdanova, N.V., Zalutsky, I.V., Antonenkova, N.N., Bermisheva, M., Prokovieva, D., Farahtdinova, A., Khusnutdinova, E., Lindblom, A., Margolin, S., Mannermaa, A., Kataja, V., Kosma, V-M., Hartikainen, J., Chen, X., Beesley, J., Lambrechts, D., Zhao, H., Neven, P., Wildiers, H., Nickels, S., Flesch-Janys, D., Radice, P., Peterlongo, P., Manoukian, S., Barile, M., Couch, F.J., Olson, J.E., Wang, X., Fredericksen, Z., Giles, G.G., Baglietto, L., McLean, C.A., Severi, G., Offit, K., Robson, M., Gaudet, M.M., Vijai, J., Alnaes, G.G., Kristensen, V., Borresen-Dale, A-L., John, E.M., Miron, A., Winqvist, R., Pylkas, K., Jukkola-Vuorinen, A., Grip, M., Andrulis, I.L., Knight, J.A., Glendon, G., Mulligan, A.M., Figueroa, J.D., Garcia-Closas, M., Lissowska, J., Sherman, M.E., Hooning, M., Martens, J.W.M., Seynaeve, C., Collee, M., Hall, P., Humpreys, K., Czene, K., Liu, J., Cox, A., Brock, I.W., Cross, S.S., Reed, M.W.R., Ahmed, S., Ghoussaini, M., Pharoah, P.D.P., Kang, D., Yoo, K-Y., Noh, D-Y., Jakubowska, A., Jaworska, K., Durda, K., Zlowocka, E., Sangrajrang, S., Gaborieau, V., Brennan, P., McKay, J., Shen, C-Y., Yu, J-C., Hsu, H-M., Hou, M-F., Orr, N., Schoemaker, M., Ashworth, A., Swerdlow, A., Trentham-Dietz, A., Newcomb, P.A., Titus, L., Egan, K.M., Chenevix-Trench, G., Antoniou, A.C., Humphreys, M.K., Morrison, J., Chang-Claude, J., Easton, D.F., Dunning, A.M., Network, GENICA, Investigators, K, and Group, AOCS
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single\ud nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports\ud about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP,\ud tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from fortyfour\ud studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European\ud descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were\ud used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER2) tumours. Models including both SNPs\ud were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer\ud risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26–\ud 1.48), p = 7.6610214 in Asians and 1.09 (95% CI 1.07–1.11), p = 6.8610218 in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI\ud 1.19–1.41), p = 1.261029 in Asians and 1.12 (95% CI 1.08–1.17), p = 3.861029 in Europeans]. SNP rs2046210 is associated with a\ud significantly greater risk of ER2 than ER+ tumours in Europeans [OR (ER2) = 1.20 (95% CI 1.15–1.25), p = 1.8610217 versus OR\ud (ER+) = 1.07 (95% CI 1.04–1.1), p = 1.361027\ud , pheterogeneity = 5.161026\ud ]. In these Asian studies, by contrast, there is no clear\ud evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other\ud SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in\ud Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER2 tumours.
Published: 2012

86. Common variants at 19p13 are associated with susceptibility to ovarian cancer

Author: Bolton, KL, Tyrer, J, Song, H, Ramus, SJ, Notaridou, M, Jones, C, Sher, T, Gentry-Maharaj, A, Wozniak, E, Tsai, YY, Weidhaas, J, Paik, D, Van Den Berg, DJ, Stram, DO, Pearce, CL, Wu, AH, Brewster, W, Anton-Culver, H, Ziogas, A, Narod, SA, Levine, DA, Kaye, SB, Brown, R, Paul, J, Flanagan, J, Sieh, W, McGuire, V, Whittemore, AS, Campbell, I, Gore, ME, Lissowska, J, Yang, HP, Medrek, K, Gronwald, J, Lubinski, J, Jakubowska, A, Le, ND, Cook, LS, Kelemen, LE, Brook-Wilson, A, Massuger, LFAG, Kiemeney, LA, Aben, KKH, Van Altena, AM, Houlston, R, Tomlinson, I, Palmieri, RT, Moorman, PG, Schildkraut, J, Iversen, ES, Phelan, C, Vierkant, RA, Cunningham, JM, Goode, EL, Fridley, BL, Kruger-Kjaer, S, Blaeker, J, Hogdall, E, Hogdall, C, Gross, J, Karlan, BY, Ness, RB, Edwards, RP, Odunsi, K, Moyisch, KB, Baker, JA, Modugno, F, Heikkinenen, T, Butzow, R, Nevanlinna, H, Leminen, A, Bogdanova, N, Antonenkova, N, Doerk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Thompson, PJ, Carney, ME, Goodman, MT, Lurie, G, Wang-Gohrke, S, Hein, R, Chang-Claude, J, Rossing, MA, Cushing-Haugen, KL, Doherty, J, Chen, C, Rafnar, T, Besenbacher, S, Sulem, P, Stefansson, K, Birrer, MJ, Terry, KL, Hernandez, D, Cramer, DW, and Vergote, I
Subjects: endocrine system diseases, female genital diseases and pregnancy complications
Abstract: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5×10-4and P = 6×10-4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3×10-9and P = 4×10-11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development. © 2010 Nature America, Inc. All rights reserved.
Published: 2010

87. Cogeneration in Single Family Homes with Fuel Cell Heating Appliances

Author: Nerlich, V., Schuler, A., Mai, A., Doerk, T., Grube, Thomas, and Stolten, Detlef
Subjects: ddc:333.7, ddc:620
Published: 2010

88. Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA

Author: Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, CK, Hogdall, E, Lundvall, L, Sellers, TA, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Giles, GG, Baglietto, L, Severi, G, Southey, MC, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Levine, DA, Bisogna, M, Schildkraut, JM, Iversen, ES, Weber, RP, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Chandran, U, Orlow, I, Olson, SH, Wik, E, Salvesen, HB, Bjorge, L, Halle, MK, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, YT, Cybulski, C, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Garcia-Closas, M, Dicks, E, Dennis, J, Easton, DF, Song, H, Tyrer, JP, Pharoah, PDP, Eccles, D, Campbell, IG, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, JH, Flanagan, JM, Paul, J, Brown, R, Phelan, CM, Risch, HA, McLaughlin, JR, Narod, SA, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Gayther, SA, Ramus, SJ, Wu, AH, Pearce, CL, Pike, MC, Dansonka-Mieszkowska, A, Rzepecka, IK, Szafron, LM, Kupryjanczyk, J, Cook, LS, Le, ND, Brooks-Wilson, A, Earp, MA, Kelemen, LE, Magliocco, AM, Swenerton, KD, Chenevix-Trench, G, Lu, Y, Hein, A, Ekici, AB, Beckmann, MW, Fasching, PA, Lambrechts, D, Despierre, E, Vergote, I, Lambrechts, S, Doherty, JA, Rossing, MA, Chang-Claude, J, Rudolph, A, Friel, G, Moysich, KB, Odunsi, K, Sucheston-Campbell, L, Lurie, G, Goodman, MT, Carney, ME, Thompson, PJ, Runnebaum, IB, Duerst, M, Hillemanns, P, Doerk, T, Antonenkova, N, Bogdanova, N, Leminen, A, Nevanlinna, H, Pelttari, LM, Butzow, R, Bunker, CH, Modugno, F, Edwards, RP, Ness, RB, du Bois, A, Heitz, F, Schwaab, I, Harter, P, Karlan, BY, Walsh, C, Lester, J, Jensen, A, Kjaer, SK, Hogdall, CK, Hogdall, E, Lundvall, L, Sellers, TA, Fridley, BL, Goode, EL, Cunningham, JM, Vierkant, RA, Giles, GG, Baglietto, L, Severi, G, Southey, MC, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Levine, DA, Bisogna, M, Schildkraut, JM, Iversen, ES, Weber, RP, Berchuck, A, Cramer, DW, Terry, KL, Poole, EM, Tworoger, SS, Bandera, EV, Chandran, U, Orlow, I, Olson, SH, Wik, E, Salvesen, HB, Bjorge, L, Halle, MK, van Altena, AM, Aben, KKH, Kiemeney, LA, Massuger, LFAG, Pejovic, T, Bean, YT, Cybulski, C, Gronwald, J, Lubinski, J, Wentzensen, N, Brinton, LA, Lissowska, J, Garcia-Closas, M, Dicks, E, Dennis, J, Easton, DF, Song, H, Tyrer, JP, Pharoah, PDP, Eccles, D, Campbell, IG, Whittemore, AS, McGuire, V, Sieh, W, Rothstein, JH, Flanagan, JM, Paul, J, Brown, R, Phelan, CM, Risch, HA, McLaughlin, JR, Narod, SA, Ziogas, A, Anton-Culver, H, Gentry-Maharaj, A, Menon, U, Gayther, SA, Ramus, SJ, Wu, AH, Pearce, CL, Pike, MC, Dansonka-Mieszkowska, A, Rzepecka, IK, Szafron, LM, Kupryjanczyk, J, Cook, LS, Le, ND, and Brooks-Wilson, A
Abstract: Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.
Published: 2014

89. Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium

Author: Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, J-I, Pilar Zamora, M, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y-D, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, J, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, M-R, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, R, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, MJ, Kriege, M, van den Ouweland, AMW, Koppert, LB, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Guenel, P, Therese, T, Sanchez, M, Mulot, C, Blot, W, Cai, Q, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Bogdanova, N, Doerk, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, McKay, J, Wang, X, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S, Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, Easton, DF, Milne, RL, Burwinkel, B, Michailidou, K, Arias-Perez, J-I, Pilar Zamora, M, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Dennis, J, Wang, Q, Bolla, MK, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, M, Ko, Y-D, Brauch, H, Hamann, U, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Matsuo, K, Ito, H, Iwata, H, Tajima, K, Li, J, Brand, JS, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Lambrechts, D, Peuteman, G, Christiaens, M-R, Smeets, A, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hartman, M, Hui, M, Lim, WY, Chan, CW, Marme, F, Yang, R, Bugert, P, Lindblom, A, Margolin, S, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Bojesen, SE, Nordestgaard, BG, Flyger, H, Hooning, MJ, Kriege, M, van den Ouweland, AMW, Koppert, LB, Fletcher, O, Johnson, N, dos-Santos-Silva, I, Peto, J, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Cox, A, Cross, SS, Reed, MWR, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, L, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Radice, P, Peterlongo, P, Azzollini, J, Barile, M, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Guenel, P, Therese, T, Sanchez, M, Mulot, C, Blot, W, Cai, Q, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Wu, AH, Tseng, C-C, Van den Berg, D, Stram, DO, Bogdanova, N, Doerk, T, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Couch, FJ, Toland, AE, Yannoukakos, D, Sangrajrang, S, McKay, J, Wang, X, Olson, JE, Vachon, C, Purrington, K, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Ahmed, S, Shah, M, Pharoah, PDP, Hall, P, Giles, GG, Benitez, J, Dunning, AM, Chenevix-Trench, G, and Easton, DF
Abstract: Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04-1.10, P = 2.9 × 10(-6)], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03-1.07, P = 1.7 × 10(-6)) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07-1.12, P = 5.1 × 10(-17)). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05-1.10, P = 1.0 × 10(-8)); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04-1.07, P = 2.0 × 10(-10)). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
Published: 2014

90. Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author: Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, Dunning, AM, Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Lari, RC-S, Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, M, Luben, R, Brown, J, Czene, K, Darabi, H, Eriksson, M, Klevebring, D, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, H, Broeks, A, Van't Veer, LJ, Rutgers, EJT, Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Peto, J, dos-Santos-Silva, I, Gibson, L, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, Humphreys, K, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Benitez, J, Pilar Zamora, M, Arias Perez, JI, Menendez, P, Shu, X-O, Lu, W, Gao, Y-T, Cai, Q, Cox, A, Cross, SS, Reed, MWR, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, Margolin, S, Teo, SH, Yip, CH, Lee, DSC, Wong, TY, Hooning, MJ, Martens, JWM, Collee, JM, van Deurzen, CHM, Hopper, JL, Southey, MC, Tsimiklis, H, Kapuscinski, MK, Shen, C-Y, Wu, P-E, Yu, J-C, Chen, S-T, Alnaes, GG, Borresen-Dale, A-L, Giles, GG, Milne, RL, McLean, C, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, Buhari, SABS, Teo, YY, Fasching, PA, Haeberle, L, Ekici, AB, Beckmann, MW, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Swerdlow, A, Ashworth, A, Orr, N, Schoemaker, MJ, Garcia-Closas, M, Figueroa, J, Chanock, SJ, Lissowska, J, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Brauch, H, Bruening, T, Koto, Y-D, Radice, P, Peterlongo, P, Bonanni, B, Volorio, S, Doerk, T, Bogdanova, NV, Helbig, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Van Asperen, CJ, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Slager, S, Toland, AE, Ambrosone, CB, Yannoukakos, D, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Hamann, U, Torres, D, Zheng, W, Long, J, Anton-Culver, H, Neuhausen, SL, Luccarini, C, Baynes, C, Ahmed, S, Maranian, M, Healey, CS, Gonzalez-Neira, A, Pita, G, Alonso, MR, Alvarez, N, Herrero, D, Tessier, DC, Vincent, D, Bacot, F, de Santiago, I, Carroll, J, Caldas, C, Brown, MA, Lupien, M, Kristensen, VN, Pharoah, PDP, Chenevix-Trench, G, French, JD, Easton, DF, and Dunning, AM
Abstract: GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.
Published: 2014

91. Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study

Author: Johnson, N, Dudbridge, F, Orr, N, Gibson, L, Jones, ME, Schoemaker, MJ, Folkerd, EJ, Haynes, BP, Hopper, JL, Southey, MC, Dite, GS, Apicella, C, Schmidt, MK, Broeks, A, Van't Veer, LJ, Atsma, F, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Ekici, AB, Renner, SP, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Truong, T, Cordina, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, R, Zamora, MP, Arias Perez, JI, Benitez, J, Bernstein, L, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Dieffenbach, AK, Meindl, A, Heil, J, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Matsuo, K, Doerk, T, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Wu, AH, Van den Berg, D, Tseng, C-C, Lambrechts, D, Smeets, D, Neven, P, Wildiers, H, Chang-Claude, J, Rudolph, A, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Pensotti, V, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Pankratz, VS, Giles, GG, Severi, G, Baglietto, L, Haiman, C, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Soucy, P, Teo, S, Yip, CH, Phuah, SY, Cornes, BK, Kristensen, VN, Alnaes, GG, Borresen-Dale, A-L, Zheng, W, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Figueroa, J, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Schoof, N, Hooning, M, Hollestelle, A, Oldenburg, RA, Tilanus-Linthorst, M, Liu, J, Cox, A, Brock, IW, Reed, MWR, Cross, SS, Blot, W, Signorello, LB, Pharoah, PDP, Dunning, AM, Shah, M, Kang, D, Noh, D-Y, Park, SK, Choi, J-Y, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Foersti, A, Ruediger, T, Ulmer, HU, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Vachon, C, Yannoukakos, D, Shen, C-Y, Yu, J-C, Huang, C-S, Hou, M-F, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Dennis, J, Michailidou, K, Bolla, MK, Wang, J, Easton, DF, Garcia-Closas, M, Dowsett, M, Ashworth, A, Swerdlow, AJ, Peto, J, Silva, IDS, Fletcher, O, Johnson, N, Dudbridge, F, Orr, N, Gibson, L, Jones, ME, Schoemaker, MJ, Folkerd, EJ, Haynes, BP, Hopper, JL, Southey, MC, Dite, GS, Apicella, C, Schmidt, MK, Broeks, A, Van't Veer, LJ, Atsma, F, Muir, K, Lophatananon, A, Fasching, PA, Beckmann, MW, Ekici, AB, Renner, SP, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Truong, T, Cordina, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, R, Zamora, MP, Arias Perez, JI, Benitez, J, Bernstein, L, Anton-Culver, H, Ziogas, A, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Dieffenbach, AK, Meindl, A, Heil, J, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Ko, Y-D, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Matsuo, K, Doerk, T, Bogdanova, NV, Antonenkova, NN, Lindblom, A, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Chenevix-Trench, G, Beesley, J, Wu, AH, Van den Berg, D, Tseng, C-C, Lambrechts, D, Smeets, D, Neven, P, Wildiers, H, Chang-Claude, J, Rudolph, A, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Bonanni, B, Pensotti, V, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Pankratz, VS, Giles, GG, Severi, G, Baglietto, L, Haiman, C, Simard, J, Goldberg, MS, Labreche, F, Dumont, M, Soucy, P, Teo, S, Yip, CH, Phuah, SY, Cornes, BK, Kristensen, VN, Alnaes, GG, Borresen-Dale, A-L, Zheng, W, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Devillee, P, Figueroa, J, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Schoof, N, Hooning, M, Hollestelle, A, Oldenburg, RA, Tilanus-Linthorst, M, Liu, J, Cox, A, Brock, IW, Reed, MWR, Cross, SS, Blot, W, Signorello, LB, Pharoah, PDP, Dunning, AM, Shah, M, Kang, D, Noh, D-Y, Park, SK, Choi, J-Y, Hartman, M, Miao, H, Lim, WY, Tang, A, Hamann, U, Foersti, A, Ruediger, T, Ulmer, HU, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Sangrajrang, S, Gaborieau, V, Brennan, P, Mckay, J, Slager, S, Toland, AE, Vachon, C, Yannoukakos, D, Shen, C-Y, Yu, J-C, Huang, C-S, Hou, M-F, Gonzalez-Neira, A, Tessier, DC, Vincent, D, Bacot, F, Luccarini, C, Dennis, J, Michailidou, K, Bolla, MK, Wang, J, Easton, DF, Garcia-Closas, M, Dowsett, M, Ashworth, A, Swerdlow, AJ, Peto, J, Silva, IDS, and Fletcher, O
Abstract: INTRODUCTION: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. METHODS: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. RESULTS: We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29). CONCLUSIONS: To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between la
Published: 2014

92. FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Author: Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, Milne, RL, Agarwal, D, Pineda, S, Michailidou, K, Herranz, J, Pita, G, Moreno, LT, Alonso, MR, Dennis, J, Wang, Q, Bolla, MK, Meyer, KB, Menendez-Rodriguez, P, Hardisson, D, Mendiola, M, Gonzalez-Neira, A, Lindblom, A, Margolin, S, Swerdlow, A, Ashworth, A, Orr, N, Jones, M, Matsuo, K, Ito, H, Iwata, H, Kondo, N, Hartman, M, Hui, M, Lim, WY, Iau, PT-C, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Kang, D, Choi, J-Y, Park, SK, Noh, D-Y, Hopper, JL, Schmidt, DF, Makalic, E, Southey, MC, Teo, SH, Yip, CH, Sivanandan, K, Tay, W-T, Brauch, H, Bruening, T, Hamann, U, Dunning, AM, Shah, M, Andrulis, IL, Knight, JA, Glendon, G, Tchatchou, S, Schmidt, MK, Broeks, A, Rosenberg, EH, van't Veer, LJ, Fasching, PA, Renner, SP, Ekici, AB, Beckmann, MW, Shen, C-Y, Hsiung, C-N, Yu, J-C, Hou, M-F, Blot, W, Cai, Q, Wu, AH, Tseng, C-C, Van Den Berg, D, Stram, DO, Cox, A, Brock, IW, Reed, MWR, Muir, K, Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Zheng, W, Deming-Halverson, S, Shrubsole, MJ, Long, J, Shu, X-O, Lu, W, Gao, Y-T, Zhang, B, Radice, P, Peterlongo, P, Manoukian, S, Mariette, F, Sangrajrang, S, Mckay, J, Couch, FJ, Toland, AE, Yannoukakos, D, Fletcher, O, Johnson, N, dos Santos Silva, I, Peto, J, Marme, F, Burwinkel, B, Guenel, P, Truong, T, Sanchez, M, Mulot, C, Bojesen, SE, Nordestgaard, BG, Flyer, H, Brenner, H, Dieffenbach, AK, Arndt, V, Stegmaier, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Wang, X, Olson, JE, Vachon, C, Purrington, K, Giles, GG, Severi, G, Baglietto, L, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Simard, J, Dumont, M, Goldberg, MS, Labreche, F, Winqvist, R, Pylkaes, K, Jukkola-Vuorinen, A, Grip, M, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Figueroa, JD, Czene, K, Eriksson, M, Humphreys, K, Darabi, H, Hooning, MJ, Kriege, M, Collee, JM, Tilanus-Linthorst, M, Li, J, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Nevanlinna, H, Muranen, TA, Aittomaeki, K, Blomqvist, C, Bogdanova, N, Doerk, T, Hall, P, Chenevix-Trench, G, Easton, DF, Pharoah, PDP, Arias-Perez, JI, Zamora, P, Benitez, J, and Milne, RL
Abstract: BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.
Published: 2014

93. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

Author: Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, H-Y, Chen, YA, Tsai, Y-Y, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, Chanock, S, Chenevix-Trench, G, Cheng, JQ, Cicek, MS, Coetzee, GA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Easton, DF, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, DA, Flanagan, JM, Garcia-Closas, M, Gentry-Maharaj, A, Giles, GG, Glasspool, RM, Gonzalez-Bosquet, J, Goodman, MT, Gore, M, Gorski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, Konecny, GE, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Lancaster, JM, Le, ND, Leminen, A, Levine, DA, Liang, D, Lim, BK, Lin, J, Lissowska, J, Lu, KH, Lubinski, J, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, SH, Orlow, I, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Raska, P, Renner, SP, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Shvetsov, YB, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Stram, D, Sutphen, R, Teo, S-H, Terry, KL, Tessier, DC, Thompson, PJ, Tworoger, SS, van Altena, AM, Vergote, I, Vierkant, RA, Vincent, D, Vitonis, AF, Wang-Gohrke, S, Weber, RP, Wentzensen, N, Whittemore, AS, Wik, E, Wilkens, LR, Winterhoff, B, Woo, YL, Wu, AH, Xiang, Y-B, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Phelan, CM, Iversen, E, Schildkraut, JM, Berchuck, A, Fridley, BL, Goode, EL, Pharoah, PDP, Monteiro, ANA, Sellers, TA, Gayther, SA, Permuth-Wey, J, Lawrenson, K, Shen, HC, Velkova, A, Tyrer, JP, Chen, Z, Lin, H-Y, Chen, YA, Tsai, Y-Y, Qu, X, Ramus, SJ, Karevan, R, Lee, J, Lee, N, Larson, MC, Aben, KK, Anton-Culver, H, Antonenkova, N, Antoniou, AC, Armasu, SM, Bacot, F, Baglietto, L, Bandera, EV, Barnholtz-Sloan, J, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Cai, Q, Campbell, I, Chang-Claude, J, Chanock, S, Chenevix-Trench, G, Cheng, JQ, Cicek, MS, Coetzee, GA, Cook, LS, Couch, FJ, Cramer, DW, Cunningham, JM, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Easton, DF, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, DA, Flanagan, JM, Garcia-Closas, M, Gentry-Maharaj, A, Giles, GG, Glasspool, RM, Gonzalez-Bosquet, J, Goodman, MT, Gore, M, Gorski, B, Gronwald, J, Hall, P, Halle, MK, Harter, P, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, CK, Hogdall, E, Hosono, S, Jakubowska, A, Jensen, A, Jim, H, Kalli, KR, Karlan, BY, Kaye, SB, Kelemen, LE, Kiemeney, LA, Kikkawa, F, Konecny, GE, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Lancaster, JM, Le, ND, Leminen, A, Levine, DA, Liang, D, Lim, BK, Lin, J, Lissowska, J, Lu, KH, Lubinski, J, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Nedergaard, L, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, SH, Orlow, I, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Raska, P, Renner, SP, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Shvetsov, YB, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Stram, D, Sutphen, R, Teo, S-H, Terry, KL, Tessier, DC, Thompson, PJ, Tworoger, SS, van Altena, AM, Vergote, I, Vierkant, RA, Vincent, D, Vitonis, AF, Wang-Gohrke, S, Weber, RP, Wentzensen, N, Whittemore, AS, Wik, E, Wilkens, LR, Winterhoff, B, Woo, YL, Wu, AH, Xiang, Y-B, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Phelan, CM, Iversen, E, Schildkraut, JM, Berchuck, A, Fridley, BL, Goode, EL, Pharoah, PDP, Monteiro, ANA, Sellers, TA, and Gayther, SA
Abstract: Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3' untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene-environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10(-8)) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10(-10)). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes.
Published: 2013

94. Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Author: Hunter, KW, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, OM, Pankratz, VS, Wang, X, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, M, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, AMW, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C, Mai, PL, Benitez, J, Southey, MC, Schmidt, MK, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q, Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Doerk, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, MJ, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, Offit, K, Hunter, KW, Gaudet, MM, Kuchenbaecker, KB, Vijai, J, Klein, RJ, Kirchhoff, T, McGuffog, L, Barrowdale, D, Dunning, AM, Lee, A, Dennis, J, Healey, S, Dicks, E, Soucy, P, Sinilnikova, OM, Pankratz, VS, Wang, X, Eldridge, RC, Tessier, DC, Vincent, D, Bacot, F, Hogervorst, FBL, Peock, S, Stoppa-Lyonnet, D, Peterlongo, P, Schmutzler, RK, Nathanson, KL, Piedmonte, M, Singer, CF, Thomassen, M, Hansen, TVO, Neuhausen, SL, Blanco, I, Greene, MH, Garber, J, Weitzel, JN, Andrulis, IL, Goldgar, DE, D'Andrea, E, Caldes, T, Nevanlinna, H, Osorio, A, van Rensburg, EJ, Arason, A, Rennert, G, van den Ouweland, AMW, van der Hout, AH, Kets, CM, Aalfs, CM, Wijnen, JT, Ausems, MGEM, Frost, D, Ellis, S, Fineberg, E, Platte, R, Evans, DG, Jacobs, C, Adlard, J, Tischkowitz, M, Porteous, ME, Damiola, F, Golmard, L, Barjhoux, L, Longy, M, Belotti, M, Ferrer, SF, Mazoyer, S, Spurdle, AB, Manoukian, S, Barile, M, Genuardi, M, Arnold, N, Meindl, A, Sutter, C, Wappenschmidt, B, Domchek, SM, Pfeiler, G, Friedman, E, Jensen, UB, Robson, M, Shah, S, Lazaro, C, Mai, PL, Benitez, J, Southey, MC, Schmidt, MK, Fasching, PA, Peto, J, Humphreys, MK, Wang, Q, Michailidou, K, Sawyer, EJ, Burwinkel, B, Guenel, P, Bojesen, SE, Milne, RL, Brenner, H, Lochmann, M, Aittomaki, K, Doerk, T, Margolin, S, Mannermaa, A, Lambrechts, D, Chang-Claude, J, Radice, P, Giles, GG, Haiman, CA, Winqvist, R, Devillee, P, Garcia-Closas, M, Schoof, N, Hooning, MJ, Cox, A, Pharoah, PDP, Jakubowska, A, Orr, N, Gonzalez-Neira, A, Pita, G, Rosario Alonso, M, Hall, P, Couch, FJ, Simard, J, Altshuler, D, Easton, DF, Chenevix-Trench, G, Antoniou, AC, and Offit, K
Abstract: Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of br
Published: 2013

95. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Author: Pharoah, PDP, Tsai, Y-Y, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Campbell, I, Carney, ME, Carvalho, RS, Chang-Claude, J, Chen, YA, Chen, Z, Chow, W-H, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, Y-T, Garcia-Closas, M, Gentry-Maharaj, A, Giles, G, Gjyshi, A, Gore, M, Gronwald, J, Guo, Q, Halle, MK, Harter, P, Hein, A, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, E, Hogdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Konecny, GE, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, N, Lee, J, Leminen, A, Lim, BK, Lissowska, J, Lubinski, J, Lundvall, L, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, S, Orlow, I, Paul, J, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Qu, X, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, I, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Sieh, W, Southey, MC, Spellman, P, Tajima, K, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tworoger, SS, van Altena, AM, van den Berg, D, Vergote, I, Vierkant, RA, Vitonis, AF, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wik, E, Winterhoff, B, Woo, YL, Wu, AH, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Goodman, MT, Hall, P, Easton, DF, Pearce, CL, Berchuck, A, Chenevix-Trench, G, Iversen, E, Monteiro, ANA, Gayther, SA, Schildkraut, JM, Sellers, TA, Pharoah, PDP, Tsai, Y-Y, Ramus, SJ, Phelan, CM, Goode, EL, Lawrenson, K, Buckley, M, Fridley, BL, Tyrer, JP, Shen, H, Weber, R, Karevan, R, Larson, MC, Song, H, Tessier, DC, Bacot, F, Vincent, D, Cunningham, JM, Dennis, J, Dicks, E, Aben, KK, Anton-Culver, H, Antonenkova, N, Armasu, SM, Baglietto, L, Bandera, EV, Beckmann, MW, Birrer, MJ, Bloom, G, Bogdanova, N, Brenton, JD, Brinton, LA, Brooks-Wilson, A, Brown, R, Butzow, R, Campbell, I, Carney, ME, Carvalho, RS, Chang-Claude, J, Chen, YA, Chen, Z, Chow, W-H, Cicek, MS, Coetzee, G, Cook, LS, Cramer, DW, Cybulski, C, Dansonka-Mieszkowska, A, Despierre, E, Doherty, JA, Doerk, T, du Bois, A, Duerst, M, Eccles, D, Edwards, R, Ekici, AB, Fasching, PA, Fenstermacher, D, Flanagan, J, Gao, Y-T, Garcia-Closas, M, Gentry-Maharaj, A, Giles, G, Gjyshi, A, Gore, M, Gronwald, J, Guo, Q, Halle, MK, Harter, P, Hein, A, Heitz, F, Hillemanns, P, Hoatlin, M, Hogdall, E, Hogdall, CK, Hosono, S, Jakubowska, A, Jensen, A, Kalli, KR, Karlan, BY, Kelemen, LE, Kiemeney, LA, Kjaer, SK, Konecny, GE, Krakstad, C, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, N, Lee, J, Leminen, A, Lim, BK, Lissowska, J, Lubinski, J, Lundvall, L, Lurie, G, Massuger, LFAG, Matsuo, K, McGuire, V, McLaughlin, JR, Menon, U, Modugno, F, Moysich, KB, Nakanishi, T, Narod, SA, Ness, RB, Nevanlinna, H, Nickels, S, Noushmehr, H, Odunsi, K, Olson, S, Orlow, I, Paul, J, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Qu, X, Risch, HA, Rodriguez-Rodriguez, L, Rossing, MA, Rudolph, A, Runnebaum, I, Rzepecka, IK, Salvesen, HB, Schwaab, I, Severi, G, Shridhar, V, Shu, X-O, Sieh, W, Southey, MC, Spellman, P, Tajima, K, Teo, S-H, Terry, KL, Thompson, PJ, Timorek, A, Tworoger, SS, van Altena, AM, van den Berg, D, Vergote, I, Vierkant, RA, Vitonis, AF, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wik, E, Winterhoff, B, Woo, YL, Wu, AH, Yang, HP, Zheng, W, Ziogas, A, Zulkifli, F, Goodman, MT, Hall, P, Easton, DF, Pearce, CL, Berchuck, A, Chenevix-Trench, G, Iversen, E, Monteiro, ANA, Gayther, SA, Schildkraut, JM, and Sellers, TA
Abstract: Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.
Published: 2013

96. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Author: Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, Pearce, CL, Shen, H, Fridley, BL, Song, H, Lawrenson, K, Cunningham, JM, Ramus, SJ, Cicek, MS, Tyrer, J, Stram, D, Larson, MC, Koebel, M, Ziogas, A, Zheng, W, Yang, HP, Wu, AH, Wozniak, EL, Woo, YL, Winterhoff, B, Wik, E, Whittemore, AS, Wentzensen, N, Weber, RP, Vitonis, AF, Vincent, D, Vierkant, RA, Vergote, I, Van Den Berg, D, Van Altena, AM, Tworoger, SS, Thompson, PJ, Tessier, DC, Terry, KL, Teo, S-H, Templeman, C, Stram, DO, Southey, MC, Sieh, W, Siddiqui, N, Shvetsov, YB, Shu, X-O, Shridhar, V, Wang-Gohrke, S, Severi, G, Schwaab, I, Salvesen, HB, Rzepecka, IK, Runnebaum, IB, Rossing, MA, Rodriguez-Rodriguez, L, Risch, HA, Renner, SP, Poole, EM, Pike, MC, Phelan, CM, Pelttari, LM, Pejovic, T, Paul, J, Orlow, I, Omar, SZ, Olson, SH, Odunsi, K, Nickels, S, Nevanlinna, H, Ness, RB, Narod, SA, Nakanishi, T, Moysich, KB, Monteiro, ANA, Moes-Sosnowska, J, Modugno, F, Menon, U, McLaughlin, JR, McGuire, V, Matsuo, K, Adenan, NAM, Massuger, LFAG, Lurie, G, Lundvall, L, Lubinski, J, Lissowska, J, Levine, DA, Leminen, A, Lee, AW, Le, ND, Lambrechts, S, Lambrechts, D, Kupryjanczyk, J, Krakstad, C, Konecny, GE, Kjaer, SK, Kiemeney, LA, Kelemen, LE, Keeney, GL, Karlan, BY, Karevan, R, Kalli, KR, Kajiyama, H, Ji, B-T, Jensen, A, Jakubowska, A, Iversen, E, Hosono, S, Hogdall, CK, Hogdall, E, Hoatlin, M, Hillemanns, P, Heitz, F, Hein, R, Harter, P, Halle, MK, Hall, P, Gronwald, J, Gore, M, Goodman, MT, Giles, GG, Gentry-Maharaj, A, Garcia-Closas, M, Flanagan, JM, Fasching, PA, Ekici, AB, Edwards, R, Eccles, D, Easton, DF, Duerst, M, du Bois, A, Doerk, T, Doherty, JA, Despierre, E, Dansonka-Mieszkowska, A, Cybulski, C, Cramer, DW, Cook, LS, Chen, X, Charbonneau, B, Chang-Claude, J, Campbell, I, Butzow, R, Bunker, CH, Brueggmann, D, Brown, R, Brooks-Wilson, A, Brinton, LA, Bogdanova, N, Block, MS, Benjamin, E, Beesley, J, Beckmann, MW, Bandera, EV, Baglietto, L, Bacot, F, Armasu, SM, Antonenkova, N, Anton-Culver, H, Aben, KK, Liang, D, Wu, X, Lu, K, Hildebrandt, MAT, Schildkraut, JM, Sellers, TA, Huntsman, D, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Pharoah, PDP, Laird, PW, Goode, EL, and Pearce, CL
Abstract: HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
Published: 2013

97. Genome-wide association analysis identifies three new breast cancer susceptibility loci

Author: Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Silva, IDS, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Rosario Alonso, M, Gonzalez-Neira, A, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Justenhoven, C, Brauch, H, Bruening, T, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Bermisheva, M, Prokofieva, D, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Manoukian, S, Bonanni, B, Fortuzzi, S, Peterlongo, P, Couch, FJ, Wang, X, Stevens, K, Lee, A, Giles, GG, Baglietto, L, Severi, G, McLean, C, Alnaes, GG, Kristensen, V, Borrensen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Glendon, G, Mulligan, AM, Devilee, P, van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Figueroa, JD, Garcia-Closas, M, Brinton, L, Lissowska, J, Hooning, MJ, Hollestelle, A, Oldenburg, RA, van den Ouweland, AMW, Cox, A, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Jones, M, Schoemaker, M, Ashworth, A, Swerdlow, A, Beesley, J, Chen, X, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Chaiwerawattana, A, Kang, D, Yoo, K-Y, Noh, D-Y, Shen, C-Y, Yu, J-C, Wu, P-E, Hsiung, C-N, Perkins, A, Swann, R, Velentzis, L, Eccles, DM, Tapper, WJ, Gerty, SM, Graham, NJ, Ponder, BAJ, Chenevix-Trench, G, Pharoah, PDP, Lathrop, M, Dunning, AM, Rahman, N, Peto, J, Easton, DF, Ghoussaini, M, Fletcher, O, Michailidou, K, Turnbull, C, Schmidt, MK, Dicks, E, Dennis, J, Wang, Q, Humphreys, MK, Luccarini, C, Baynes, C, Conroy, D, Maranian, M, Ahmed, S, Driver, K, Johnson, N, Orr, N, Silva, IDS, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Hall, P, Czene, K, Irwanto, A, Liu, J, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lichtner, P, Chang-Claude, J, Hein, R, Nickels, S, Flesch-Janys, D, Tsimiklis, H, Makalic, E, Schmidt, D, Bui, M, Hopper, JL, Apicella, C, Park, DJ, Southey, M, Hunter, DJ, Chanock, SJ, Broeks, A, Verhoef, S, Hogervorst, FBL, Fasching, PA, Lux, MP, Beckmann, MW, Ekici, AB, Sawyer, E, Tomlinson, I, Kerin, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Truong, T, Cordina-Duverger, E, Menegaux, F, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Milne, RL, Rosario Alonso, M, Gonzalez-Neira, A, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Justenhoven, C, Brauch, H, Bruening, T, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Bermisheva, M, Prokofieva, D, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Lambrechts, D, Yesilyurt, BT, Floris, G, Leunen, K, Manoukian, S, Bonanni, B, Fortuzzi, S, Peterlongo, P, Couch, FJ, Wang, X, Stevens, K, Lee, A, Giles, GG, Baglietto, L, Severi, G, McLean, C, Alnaes, GG, Kristensen, V, Borrensen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Kauppila, S, Andrulis, IL, Glendon, G, Mulligan, AM, Devilee, P, van Asperen, CJ, Tollenaar, RAEM, Seynaeve, C, Figueroa, JD, Garcia-Closas, M, Brinton, L, Lissowska, J, Hooning, MJ, Hollestelle, A, Oldenburg, RA, van den Ouweland, AMW, Cox, A, Reed, MWR, Shah, M, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Jones, M, Schoemaker, M, Ashworth, A, Swerdlow, A, Beesley, J, Chen, X, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Chaiwerawattana, A, Kang, D, Yoo, K-Y, Noh, D-Y, Shen, C-Y, Yu, J-C, Wu, P-E, Hsiung, C-N, Perkins, A, Swann, R, Velentzis, L, Eccles, DM, Tapper, WJ, Gerty, SM, Graham, NJ, Ponder, BAJ, Chenevix-Trench, G, Pharoah, PDP, Lathrop, M, Dunning, AM, Rahman, N, Peto, J, and Easton, DF
Abstract: Breast cancer is the most common cancer among women. To date, 22 common breast cancer susceptibility loci have been identified accounting for ∼8% of the heritability of the disease. We attempted to replicate 72 promising associations from two independent genome-wide association studies (GWAS) in ∼70,000 cases and ∼68,000 controls from 41 case-control studies and 9 breast cancer GWAS. We identified three new breast cancer risk loci at 12p11 (rs10771399; P = 2.7 × 10(-35)), 12q24 (rs1292011; P = 4.3 × 10(-19)) and 21q21 (rs2823093; P = 1.1 × 10(-12)). rs10771399 was associated with similar relative risks for both estrogen receptor (ER)-negative and ER-positive breast cancer, whereas the other two loci were associated only with ER-positive disease. Two of the loci lie in regions that contain strong plausible candidate genes: PTHLH (12p11) has a crucial role in mammary gland development and the establishment of bone metastasis in breast cancer, and NRIP1 (21q21) encodes an ER cofactor and has a role in the regulation of breast cancer cell growth.
Published: 2012

98. Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)

Author: Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, Dunning, AM, Chan, KYK, Hein, R, Maranian, M, Hopper, JL, Kapuscinski, MK, Southey, MC, Park, DJ, Schmidt, MK, Broeks, A, Hogervorst, FBL, Bueno-de-Mesquit, HB, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Fasching, PA, Hein, A, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Marmee, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Guenel, P, Cordina-Duverger, E, Menegaux, F, Truong, T, Bojesen, SE, Nordestgaard, BG, Flyger, H, Milne, RL, Arias Perez, JI, Pilar Zamora, M, Benitez, J, Anton-Culver, H, Ziogas, A, Bernstein, L, Clarke, CA, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Rahman, N, Seal, S, Turnbull, C, Renwick, A, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Brauch, H, Hamann, U, Ko, Y-D, Wang-Gohrke, S, Doerk, T, Schuermann, P, Karstens, JH, Hillemanns, P, Nevanlinna, H, Heikkinen, T, Aittomaki, K, Blomqvist, C, Bogdanova, NV, Zalutsky, IV, Antonenkova, NN, Bermisheva, M, Prokovieva, D, Farahtdinova, A, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chen, X, Beesley, J, Lambrechts, D, Zhao, H, Neven, P, Wildiers, H, Nickels, S, Flesch-Janys, D, Radice, P, Peterlongo, P, Manoukian, S, Barile, M, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Giles, GG, Baglietto, L, McLean, CA, Severi, G, Offit, K, Robson, M, Gaudet, MM, Vijai, J, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Figueroa, JD, Garcia-Closas, M, Lissowska, J, Sherman, ME, Hooning, M, Martens, JWM, Seynaeve, C, Collee, M, Hall, P, Humpreys, K, Czene, K, Liu, J, Cox, A, Brock, IW, Cross, SS, Reed, MWR, Ahmed, S, Ghoussaini, M, Pharoah, PDP, Kang, D, Yoo, K-Y, Noh, D-Y, Jakubowska, A, Jaworska, K, Durda, K, Zlowocka, E, Sangrajrang, S, Gaborieau, V, Brennan, P, McKay, J, Shen, C-Y, Yu, J-C, Hsu, H-M, Hou, M-F, Orr, N, Schoemaker, M, Ashworth, A, Swerdlow, A, Trentham-Dietz, A, Newcomb, PA, Titus, L, Egan, KM, Chenevix-Trench, G, Antoniou, AC, Humphreys, MK, Morrison, J, Chang-Claude, J, Easton, DF, and Dunning, AM
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of
Published: 2012

99. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author: Lambrechts, D, Truong, T, Justenhoven, C, Humphreys, MK, Wang, J, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Cornelissen, S, van Hien, R, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Milne, RL, Pilar Zamora, M, Arias Perez, JI, Benitez, J, Hamann, U, Ko, Y-D, Bruening, T, Chang-Claude, J, Eilber, U, Hein, R, Nickels, S, Flesch-Janys, D, Wang-Gohrke, S, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Chenevix-Trench, G, Beesley, J, Chen, X, Menegaux, F, Cordina-Duverger, E, Shen, C-Y, Yu, J-C, Wu, P-E, Hou, M-F, Andrulis, IL, Selander, T, Glendon, G, Mulligan, AM, Anton-Culver, H, Ziogas, A, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Jones, M, Orr, N, Ashworth, A, Swerdlow, A, Severi, G, Baglietto, L, Giles, G, Southey, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Yesilyurt, BT, Neven, P, Paridaens, R, Wildiers, H, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Cox, A, Brock, IW, Elliott, G, Cross, SS, Fasching, PA, Schulz-Wendtland, R, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Khusnutdinova, E, Bermisheva, M, Prokofieva, D, Gancev, S, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Nordestgaard, BG, Bojesen, SE, Lanng, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, Devilee, P, Tollenaar, RAEM, Seynaeve, CM, Hooning, MJ, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Liu, J, Czene, K, Kang, D, Yoo, K-Y, Noh, D-Y, Lindblom, A, Margolin, S, Dunning, AM, Pharoah, PDP, Easton, DF, Guenel, P, Brauch, H, Lambrechts, D, Truong, T, Justenhoven, C, Humphreys, MK, Wang, J, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Cornelissen, S, van Hien, R, Sawyer, E, Tomlinson, I, Kerin, M, Miller, N, Milne, RL, Pilar Zamora, M, Arias Perez, JI, Benitez, J, Hamann, U, Ko, Y-D, Bruening, T, Chang-Claude, J, Eilber, U, Hein, R, Nickels, S, Flesch-Janys, D, Wang-Gohrke, S, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Chenevix-Trench, G, Beesley, J, Chen, X, Menegaux, F, Cordina-Duverger, E, Shen, C-Y, Yu, J-C, Wu, P-E, Hou, M-F, Andrulis, IL, Selander, T, Glendon, G, Mulligan, AM, Anton-Culver, H, Ziogas, A, Muir, KR, Lophatananon, A, Rattanamongkongul, S, Puttawibul, P, Jones, M, Orr, N, Ashworth, A, Swerdlow, A, Severi, G, Baglietto, L, Giles, G, Southey, M, Marme, F, Schneeweiss, A, Sohn, C, Burwinkel, B, Yesilyurt, BT, Neven, P, Paridaens, R, Wildiers, H, Brenner, H, Mueller, H, Arndt, V, Stegmaier, C, Meindl, A, Schott, S, Bartram, CR, Schmutzler, RK, Cox, A, Brock, IW, Elliott, G, Cross, SS, Fasching, PA, Schulz-Wendtland, R, Ekici, AB, Beckmann, MW, Fletcher, O, Johnson, N, Silva, IDS, Peto, J, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Bogdanova, NV, Antonenkova, NN, Rogov, YI, Karstens, JH, Khusnutdinova, E, Bermisheva, M, Prokofieva, D, Gancev, S, Jakubowska, A, Lubinski, J, Jaworska, K, Durda, K, Nordestgaard, BG, Bojesen, SE, Lanng, C, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, JM, Radice, P, Peterlongo, P, Manoukian, S, Bernard, L, Couch, FJ, Olson, JE, Wang, X, Fredericksen, Z, Alnaes, GG, Kristensen, V, Borresen-Dale, A-L, Devilee, P, Tollenaar, RAEM, Seynaeve, CM, Hooning, MJ, Garcia-Closas, M, Chanock, SJ, Lissowska, J, Sherman, ME, Hall, P, Liu, J, Czene, K, Kang, D, Yoo, K-Y, Noh, D-Y, Lindblom, A, Margolin, S, Dunning, AM, Pharoah, PDP, Easton, DF, Guenel, P, and Brauch, H
Abstract: A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P ≤ 3 × 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 × 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.
Published: 2012

100. 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Warren, H, Dudbridge, F, Fletcher, O, Orr, N, Johnson, N, Hopper, JL, Apicella, C, Southey, MC, Mahmoodi, M, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, LM, Muir, KR, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Sawyer, EJ, Tomlinson, I, Kerin, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Therese, T, Laurent-Puig, P, Mulot, C, Bojesen, SE, Nielsen, SF, Flyger, H, Nordestgaard, BG, Milne, RL, Benitez, J, Arias-Perez, J-I, Pilar Zamora, M, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Langheinz, A, Meindl, A, Golatta, M, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Bruening, T, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, N, Antonenkova, N, Rogov, Y, Bermisheva, M, Prokofyeva, D, Zinnatullina, G, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Beesley, J, Chen, X, Lambrechts, D, Smeets, A, Paridaens, R, Weltens, C, Flesch-Janys, D, Buck, K, Behrens, S, Peterlongo, P, Bernard, L, Manoukian, S, Radice, P, Couch, FJ, Vachon, C, Wang, X, Olson, J, Giles, G, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Mulligan, AM, Weerasooriya, N, Devilee, P, Tollenaar, RAEM, Martens, JWM, Seynaeve, CM, Hooning, MJ, Hollestelle, A, Jager, A, Tilanus-Linthorst, MMA, Hall, P, Czene, K, Liu, J, Li, J, Cox, A, Cross, SS, Brock, IW, Reed, MWR, Pharoah, P, Blows, FM, Dunning, AM, Ghous-saini, M, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, M, Easton, DF, Humphreys, M, Wang, Q, Peto, J, dos-Santos-Silva, I, Warren, H, Dudbridge, F, Fletcher, O, Orr, N, Johnson, N, Hopper, JL, Apicella, C, Southey, MC, Mahmoodi, M, Schmidt, MK, Broeks, A, Cornelissen, S, Braaf, LM, Muir, KR, Lophatananon, A, Chaiwerawattana, A, Wiangnon, S, Fasching, PA, Beckmann, MW, Ekici, AB, Schulz-Wendtland, R, Sawyer, EJ, Tomlinson, I, Kerin, M, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, Guenel, P, Therese, T, Laurent-Puig, P, Mulot, C, Bojesen, SE, Nielsen, SF, Flyger, H, Nordestgaard, BG, Milne, RL, Benitez, J, Arias-Perez, J-I, Pilar Zamora, M, Anton-Culver, H, Ziogas, A, Bernstein, L, Dur, CC, Brenner, H, Mueller, H, Arndt, V, Langheinz, A, Meindl, A, Golatta, M, Bartram, CR, Schmutzler, RK, Brauch, H, Justenhoven, C, Bruening, T, Chang-Claude, J, Wang-Gohrke, S, Eilber, U, Doerk, T, Schuermann, P, Bremer, M, Hillemanns, P, Nevanlinna, H, Muranen, TA, Aittomaki, K, Blomqvist, C, Bogdanova, N, Antonenkova, N, Rogov, Y, Bermisheva, M, Prokofyeva, D, Zinnatullina, G, Khusnutdinova, E, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Hartikainen, JM, Kataja, V, Chenevix-Trench, G, Beesley, J, Chen, X, Lambrechts, D, Smeets, A, Paridaens, R, Weltens, C, Flesch-Janys, D, Buck, K, Behrens, S, Peterlongo, P, Bernard, L, Manoukian, S, Radice, P, Couch, FJ, Vachon, C, Wang, X, Olson, J, Giles, G, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkas, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, IL, Knight, JA, Mulligan, AM, Weerasooriya, N, Devilee, P, Tollenaar, RAEM, Martens, JWM, Seynaeve, CM, Hooning, MJ, Hollestelle, A, Jager, A, Tilanus-Linthorst, MMA, Hall, P, Czene, K, Liu, J, Li, J, Cox, A, Cross, SS, Brock, IW, Reed, MWR, Pharoah, P, Blows, FM, Dunning, AM, Ghous-saini, M, Ashworth, A, Swerdlow, A, Jones, M, Schoemaker, M, Easton, DF, Humphreys, M, Wang, Q, Peto, J, and dos-Santos-Silva, I
Abstract: BACKGROUND: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). METHODS: To further investigate the rs865686-breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case-control studies (48,394 cases, 50,836 controls). RESULTS: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors. CONCLUSIONS: This study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer. IMPACT: The findings further support the view that genetic susceptibility varies according to tumor subtype.
Published: 2012

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Database

Publisher

162 results on '"Doerk, T"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources