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1. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Köbel, Martin, Kang, Eun-Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng-Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney-Brooks, Madeleine, Cushing-Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, AOCS Group, Fischer, Anna, Gayther, Simon A, Barquin-Garcia, Arantzazu, Gentry-Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez-Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz-Ares, Luis, Ramón Y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, Martin, Stewart G, Menon, Usha, Modugno, Francesmary, Pharoah, Paul Dp, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
Subjects: clear cell, p53, Ovarian Neoplasms, ovarian cancer, high-grade serous carcinoma, Humans, Female, TP53, prognosis, Tumor Suppressor Protein p53, Carcinoma, Ovarian Epithelial, endometrioid, Carcinoma, Endometrioid
Abstract: Funder: Biomedical Research Centre, Funder: European Regional Development Fund, Funder: Mayo Foundation for Medical Education and Research, Funder: Pomeranian Medical University, Funder: Pomorski Uniwersytet Medyczny W Szczecinie, Funder: Cancer Council NSW, Funder: Cancer Institute NSW, Funder: Deutsches Krebsforschungszentrum, Funder: The BC Cancer Foundation, Funder: University College London Hospitals Biomedical Research Centre, Funder: Breast Cancer Now, Funder: Cancer Council Tasmania, Funder: Clinical Academic Reserve, Funder: ELAN Funds of the University of Erlangen-Nuremberg, Funder: Fondo Europeo de Desarrollo Regional, Funder: National Institute for Health Research (NIHR), Funder: National Institute for Health and Care Research, Funder: Ovarian Cancer Australia, Funder: Queensland Cancer Fund, Funder: Cancer Council New South Wales, Funder: Fred C. and Katherine B. Andersen Foundation, Funder: German Cancer Research Center, Funder: Institute of Cancer Research, Funder: Mayo Foundation, Funder: Minnesota Ovarian Cancer Alliance, Funder: Peter MacCallum Foundation, Funder: University of Cambridge, Funder: Cancer Foundation of Western Australia, Funder: VGH and UBC Hospital Foundation, Funder: Cancer Council Victoria, Funder: NHS, Funder: UK National Institute for Health Research, Funder: Cancer Council South Australia, Funder: Oak Foundation, Funder: Sydney West Translational Cancer Research Centre, Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Published: 2023

2. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author: Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón Y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido Dos Reis, Francisco J, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, Martin, Stewart G, Menon, Usha, Modugno, Francesmary, Pharoah, Paul DP, Schildkraut, Joellen M, Sieh, Weiva, Staebler, Annette, Sundfeldt, Karin, Swerdlow, Anthony J, Ramus, Susan J, Brenton, James D, Köbel, Martin [0000-0002-6615-2037], Weir, Ashley [0000-0002-3072-2616], Anglesio, Michael S [0000-0003-1639-5003], Erber, Ramona [0000-0003-0315-1229], Gilks, C Blake [0000-0001-7889-8250], Shvetsov, Yurii B [0000-0001-5131-9618], Campbell, Ian [0000-0002-7773-4155], Huntsman, David G [0000-0003-4934-3322], and Apollo - University of Cambridge Repository
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous [HGSC], endometrioid [EC] and clear cell carcinomas [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93% (4630/4957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (HR=2.18, 95% CI 1.36-3.47, p=0.0011) as well as with CCC (HR=1.57, 95% CI 1.11-2.22, p=0.012). Abnormal p53 was also associated with shorter overall survival in FIGO stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC., CRUK
Published: 2023
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3. CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

Author: Kang, Eun-Young, Weir, Ashley, Meagher, Nicola S, Farrington, Kyo, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Bolithon, Adelyn, Popovic, Gordana, Leung, Betty, Tang, Katrina, Lambie, Neil, Millstein, Joshua, Alsop, Jennifer, Anglesio, Michael S, Ataseven, Beyhan, Barlow, Ellen, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Bösmüller, Hans, Boros, Jessica, Brand, Alison H, Brooks-Wilson, Angela, Brucker, Sara Y, Carney, Michael E, Casablanca, Yovanni, Cazorla-Jiménez, Alicia, Cohen, Paul A, Conrads, Thomas P, Cook, Linda S, Coulson, Penny, Courtney-Brooks, Madeleine, Cramer, Daniel W, Crowe, Philip, Cunningham, Julie M, Cybulski, Cezary, Darcy, Kathleen M, El-Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Farrell, Rhonda, Fereday, Sian, Fischer, Anna, García, María J, Gayther, Simon A, Gentry-Maharaj, Aleksandra, Gilks, C Blake, AOCS Group, Grube, Marcel, Harnett, Paul R, Harrington, Shariska Petersen, Harter, Philipp, Hartmann, Arndt, Hecht, Jonathan L, Heikaus, Sebastian, Hein, Alexander, Heitz, Florian, Hendley, Joy, Hernandez, Brenda Y, Polo, Susanna Hernando, Heublein, Sabine, Hirasawa, Akira, Høgdall, Estrid, Høgdall, Claus K, Horlings, Hugo M, Huntsman, David G, Huzarski, Tomasz, Jewell, Andrea, Jimenez-Linan, Mercedes, Jones, Michael E, Kaufmann, Scott H, Kennedy, Catherine J, Khabele, Dineo, Kommoss, Felix KF, Kruitwagen, Roy FPM, Lambrechts, Diether, Le, Nhu D, Lener, Marcin, Lester, Jenny, Leung, Yee, Linder, Anna, Loverix, Liselore, Lubiński, Jan, Madan, Rashna, Maxwell, G Larry, Modugno, Francesmary, Neuhausen, Susan L, Olawaiye, Alexander, Olbrecht, Siel, Orsulic, Sandra, Palacios, José, Pearce, Celeste Leigh, Pike, Malcolm C, Quinn, Carmel M, Mohan, Ganendra Raj, Rodríguez-Antona, Cristina, Ruebner, Matthias, Ryan, Andy, Salfinger, Stuart G, Sasamoto, Naoko, Schildkraut, Joellen M, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Singh, Naveena, Sonke, Gabe S, Steele, Linda, Stewart, Colin, Sundfeldt, Karin, Swerdlow, Anthony J, Talhouk, Aline, Tan, Adeline, Taylor, Sarah E, Terry, Kathryn L, Tołoczko, Aleksandra, Traficante, Nadia, Van De Vijver, Koen K, Van Der Aa, Maaike A, Van Gorp, Toon, Van Nieuwenhuysen, Els, Van-Wagensveld, Lilian, Vergote, Ignace, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Wu, Anna H, Benitez, Javier, Berchuck, Andrew, Candido Dos Reis, Francisco J, DeFazio, Anna, Fasching, Peter A, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Karlan, Beth Y, Kommoss, Stefan, Menon, Usha, Sinn, Hans-Peter, Staebler, Annette, Brenton, James D, Bowtell, David D, Pharoah, Paul DP, Ramus, Susan J, Köbel, Martin, Meagher, Nicola S [0000-0001-9134-2118], Lee, Cheng-Han [0000-0003-2094-1222], Fereday, Sian [0000-0002-8559-8579], Kennedy, Catherine J [0000-0002-4465-5784], Sasamoto, Naoko [0000-0002-4526-2181], Schildkraut, Joellen M [0000-0002-0990-9339], Talhouk, Aline [0000-0001-7760-410X], Vergote, Ignace [0000-0002-7589-8981], Köbel, Martin [0000-0002-6615-2037], and Apollo - University of Cambridge Repository
Subjects: Ovarian Neoplasms, Oncogene Proteins, Carcinoma, Cystadenocarcinoma, Serous, ovarian cancer, high-grade serous carcinoma, Cyclin E, Humans, Female, prognosis, RNA, Messenger, CCNE1 amplification, cyclin E1 expression, Transcription Factors
Abstract: BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Published: 2023
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4. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author: Grootes, Isabelle, Keeman, Renske, Blows, Fiona M, Milne, Roger L, Giles, Graham G, Swerdlow, Anthony J, Fasching, Peter A, Abubakar, Mustapha, Andrulis, Irene L, Anton-Culver, Hoda, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Briceno, Ignacio, Burwinkel, Barbara, Camp, Nicola J, Castelao, Jose E, Choi, Ji-Yeob, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Eriksson, Mikael, Ernst, Kristina, Evans, D Gareth, Figueroa, Jonine D, Fink, Visnja, Floris, Giuseppe, Fox, Stephen, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Sáenz, José A, González-Neira, Anna, Haeberle, Lothar, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Hartman, Mikael, Hein, Alexander, Hooning, Maartje J, Hou, Ming-Feng, Howell, Sacha J, ABCTB Investigators, kConFab Investigators, Ito, Hidemi, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kang, Daehee, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Li, Jingmei, Lubiński, Jan, Manoochehri, Mehdi, Margolin, Sara, Matsuo, Keitaro, Taib, Nur Aishah Mohd, Mulligan, Anna Marie, Nevanlinna, Heli, Newman, William G, Offit, Kenneth, Osorio, Ana, Park, Sue K, Park-Simon, Tjoung-Won, Patel, Alpa V, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Rennert, Gad, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor J, Schneeweiss, Andreas, Schochter, Fabienne, Schoemaker, Minouk J, Shen, Chen-Yang, Shibli, Rana, Sinn, Peter, Tapper, William J, Tawfiq, Essa, Teo, Soo Hwang, Teras, Lauren R, Torres, Diana, Vachon, Celine M, van Deurzen, Carolien HM, Wendt, Camilla, Williams, Justin A, Winqvist, Robert, Elwood, Mark, Schmidt, Marjanka K, García-Closas, Montserrat, Pharoah, Paul DP, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: breast cancer, Receptor, ErbB-2, Humans, PREDICT Breast, Breast Neoplasms, Female, Prognosis, Receptors, Progesterone, Progesterone, Progesterone receptor
Abstract: BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
Published: 2022
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5. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author: Kang, Eun Young, Millstein, Joshua, Popovic, Gordana, Meagher, Nicola S, Bolithon, Adelyn, Talhouk, Aline, Chiu, Derek S, Anglesio, Michael S, Leung, Betty, Tang, Katrina, Lambie, Neil, Pavanello, Marina, Da-Anoy, Annalyn, Lambrechts, Diether, Loverix, Liselore, Olbrecht, Siel, Bisinotto, Christiani, Garcia-Donas, Jesus, Ruiz-Llorente, Sergio, Yagüe-Fernandez, Monica, Edwards, Robert P, Elishaev, Esther, Olawaiye, Alexander, Taylor, Sarah, Ataseven, Beyhan, du Bois, Andreas, Harter, Philipp, Lester, Jenny, Høgdall, Claus K, Armasu, Sebastian M, Huang, Yajue, Vierkant, Robert A, Wang, Chen, Winham, Stacey J, Heublein, Sabine, Kommoss, Felix KF, Cramer, Daniel W, Sasamoto, Naoko, van-Wagensveld, Lilian, Lycke, Maria, Mateoiu, Constantina, Joseph, Janine, Pike, Malcolm C, Odunsi, Kunle, Tseng, Chiu-Chen, Pearce, Celeste L, Bilic, Sanela, Conrads, Thomas P, Hartmann, Arndt, Hein, Alexander, Jones, Michael E, Leung, Yee, Beckmann, Matthias W, Ruebner, Matthias, Schoemaker, Minouk J, Terry, Kathryn L, El-Bahrawy, Mona A, Coulson, Penny, Etter, John L, LaVigne-Mager, Katherine, Andress, Juergen, Grube, Marcel, Fischer, Anna, Neudeck, Nina, Robertson, Greg, Farrell, Rhonda, Barlow, Ellen, Quinn, Carmel, Hettiaratchi, Anusha, Casablanca, Yovanni, Erber, Ramona, Stewart, Colin JR, Tan, Adeline, Yu, Yu, Boros, Jessica, Brand, Alison H, Harnett, Paul R, Kennedy, Catherine J, Nevins, Nikilyn, Morgan, Terry, Fasching, Peter A, Vergote, Ignace, Swerdlow, Anthony J, Candido Dos Reis, Francisco J, Maxwell, G Larry, Neuhausen, Susan L, Barquin-Garcia, Arantzazu, Modugno, Francesmary, Moysich, Kirsten B, Crowe, Philip J, Hirasawa, Akira, Heitz, Florian, Karlan, Beth Y, Goode, Ellen L, Sinn, Peter, Horlings, Hugo M, Høgdall, Estrid, Sundfeldt, Karin, Kommoss, Stefan, and Staebler, Annette
Subjects: Ovarian Neoplasms, Tumor, Messenger, Proliferation, Clinical Sciences, Cystadenocarcinoma, Serous, Minichromosome Maintenance Complex Component 3, High-grade serous carcinoma, Survival Rate, Ki-67 Antigen, Rare Diseases, MCM3, Genetics, Pathology, Humans, RNA, 2.1 Biological and endogenous factors, Female, Aetiology, Biomarkers, Cell Proliferation, Cancer
Abstract: Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p
Published: 2022

6. Additional file 4 of Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, Thomas U., Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L., Bolla, Manjeet K., Dennis, Joe, Dunning, Alison M., Lush, Michael, Wang, Qin, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Auer, Paul L., Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E., Bonanni, Bernardo, B��rresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Br��ning, Thomas, Burwinkel, Barbara, Buys, Saundra S., Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Coll��e, J. Margriet, Cox, Angela, Cross, Simon S., Czene, Kamila, Daly, Mary B., Devilee, Peter, D��rk, Thilo, Dwek, Miriam, Eccles, Diana M., Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M., Garc��a-S��enz, Jos�� A., Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., Gonz��lez-Neira, Anna, Aln��s, Grethe I. Grenaker, Grip, Mervi, Gu��nel, Pascal, Haiman, Christopher A., Hall, Per, Hamann, Ute, Harkness, Elaine F., Heemskerk-Gerritsen, Bernadette A. M., Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J., Hoover, Robert N., Hopper, John L., Howell, Anthony, Jakimovska, Milena, Jakubowska, Anna, John, Esther M., Jones, Michael E., Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N., Kr��ger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W., Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G., Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J., Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, McLean, Catriona, Meindl, Alfons, Menon, Usha, Nevanlinna, Heli, Newman, William G., Nodora, Jesse, Offit, Kenneth, Olsson, H��kan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V., Peto, Julian, Pita, Guillermo, Plaseska-Karanfilska, Dijana, Prentice, Ross, Punie, Kevin, Pylk��s, Katri, Radice, Paolo, Rennert, Gad, Romero, Atocha, R��diger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Schoemaker, Minouk J., Sch��ttker, Ben, Sherman, Mark E., Shu, Xiao-Ou, Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Taylor, Jack A., Teras, Lauren R., Terry, Mary Beth, Torres, Diana, Troester, Melissa A., Vachon, Celine M., van Deurzen, Carolien H. M., van Veen, Elke M., Wagner, Philippe, Weinberg, Clarice R., Wendt, Camilla, Wesseling, Jelle, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R., Zheng, Wei, Couch, Fergus J., Simard, Jacques, Kraft, Peter, Easton, Douglas F., Pharoah, Paul D. P., Schmidt, Marjanka K., Garc��a-Closas, Montserrat, and Chatterjee, Nilanjan
Subjects: Data_FILES
Abstract: Additional file 4. Funding and Acknowledgement. This file contains the additional funding not included in the main text, the acknowledgments, and the names of the people in the collaboration groups.
Published: 2022
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7. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, and Wolk, Alicja
Subjects: screening and diagnosis, Tumor, Prevention, kConFab/AOCS Investigators, Genetic Variation, Breast Neoplasms, Single Nucleotide, Kaplan-Meier Estimate, 4.1 Discovery and preclinical testing of markers and technologies, Detection, Germ Cells, Cancer Survivors, Breast Cancer, Genetics, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Female, Polymorphism, Aetiology, skin and connective tissue diseases, Germ-Line Mutation, Biomarkers, Cancer
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

8. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author: Kapoor, Pooja Middha, Mavaddat, Nasim, Choudhury, Parichoy Pal, Wilcox, Amber N, Lindström, Sara, Behrens, Sabine, Michailidou, Kyriaki, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Jung, Audrey, Abu-Ful, Zomoroda, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chatterjee, Nilanjan, Chenevix-Trench, Georgia, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Earp, H Shelton, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hatse, Sigrid, Heyworth, Jane, Holleczek, Bernd, Hoover, Robert N, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab/AOCS Investigators, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, MacInnis, Robert J, Martinez, Maria Elena, Maurer, Tabea, McLean, Catriona, Neuhausen, Susan L, Newman, William G, Norman, Aaron, O'Brien, Katie M, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orr, Nick, Perou, Charles M, Pita, Guillermo, Polley, Eric C, Prentice, Ross L, Rennert, Gad, Rennert, Hedy S, Ruddy, Kathryn J, Sandler, Dale P, Saunders, Christobel, Schoemaker, Minouk J, Schöttker, Ben, Schumacher, Fredrick, Scott, Christopher, Scott, Rodney J, Shu, Xiao-Ou, Smeets, Ann, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Troester, Melissa A, Vachon, Celine M, van Veen, Elke M, Wang, Xiaoliang, Weinberg, Clarice R, Weltens, Caroline, Willett, Walter, Winham, Stacey J, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul DP, Schmidt, Marjanka K, Kraft, Peter, Easton, Douglas F, Milne, Roger L, García-Closas, Montserrat, Chang-Claude, Jenny, Mavaddat, Nasim [0000-0003-0307-055X], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Aged, 80 and over, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, White People, Body Mass Index, Logistic Models, Receptors, Estrogen, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Medical History Taking, Aged
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Published: 2021

9. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author: Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, AOCS Group, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, kConFab Investigators, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, and Nielsen, Sune F
Subjects: Aging, Estrone, Oncology and Carcinogenesis, ABCTB Investigators, Breast Neoplasms, NBCS Collaborators, Clinical Research, Receptors, Breast Cancer, Genetics, Humans, Cytochrome P-450 CYP3A, 2.1 Biological and endogenous factors, Oncology & Carcinogenesis, Polymorphism, Aetiology, Progesterone, Alleles, Cancer, Human Genome, Single Nucleotide, AOCS Group, Estrogen, Premenopause, Case-Control Studies, Public Health and Health Services, Pregnanediol, kConFab Investigators, Female, Genome-Wide Association Study
Abstract: BackgroundEpidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.MethodsWe carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.ResultsFor pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8).ConclusionsThe CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Published: 2021

10. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Hillemanns, Peter, Hogervorst, Frans BL, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huebner, Hanna, Hulick, Peter J, Imyanitov, Evgeny N, kConFab Investigators, ABCTB Investigators, Isaacs, Claudine, Izatt, Louise, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Khan, Sofia, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Laenkholm, Anne-Vibeke, Lambrechts, Diether, Larsson, Susanna C, Laurent-Puig, Pierre, Lazaro, Conxi, Lazarova, Emilija, Lejbkowicz, Flavio, Leslie, Goska, Lesueur, Fabienne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing-Yee, Loud, Jennifer T, Lubinski, Jan, Lukomska, Alicja, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matricardi, Laura, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Mingazheva, Elvira, Montagna, Marco, Mulligan, Anna Marie, Mulot, Claire, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Newman, William G, Nielsen, Finn C, Nikitina-Zake, Liene, Nodora, Jesse, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Papi, Laura, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Peissel, Bernard, Peixoto, Ana, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Phillips, Kelly-Anne, Piedmonte, Marion, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Prokofyeva, Darya, Rack, Brigitte, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Risch, Harvey A, Romero, Atocha, Rookus, Matti A, Rübner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Scheuner, Maren T, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Senter, Leigha, Sharma, Priyanka, Sherman, Mark E, Shu, Xiao-Ou, Singer, Christian F, Smichkoska, Snezhana, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Stoppa-Lyonnet, Dominique, EMBRACE Study, GEMO Study Collaborators, Swerdlow, Anthony J, Szabo, Csilla I, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, MaryBeth, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M, van den Ouweland, Ans MW, van der Kolk, Lizet E, van Veen, Elke M, vanRensburg, Elizabeth J, Vega, Ana, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zheng, Wei, Zorn, Kristin K, Milne, Roger L, Kraft, Peter, Simard, Jacques, Pharoah, Paul DP, Michailidou, Kyriaki, Antoniou, Antonis C, Schmidt, Marjanka K, Chenevix-Trench, Georgia, Easton, Douglas F, Chatterjee, Nilanjan, García-Closas, Montserrat, Barnes, Daniel [0000-0002-3781-7570], O'Mara, Tracy A [0000-0002-5436-3232], Dunning, Alison M [0000-0001-6651-7166], Dennis, Joe [0000-0003-4591-1214], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Caldés, Trinidad [0000-0002-1038-5392], Calvello, Mariarosaria [0000-0003-2113-8503], Chanock, Stephen J [0000-0002-2324-3393], Claes, Kathleen BM [0000-0003-0841-7372], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Ekici, Arif B [0000-0001-6099-7066], Fasching, Peter A [0000-0003-4885-8471], García-Sáenz, José A [0000-0001-6880-0301], Gayther, Simon A [0000-0001-7937-5443], Giles, Graham G [0000-0003-4946-9099], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Harkness, Elaine F [0000-0001-6625-7739], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Huebner, Hanna [0000-0001-6889-1493], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Larsson, Susanna C [0000-0003-0118-0341], Laurent-Puig, Pierre [0000-0001-8475-5459], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Lissowska, Jolanta [0000-0003-2695-5799], Matricardi, Laura [0000-0002-0241-1810], McLean, Catriona [0000-0002-0302-5727], Menon, Usha [0000-0003-3708-1732], Miller, Austin [0000-0001-9739-8462], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Newman, William G [0000-0002-6382-4678], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Parsons, Michael T [0000-0003-3242-8477], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Stone, Jennifer [0000-0001-5077-0124], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], van Veen, Elke M [0000-0001-8618-2332], vanRensburg, Elizabeth J [0000-0003-2077-230X], Weitzel, Jeffrey N [0000-0001-6714-092X], Winqvist, Robert [0000-0003-0932-9104], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Zheng, Wei [0000-0003-1226-070X], Milne, Roger L [0000-0001-5764-7268], Kraft, Peter [0000-0002-4472-8103], Simard, Jacques [0000-0001-6906-3390], Pharoah, Paul DP [0000-0001-8494-732X], Michailidou, Kyriaki [0000-0001-7065-1237], Schmidt, Marjanka K [0000-0002-2228-429X], Easton, Douglas F [0000-0003-2444-3247], Chatterjee, Nilanjan [0000-0002-9060-008X], García-Closas, Montserrat [0000-0003-1033-2650], and Apollo - University of Cambridge Repository
Subjects: BRCA1 Protein, Case-Control Studies, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Triple Negative Breast Neoplasms, Linkage Disequilibrium, Genome-Wide Association Study
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

11. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, Haoyu, Ahearn, Thomas U, Lecarpentier, Julie, Barnes, Daniel, Beesley, Jonathan, Qi, Guanghao, Jiang, Xia, O'Mara, Tracy A, Zhao, Ni, Bolla, Manjeet K, Dunning, Alison M, Dennis, Joe, Wang, Qin, Ful, Zumuruda Abu, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auer, Paul L, Azzollini, Jacopo, Barrowdale, Daniel, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bialkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Bondavalli, Davide, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Byers, Helen, Caldés, Trinidad, Caligo, Maria A, Calvello, Mariarosaria, Campa, Daniele, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiaens, Melissa, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Foretova, Lenka, Fostira, Florentia, Friedman, Eitan, Frost, Debra, Gago-Dominguez, Manuela, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Gayther, Simon A, Giles, Graham G, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Häberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hake, Christopher R, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Hillemanns, Peter, Hogervorst, Frans BL, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huebner, Hanna, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, ABCTB Investigators, Isaacs, Claudine, Izatt, Louise, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Khan, Sofia, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Koppert, Linetta B, Koutros, Stella, Kristensen, Vessela N, Laenkholm, Anne-Vibeke, Lambrechts, Diether, Larsson, Susanna C, Laurent-Puig, Pierre, Lazaro, Conxi, Lazarova, Emilija, Lejbkowicz, Flavio, Leslie, Goska, Lesueur, Fabienne, Lindblom, Annika, Lissowska, Jolanta, Lo, Wing-Yee, Loud, Jennifer T, Lubinski, Jan, Lukomska, Alicja, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matricardi, Laura, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Menon, Usha, Miller, Austin, Mingazheva, Elvira, Montagna, Marco, Mulligan, Anna Marie, Mulot, Claire, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Newman, William G, Nielsen, Finn C, Nikitina-Zake, Liene, Nodora, Jesse, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Papi, Laura, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Peissel, Bernard, Peixoto, Ana, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Phillips, Kelly-Anne, Piedmonte, Marion, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Prokofyeva, Darya, Rack, Brigitte, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Risch, Harvey A, Romero, Atocha, Rookus, Matti A, Rübner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Scheuner, Maren T, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Senter, Leigha, Sharma, Priyanka, Sherman, Mark E, Shu, Xiao-Ou, Singer, Christian F, Smichkoska, Snezhana, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Stoppa-Lyonnet, Dominique, EMBRACE Study, GEMO Study Collaborators, Swerdlow, Anthony J, Szabo, Csilla I, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, MaryBeth, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Untch, Michael, Vachon, Celine M, Van Den Ouweland, Ans MW, Van Der Kolk, Lizet E, Van Veen, Elke M, VanRensburg, Elizabeth J, Vega, Ana, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Yannoukakos, Drakoulis, Zheng, Wei, Zorn, Kristin K, Milne, Roger L, Kraft, Peter, Simard, Jacques, Pharoah, Paul DP, Michailidou, Kyriaki, Antoniou, Antonis C, Schmidt, Marjanka K, Chenevix-Trench, Georgia, Easton, Douglas F, Chatterjee, Nilanjan, and García-Closas, Montserrat
Subjects: BRCA1 Protein, Case-Control Studies, Mutation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Triple Negative Breast Neoplasms, Linkage Disequilibrium, Genome-Wide Association Study
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020
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12. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I, Kitahara, Cari M, Knight, Julia A, Ko, Yon-Dschun, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P, MacInnis, Robert J, Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L, Newman, William T, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V Shane, Park-Simon, Tjoung-Won, Perez, Jose IA, Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J, Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Talhouk, Aline, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, van Asperen, Christi J, van den Ouweland, Ans MW, van Veen, Elke M, Wendt, Camilla, Whittemore, Alice S, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zhang, Yan, Easton, Douglas F, Fasching, Peter A, Nevanlinna, Heli, Eccles, Diana M, Pharoah, Paul DP, Schmidt, Marjanka K, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Abraham, Jean [0000-0003-0688-4807], Caldas, Carlos [0000-0003-3547-1489], Chin, Suet-Feung [0000-0001-5697-1082], Dunning, Alison [0000-0001-6651-7166], Earl, Helena [0000-0003-1549-8094], Rhenius, Valerie [0000-0003-4215-3235], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Receptors, Estrogen, Genetic Variation, Humans, Bayes Theorem, Breast Neoplasms, Female, Prognosis, Chromosomes, Human, Pair 7, White People, Genome-Wide Association Study, Proportional Hazards Models
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P
Published: 2019

13. Genome-wide association study of germline variants and breast cancer-specific mortality

Author: Escala-Garcia, Maria, Guo, Qi, Dörk, Thilo, Canisius, Sander, Keeman, Renske, Dennis, Joe, Beesley, Jonathan, Lecarpentier, Julie, Bolla, Manjeet K, Wang, Qin, Abraham, Jean, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bernstein, Leslie, Blomqvist, Carl, Boeckx, Bram, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brentnall, Adam, Brinton, Louise, Broberg, Per, Brock, Ian W, Brucker, Sara Y, Burwinkel, Barbara, Caldas, Carlos, Caldés, Trinidad, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Cheng, Ting-Yuan David, Chin, Suet-Feung, Clarke, Christine L, NBCS Collaborators, Cordina-Duverger, Emilie, Couch, Fergus J, Cox, David G, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dunn, Janet A, Dunning, Alison M, Durcan, Lorraine, Dwek, Miriam, Earl, Helena M, Ekici, Arif B, Eliassen, A Heather, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine, Flesch-Janys, Dieter, Flyger, Henrik, Gabrielson, Marike, Gago-Dominguez, Manuela, Galle, Eva, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, George, Angela, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Goldgar, David E, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hankinson, Susan, Harkness, Elaine F, Harrington, Patricia A, Hart, Steven N, Hartikainen, Jaana M, Hein, Alexander, Hillemanns, Peter, Hiller, Louise, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Humphreys, Keith, Hunter, David J, Janni, Wolfgang, John, Esther M, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kabisch, Maria, Kaczmarek, Katarzyna, Kerin, Michael J, Khan, Sofia, Khusnutdinova, Elza, Kiiski, Johanna I, Kitahara, Cari M, Knight, Julia A, Ko, Yon-Dschun, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Krüger, Ute, Kühl, Tabea, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Li, Lian, Lindblom, Annika, Lindström, Sara, Linet, Martha, Lissowska, Jolanta, Lo, Wing-Yee, Loibl, Sibylle, Lubiński, Jan, Lux, Michael P, MacInnis, Robert J, Maierthaler, Melanie, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Mavroudis, Dimitrios, McLean, Catriona, Meindl, Alfons, Middha, Pooja, Miller, Nicola, Milne, Roger L, Moreno, Fernando, Mulligan, Anna Marie, Mulot, Claire, Nassir, Rami, Neuhausen, Susan L, Newman, William T, Nielsen, Sune F, Nordestgaard, Børge G, Norman, Aaron, Olsson, Håkan, Orr, Nick, Pankratz, V Shane, Park-Simon, Tjoung-Won, Perez, Jose IA, Pérez-Barrios, Clara, Peterlongo, Paolo, Petridis, Christos, Pinchev, Mila, Prajzendanc, Karoliona, Prentice, Ross, Presneau, Nadege, Prokofieva, Darya, Pylkäs, Katri, Rack, Brigitte, Radice, Paolo, Ramachandran, Dhanya, Rennert, Gadi, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Roylance, Rebecca, Saloustros, Emmanouil, Sawyer, Elinor J, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schumacher, Fredrick, Schwentner, Lukas, Scott, Rodney J, Scott, Christopher, Seynaeve, Caroline, Shah, Mitul, Simard, Jacques, Smeets, Ann, Sohn, Christof, Southey, Melissa C, Swerdlow, Anthony J, Talhouk, Aline, Tamimi, Rulla M, Tapper, William J, Teixeira, Manuel R, Tengström, Maria, Terry, Mary Beth, Thöne, Kathrin, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Turman, Constance, Turnbull, Clare, Ulmer, Hans-Ulrich, Untch, Michael, Vachon, Celine, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Veen, Elke M, Wendt, Camilla, Whittemore, Alice S, Willett, Walter, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zhang, Yan, Easton, Douglas F, Fasching, Peter A, Nevanlinna, Heli, Eccles, Diana M, Pharoah, Paul DP, and Schmidt, Marjanka K
Subjects: Receptors, Estrogen, Genetic Variation, Humans, Bayes Theorem, Breast Neoplasms, Female, Prognosis, Chromosomes, Human, Pair 7, White People, Genome-Wide Association Study, Proportional Hazards Models
Abstract: BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
Published: 2019
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14. Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma

Author: Atkins, Isabelle, Kinnersley, Ben, Ostrom, Quinn T., Labreche, Karim, Il'yasova, Dora, Armstrong, Georgina N., Eckel-Passow, Jeanette E., Schoemaker, Minouk J., Nothen, Markus M., Barnholtz-Sloan, Jill S., Swerdlow, Anthony J., Simon, Matthias, Rajaraman, Preetha, Chanock, Stephen J., Shildkraut, Joellen, Bernstein, Jonine L., Hoffmann, Per, Jöckel, Karl-Heinz, Lai, Rose K., Claus, Elizabeth B., Olson, Sara H., Johansen, Christoffer, Wrensch, Margaret R., Melin, Beatrice, Jenkins, Robert B., Sanson, Marc, Bondy, Melissa L., and Houlston, Richard S.
Subjects: Genotype, Quantitative Trait Loci, Medizin, Glioma, Prognosis, Polymorphism, Single Nucleotide, Article, nervous system diseases, Gene Expression Regulation, Neoplastic, Case-Control Studies, Biomarkers, Tumor, Humans, Genetic Predisposition to Disease, Transcriptome, Genome-Wide Association Study
Abstract: Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in non-coding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM, 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P
Published: 2018

15. The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity

Author: Colombo, Mara, Lòpez-Perolio, Irene, Meeks, Huong D, Caleca, Laura, Parsons, Michael T, Li, Hongyan, De Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B Gómez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y, Varesco, Liliana, Wappenschmidt, Barbara, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Chang-Claude, Jenny, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L, Jakubowska, Anna, Jung, Audrey, Kosma, Veli-Matti, Lambrechts, Diether, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Peterlongo, Paolo, Peto, Julian, Pylkäs, Katri, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, See, Mee Hoong, Southey, Melissa C, Swerdlow, Anthony, Teo, Soo H, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Der Kolk, Lizet E, Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, KConFab/AOCS Investigators, Dunning, Alison M, Easton, Douglas F, Henderson, Alex, Hogervorst, Frans BL, Izatt, Louise, Offitt, Kenneth, Side, Lucy E, Van Rensburg, Elizabeth J, Embrace, Study, Hebon, Study, McGuffog, Lesley, Antoniou, Antonis C, Chenevix-Trench, Georgia, Spurdle, Amanda B, Goldgar, David E, Hoya, Miguel De La, and Radice, Paolo
Subjects: BRCA2 Protein, Base Sequence, Models, Genetic, digital PCR, multifactorial likelihood analysis, spliceogenic variants, Mitomycin, RNA Splicing, Genetic Variation, Exons, BRCA2, Cell Line, Calibration, Humans, Female, Genetic Predisposition to Disease, quantitative real-time PCR, RNA, Messenger
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018
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16. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

Author: Shimelis, Hermela, Mesman, Romy LS, Von Nicolai, Catharina, Ehlen, Asa, Guidugli, Lucia, Martin, Charlotte, Calléja, Fabienne MGR, Meeks, Huong, Hallberg, Emily, Hinton, Jamie, Lilyquist, Jenna, Hu, Chunling, Aalfs, Cora M, Aittomäki, Kristiina, Andrulis, Irene, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Benitez, Javier, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen-Dale, Anne-Lise, Brauch, Hiltrud, Brennan, Paul, Brenner, Hermann, Broeks, Annegien, Brouwers, Barbara, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Cheng, Ching-Yu, Choi, Ji-Yeob, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Dennis, Joe, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, García-Closas, Montserrat, Giles, Graham G, Glendon, Gord, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hogervorst, Frans B, Hollestelle, Antoinette, Hopper, John L, Ito, Hidemi, Jakubowska, Anna, Kang, Daehee, Kosma, Veli-Matti, Kristensen, Vessela, Lai, Kah-Nyin, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Machackova, Eva, Mannermaa, Arto, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, Miao, Hui, Michailidou, Kyriaki, Milne, Roger L, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Olswold, Curtis, Oosterwijk, Jan JC, Osorio, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Pylkäs, Katri, Radice, Paolo, Rashid, Muhammad Usman, Rhenius, Valerie, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schoemaker, Minouk J, Seynaeve, Caroline, Shah, Mitul, Shen, Chen-Yang, and Shrubsole, Martha
Subjects: BRCA2 Protein, Risk, Genotype, Oncology and Carcinogenesis, Breast Neoplasms, Mice, Amino Acid Substitution, Case-Control Studies, Mutation, Breast Cancer, Genetics, for NBCS Collaborators, Animals, Humans, 2.1 Biological and endogenous factors, Female, for kConFab/AOCS Investigators, Oncology & Carcinogenesis, Missense, Aetiology, Germ-Line Mutation, Aged, Cancer
Abstract: Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case-control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789-99. ©2017 AACR.
Published: 2017

17. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

Author: Melin, Beatrice S, Barnholtz-Sloan, Jill S, Wrensch, Margaret R, Johansen, Christoffer, Il'yasova, Dora, Kinnersley, Ben, Ostrom, Quinn T, Labreche, Karim, Chen, Yanwen, Armstrong, Georgina, Liu, Yanhong, Eckel-Passow, Jeanette E, Decker, Paul A, Labussière, Marianne, Idbaih, Ahmed, Hoang-Xuan, Khe, Di Stefano, Anna-Luisa, Mokhtari, Karima, Delattre, Jean-Yves, Broderick, Peter, Galan, Pilar, Gousias, Konstantinos, Schramm, Johannes, Schoemaker, Minouk J, Fleming, Sarah J, Herms, Stefan, Heilmann, Stefanie, Nöthen, Markus M, Wichmann, Heinz-Erich, Schreiber, Stefan, Swerdlow, Anthony, Lathrop, Mark, Simon, Matthias, Sanson, Marc, Andersson, Ulrika, Rajaraman, Preetha, Chanock, Stephen, Linet, Martha, Wang, Zhaoming, Yeager, Meredith, GliomaScan Consortium, Wiencke, John K, Hansen, Helen, McCoy, Lucie, Rice, Terri, Kosel, Matthew L, Sicotte, Hugues, Amos, Christopher I, Bernstein, Jonine L, Davis, Faith, Lachance, Dan, Lau, Ching, Merrell, Ryan T, Shildkraut, Joellen, Ali-Osman, Francis, Sadetzki, Siegal, Scheurer, Michael, Shete, Sanjay, Lai, Rose K, Claus, Elizabeth B, Olson, Sara H, Jenkins, Robert B, Houlston, Richard S, and Bondy, Melissa L
Subjects: Genotype, Quantitative Trait Loci, Medical and Health Sciences, Rare Diseases, Meta-Analysis as Topic, Genetics, Humans, Genetic Predisposition to Disease, GliomaScan Consortium, Polymorphism, Alleles, Cancer, Neoplastic, Brain Neoplasms, Prevention, Human Genome, Neurosciences, Glioma, Single Nucleotide, Biological Sciences, Brain Disorders, Brain Cancer, Gene Expression Regulation, Glioblastoma, Genome-Wide Association Study, Developmental Biology
Abstract: Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.
Published: 2017

18. Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

Author: Ghoussaini, Maya, French, Juliet D., Michailidou, Kyriaki, Nord, Silje, Beesley, Jonathan, Canisus, Sander, Hillman, Kristine M., Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S., Dennis, Joe, Bolla, Manjeet K., Wang, Qin, Dicks, Ed, Milne, Roger L., Hopper, John L., Southey, Melissa C., Schmidt, Marjanka K., Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A., Beckmann, Matthias W., Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J., Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E., Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Alonso, M. Rosario, Pita, Guillermo, Neuhausen, Susan L., Anton-Culver, Hoda, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K., Brauch, Hiltrud, Hamann, Ute, Tessier, Daniel C., Vincent, Daniel, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Dörk, Thilo, Bogdanova, Natalia V., Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli Matti, Wu, Anna H., Van Den Berg, David, Lambrechts, Diether, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Barile, Monica, Couch, Fergus J., Hallberg, Emily, Giles, Graham G., Haiman, Christopher A., Le Marchand, Loic, Goldberg, Mark S., Teo, Soo H., Yip, Cheng Har, Borresen-Dale, Anne Lise, Zheng, Wei, Cai, Qiuyin, Winqvist, Robert, Pylkäs, Katri, Andrulis, Irene L., Devilee, Peter, Tollenaar, Rob A E M, García-Closas, Montserrat, Figueroa, Jonine, Hall, Per, Czene, Kamila, Brand, Judith S., Darabi, Hatef, Eriksson, Mikael, Hooning, Maartje J., Koppert, Linetta B., Li, Jingmei, Shu, Xiao Ou, Zheng, Ying, Cox, Angela, Cross, Simon S., Shah, Mitul, Rhenius, Valerie, Choi, Ji Yeob, Kang, Daehee, Hartman, Mikael, Chia, Kee Seng, Kabisch, Maria, Torres, Diana, Luccarini, Craig, Conroy, Don M., Jakubowska, Anna, Lubinski, Jan, Sangrajrang, Suleeporn, Brennan, Paul, Olswold, Curtis, Slager, Susan, Shen, Chen Yang, Hou, Ming Feng, Swerdlow, Anthony, Schoemaker, Minouk J., Simard, Jacques, Pharoah, Paul D P, Kristensen, Vessela, Chenevix-Trench, Georgia, Easton, Douglas F., Dunning, Alison M., Edwards, Stacey L., Obstetrics & Gynecology, Medical Oncology, and Surgery
Subjects: Quantitative Trait Loci, Breast Neoplasms, Polymorphism, Single Nucleotide, Enhancer Elements, Genetic, Haplotypes, Receptors, Estrogen, SDG 3 - Good Health and Well-being, Case-Control Studies, Cell Line, Tumor, Report, Genetics, Chromosomes, Human, Pair 5, Humans, Genetic Predisposition to Disease, Genetics(clinical), Receptor, Fibroblast Growth Factor, Type 2, Promoter Regions, Genetic, Fibroblast Growth Factor 10, Alleles
Abstract: Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495-45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER(+)) breast cancer (per-g allele OR ER(+) = 1.15; 95% CI 1.13-1.18; p = 8.35 × 10(-30)). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER(-)) breast cancer (lead SNP rs6864776: per-a allele OR ER(-) = 1.10; 95% CI 1.05-1.14; p conditional = 1.44 × 10(-12)), and a single signal 3 SNP (rs200229088: per-t allele OR ER(+) = 1.12; 95% CI 1.09-1.15; p conditional = 1.12 × 10(-05)). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis. ispartof: American Journal of Human Genetics vol:99 issue:4 pages:903-911 ispartof: location:United States status: published
Published: 2016

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

Author: Johnson, Nichola, Dudbridge, Frank, Orr, Nick, Gibson, Lorna, Jones, Michael E, Schoemaker, Minouk J, Folkerd, Elizabeth J, Haynes, Ben P, Hopper, John L, Southey, Melissa C, Dite, Gillian S, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Atsma, Femke, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Renner, Stefan P, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Therese, Cordina, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Bernstein, Leslie, Anton-Culver, Hoda, Ziogas, Argyrios, Clarke Dur, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Dieffenbach, Aida Karina, Meindl, Alfons, Heil, Joerg, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Dörk, Thilo, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, Beesley, Jonathan, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Van den Berg, David, Tseng, Chiu-Chen, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Pensotti, Valeria, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Haiman, Chris, Simard, Jacques, and Goldberg, Mark S
Subjects: Australian Ovarian Cancer Study Group, Adult, Aging, Genotype, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, European Continental Ancestry Group, Oncology and Carcinogenesis, Breast Neoplasms, White People, Risk Factors, Clinical Research, Breast Cancer, Genetics, Humans, Cytochrome P-450 CYP3A, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Age of Onset, Polymorphism, Reproductive History, Genetic Association Studies, Aged, Cancer, Menarche, Prevention, Human Genome, Age Factors, Single Nucleotide, Middle Aged, Premenopause, kConFab Investigators, Female
Abstract: IntroductionWe 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.MethodsWe 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.ResultsWe 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).ConclusionsTo 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 later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Published: 2014

20. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, D��rk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, Garc��a-Closas, Montserrat, Garc��a-S��enz, Jos�� A, Geisler, J��rgen, Giles, Graham G, Grip, Mervi, G��ndert, Melanie, Hahnen, Eric, Haiman, Christopher A, H��kansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette A M, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubi��ski, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, H��kan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul D P, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, R��diger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Michailidou, Kyriaki, Chenevix-Trench, Georgia, Bachelot, Thomas, and Schmidt, Marjanka K
Subjects: skin and connective tissue diseases, 3. Good health
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 �� 10-8 and 4.42 �� 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

21. Comparative validation of the BOADICEA and Tyrer-Cuzick breast cancer risk models incorporating classical risk factors and polygenic risk in a population-based prospective cohort of women of European ancestry

Author: Pal Choudhury, Parichoy, Brook, Mark N., Hurson, Amber N., Lee, Andrew, Mulder, Charlotta V., Coulson, Penny, Schoemaker, Minouk J., Jones, Michael E., Swerdlow, Anthony J., Chatterjee, Nilanjan, Antoniou, Antonis C., and Garcia-Closas, Montserrat
Subjects: Breast cancer, Tyrer-Cuzick, Model validation, Short Report, IBIS, BOADICEA, Absolute risk, Prospective cohort, Risk prediction, 3. Good health
Abstract: Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. Methods: Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study. Results: The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women. Conclusion: The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.

22. Transcriptome-wide association study of breast cancer risk by estrogen-receptor status

Author: Feng, Helian, Gusev, Alexander, Pasaniuc, Bogdan, Wu, Lang, Long, Jirong, Abu-Full, Zomoroda, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Antoniou, Antonis C, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Asseryanis, Ella, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barrowdale, Daniel, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Ana, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Canisius, Sander, Campa, Daniele, Carter, Brian D, Carter, Jonathan, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, GC-HBOC Study Collaborators, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, De Leeneer, Kim, Dennis, Joe, Devilee, Peter, Diez, Orland, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Dunning, Alison M, Dwek, Miriam, Eccles, Diana M, Ejlertsen, Bent, Ellberg, Carolina, Engel, Christoph, Eriksson, Mikael, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Greene, Mark H, Gronwald, Jacek, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hake, Christopher, He, Wei, Heyworth, Jane, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Huang, Guanmengqian, Hulick, Peter J, Humphreys, Keith, Imyanitov, Evgeny N, ABCTB Investigators, HEBON Investigators, BCFR Investigators, OCGN Investigators, Isaacs, Claudine, Jakimovska, Milena, Jakubowska, Anna, James, Paul, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Joseph, Vijai, Jung, Audrey, Karlan, Beth Y, Khusnutdinova, Elza, Kiiski, Johanna I, Konstantopoulou, Irene, Kristensen, Vessela N, Laitman, Yael, Lambrechts, Diether, Lazaro, Conxi, Leroux, Dominique, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindor, Noralane, Lindström, Sara, Lo, Wing-Yee, Loud, Jennifer T, Lubiński, Jan, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Martinez, Maria E, Matricardi, Laura, Maurer, Tabea, Mavroudis, Dimitrios, McGuffog, Lesley, Meindl, Alfons, Menon, Usha, Michailidou, Kyriaki, Kapoor, Pooja M, Miller, Austin, Montagna, Marco, Moreno, Fernando, Moserle, Lidia, Mulligan, Anna M, Muranen, Taru A, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nevelsteen, Ines, Nielsen, Finn C, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Osorio, Ana, Papp, Janos, Park-Simon, Tjoung-Won, Parsons, Michael T, Pedersen, Inge S, Peixoto, Ana, Peterlongo, Paolo, Peto, Julian, Pharoah, Paul DP, Phillips, Kelly-Anne, Plaseska-Karanfilska, Dijana, Poppe, Bruce, Pradhan, Nisha, Prajzendanc, Karolina, Presneau, Nadege, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad Usman, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Saloustros, Emmanouil, Sandler, Dale P, Santos, Catarina, Sawyer, Elinor J, Schmidt, Marjanka K, Schmidt, Daniel F, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Rodney J, Sharma, Priyanka, Shu, Xiao-Ou, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Soucy, Penny, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Swerdlow, Anthony J, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thöne, Kathrin, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Torres, Diana, Truong, Thérèse, Tung, Nadine, Vachon, Celine M, Van Asperen, Christi J, Van Den Ouweland, Ans MW, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vieiro-Balo, Paula, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Winqvist, Robert, Yang, Xiaohong R, Yannoukakos, Drakoulis, Ziogas, Argyrios, Milne, Roger L, Easton, Douglas F, Chenevix-Trench, Georgia, Zheng, Wei, Kraft, Peter, and Jiang, Xia
Subjects: causal gene, TWAS, Vesicular Transport Proteins, Breast Neoplasms, Estrogens, Genomics, Risk Assessment, 3. Good health, Receptors, Estrogen, breast cancer subtype, GWAS, Humans, Female, Genetic Predisposition to Disease, Transcriptome, Genome-Wide Association Study
Abstract: Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.

23. Comparative validation of the BOADICEA and Tyrer-Cuzick breast cancer risk models incorporating classical risk factors and polygenic risk in a population-based prospective cohort of women of European ancestry

Author: Pal Choudhury, Parichoy, Brook, Mark N., Hurson, Amber N., Lee, Andrew, Mulder, Charlotta V., Coulson, Penny, Schoemaker, Minouk J., Jones, Michael E., Swerdlow, Anthony J., Chatterjee, Nilanjan, Antoniou, Antonis C., and Garcia-Closas, Montserrat
Subjects: Breast cancer, Tyrer-Cuzick, Model validation, Short Report, IBIS, BOADICEA, Absolute risk, Prospective cohort, Risk prediction, 3. Good health
Abstract: Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. Methods: Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study. Results: The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women. Conclusion: The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.

24. Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element

Author: Baxter, Joseph S, Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Brucker, Sara Y, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, NBCS Collaborators, Colonna, Sarah, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, García-Closas, Montserrat, García-Sáenz, José A, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hou, Ming-Feng, KConFab Investigators, ABCTB Investigators, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Larsson, Susanna C, Le Marchand, Loic, Lejbkowicz, Flavio, Li, Jingmei, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Mavroudis, Dimitrios, Mayes, Rebecca, Menon, Usha, Milne, Roger L, Mohd Taib, Nur Aishah, Muir, Kenneth, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, O'Brien, Katie M, Offit, Kenneth, Olson, Janet E, Olsson, Håkan, Park, Sue K, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Pylkäs, Katri, Rack, Brigitte, Rennert, Gad, Romero, Atocha, Ruebner, Matthias, Rüdiger, Thomas, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Southey, Melissa C, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teo, Soo Hwang, Teras, Lauren R, Terry, Mary Beth, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tseng, Chiu-Chen, Untch, Michael, Vachon, Celine M, Van Den Ouweland, Ans MW, Wang, Sophia S, Weinberg, Clarice R, Wendt, Camilla, Winham, Stacey J, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yamaji, Taiki, Zheng, Wei, Ziogas, Argyrios, Pharoah, Paul DP, Dunning, Alison M, Easton, Douglas F, Pettitt, Stephen J, Lord, Christopher J, Haider, Syed, Orr, Nick, and Fletcher, Olivia
Subjects: Chromosome Mapping, Genetic Variation, Breast Neoplasms, Molecular Sequence Annotation, functional annotation, 3. Good health, Cell Line, breast cancer risk, risk locus, Risk Factors, Chromosomes, Human, Pair 2, Humans, Female, CRISPR-Cas Systems, Insulin-Like Growth Factor Binding Protein 5, Promoter Regions, Genetic, Genetic Association Studies, Sequence Deletion
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

25. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author: Kapoor, Pooja Middha, Mavaddat, Nasim, Choudhury, Parichoy Pal, Wilcox, Amber N, Lindström, Sara, Behrens, Sabine, Michailidou, Kyriaki, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, Jung, Audrey, Abu-Ful, Zomoroda, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Freeman, Laura E Beane, Becher, Heiko, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Carracedo, Angel, Carter, Brian D, Castelao, Jose E, Chanock, Stephen J, Chatterjee, Nilanjan, Chenevix-Trench, Georgia, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dai, James Y, Earp, H Shelton, Ekici, Arif B, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, Gaudet, Mia M, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hatse, Sigrid, Heyworth, Jane, Holleczek, Bernd, Hoover, Robert N, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, KConFab/AOCS Investigators, John, Esther M, Jones, Michael E, Kaaks, Rudolf, Keeman, Renske, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lee, Eunjung, Lejbkowicz, Flavio, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, MacInnis, Robert J, Martinez, Maria Elena, Maurer, Tabea, McLean, Catriona, Neuhausen, Susan L, Newman, William G, Norman, Aaron, O'Brien, Katie M, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orr, Nick, Perou, Charles M, Pita, Guillermo, Polley, Eric C, Prentice, Ross L, Rennert, Gad, Rennert, Hedy S, Ruddy, Kathryn J, Sandler, Dale P, Saunders, Christobel, Schoemaker, Minouk J, Schöttker, Ben, Schumacher, Fredrick, Scott, Christopher, Scott, Rodney J, Shu, Xiao-Ou, Smeets, Ann, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Troester, Melissa A, Vachon, Celine M, Van Veen, Elke M, Wang, Xiaoliang, Weinberg, Clarice R, Weltens, Caroline, Willett, Walter, Winham, Stacey J, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul DP, Schmidt, Marjanka K, Kraft, Peter, Easton, Douglas F, Milne, Roger L, García-Closas, Montserrat, and Chang-Claude, Jenny
Subjects: Aged, 80 and over, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, White People, 3. Good health, Body Mass Index, Logistic Models, Receptors, Estrogen, Risk Factors, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, 10. No inequality, Medical History Taking, Aged
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.

26. Two truncating variants in FANCC and breast cancer risk

Author: Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L., Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Freeman, Laura E. Beane, Beckmann, Matthias W., Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L., Chang-Claude, Jenny, Chanock, Stephen J., Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L., Couch, Fergus J., Czene, Kamila, Daly, Mary B., Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M., Ekici, Arif B., Eriksson, Mikael, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M., García-Closas, Montserrat, García-Sáenz, José A., Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., Goldgar, David E., Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans B. L., Hooning, Maartje J., Hopper, John L., Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M., Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M., Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kwong, Ava, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindström, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, Meindl, Alfons, Menon, Usha, Milne, Roger L., Mohd Taib, Nur Aishah, Muir, Kenneth, Mulligan, Anna Marie, Neuhausen, Susan L., Nevanlinna, Heli, Neven, Patrick, Newman, William G., Offit, Kenneth, Olopade, Olufunmilayo I., Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Park, Sue K., Park-Simon, Tjoung-Won, Peto, Julian, Plaseska-Karanfilska, Dijana, Pohl-Rescigno, Esther, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad U., Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Ruebner, Matthias, Saloustros, Emmanouil, Schmidt, Marjanka K., Schmutzler, Rita K., Schneider, Michael O., Schoemaker, Minouk J., Scott, Christopher, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Slager, Susan, Smichkoska, Snezhana, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Tapper, William J., Teo, Soo H., Terry, Mary Beth, Toland, Amanda E., Tollenaar, Rob A. E. M., Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A., Truong, Thérèse, Tsugane, Shoichiro, Untch, Michael, Vachon, Celine M., Ouweland, Ans M. W. Van Den, Veen, Elke M. Van, Vijai, Joseph, Wendt, Camilla, Wolk, Alicja, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Ziv, Elad, Dunning, Alison M., Pharoah, Paul D. P., Schindler, Detlev, Devilee, Peter, Easton, Douglas F., Balleine, Rosemary, Baxter, Robert, Braye, Stephen, Carpenter, Jane, Dahlstrom, Jane, Forbes, John, Lee, C. Soon, Marsh, Deborah, Morey, Adrienne, Pathmanathan, Nirmala, Scott, Rodney, Simpson, Peter, Spigelman, Allan, Wilcken, Nicholas, Yip, Desmond, Zeps, Nikolajs, Børresen-Dale, Anne-Lise, Grenaker Alnæs, Grethe I., Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, and Geisler, Jürgen
Subjects: 45, article, 45/47, 692/499, 3. Good health, 692/4028
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

27. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author: Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E, Schoemaker, Minouk J, Gilham, Clare, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E Beane, Beckmann, Matthias W, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Closas, Montserrat, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, AOCS Group, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hart, Steven N, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Hunter, David J, ABCTB Investigators, KConFab Investigators, Jager, Agnes, Jakubowska, Anna, John, Esther M, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John WM, Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Newman, William G, Nielsen, Sune F, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S, Ruddy, Kathryn J, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmutzler, Rita K, Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Tamimi, Rulla M, Taylor, Jack A, Tollenaar, Rob AEM, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Van Veen, Elke M, Wang, Sophia S, Weinberg, Clarice R, Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Howie, A Forbes, Peto, Julian, Dos-Santos-Silva, Isabel, Swerdlow, Anthony J, Chang-Claude, Jenny, Schmidt, Marjanka K, Orr, Nick, and Fletcher, Olivia
Subjects: Estrone, Breast Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Premenopause, Receptors, Estrogen, Case-Control Studies, Cytochrome P-450 CYP3A, Humans, Pregnanediol, Female, Receptors, Progesterone, Alleles, Progesterone, Genome-Wide Association Study
Abstract: BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

28. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Collée, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Alnæs, Grethe I Grenaker, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, ABCTB Investigators, KConFab/AOCS Investigators, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Krüger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, McLean, Catriona, Meindl, Alfons, Menon, Usha, Nevanlinna, Heli, Newman, William G, Nodora, Jesse, Offit, Kenneth, Olsson, Håkan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V, Peto, Julian, Pita, Guillermo, Plaseska-Karanfilska, Dijana, Prentice, Ross, Punie, Kevin, Pylkäs, Katri, Radice, Paolo, Rennert, Gad, Romero, Atocha, Rüdiger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Schöttker, Ben, Sherman, Mark E, Shu, Xiao-Ou, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Torres, Diana, Troester, Melissa A, Vachon, Celine M, Van Deurzen, Carolien HM, Van Veen, Elke M, Wagner, Philippe, Weinberg, Clarice R, Wendt, Camilla, Wesseling, Jelle, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Couch, Fergus J, Simard, Jacques, Kraft, Peter, Easton, Douglas F, Pharoah, Paul DP, Schmidt, Marjanka K, García-Closas, Montserrat, and Chatterjee, Nilanjan
Subjects: Common breast cancer susceptibility variants, Risk, Receptor, ErbB-2, Genetic predisposition, Etiologic heterogeneity, Breast Neoplasms, 3. Good health, Breast cancer, Receptors, Estrogen, Biomarkers, Tumor, Humans, Female, Receptors, Progesterone, Genome-Wide Association Study
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.

29. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author: Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Allen, Jamie, Kar, Siddhartha, Pooley, Karen A, Dennis, Joe, Michailidou, Kyriaki, Turman, Constance, Soucy, Penny, Lemaçon, Audrey, Lush, Michael, Tyrer, Jonathan P, Ghoussaini, Maya, Moradi Marjaneh, Mahdi, Jiang, Xia, Agata, Simona, Aittomäki, Kristiina, Alonso, M Rosario, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arason, Adalgeir, Arndt, Volker, Aronson, Kristan J, Arun, Banu K, Auber, Bernd, Auer, Paul L, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Beeghly-Fadiel, Alicia, Benitez, Javier, Bermisheva, Marina, Białkowska, Katarzyna, Blanco, Amie M, Blomqvist, Carl, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Bonanni, Bernardo, Borg, Ake, Bosse, Kristin, Brauch, Hiltrud, Brenner, Hermann, Briceno, Ignacio, Brock, Ian W, Brooks-Wilson, Angela, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Cai, Qiuyin, Caldés, Trinidad, Caligo, Maria A, Camp, Nicola J, Campbell, Ian, Canzian, Federico, Carroll, Jason S, Carter, Brian D, Castelao, Jose E, Chiquette, Jocelyne, Christiansen, Hans, Chung, Wendy K, Claes, Kathleen BM, Clarke, Christine L, GEMO Study Collaborators, EMBRACE Collaborators, Collée, J Margriet, Cornelissen, Sten, Couch, Fergus J, Cox, Angela, Cross, Simon S, Cybulski, Cezary, Czene, Kamila, Daly, Mary B, De La Hoya, Miguel, Devilee, Peter, Diez, Orland, Ding, Yuan Chun, Dite, Gillian S, Domchek, Susan M, Dörk, Thilo, Dos-Santos-Silva, Isabel, Droit, Arnaud, Dubois, Stéphane, Dumont, Martine, Duran, Mercedes, Durcan, Lorraine, Dwek, Miriam, Eccles, Diana M, Engel, Christoph, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Fletcher, Olivia, Floris, Giuseppe, Flyger, Henrik, Foretova, Lenka, Foulkes, William D, Friedman, Eitan, Fritschi, Lin, Frost, Debra, Gabrielson, Marike, Gago-Dominguez, Manuela, Gambino, Gaetana, Ganz, Patricia A, Gapstur, Susan M, Garber, Judy, García-Sáenz, José A, Gaudet, Mia M, Georgoulias, Vassilios, Giles, Graham G, Glendon, Gord, Godwin, Andrew K, Goldberg, Mark S, Goldgar, David E, González-Neira, Anna, Tibiletti, Maria Grazia, Greene, Mark H, Grip, Mervi, Gronwald, Jacek, Grundy, Anne, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A, Hartikainen, Jaana M, Hartman, Mikael, He, Wei, Healey, Catherine S, Heemskerk-Gerritsen, Bernadette AM, Heyworth, Jane, Hillemanns, Peter, Hogervorst, Frans BL, Hollestelle, Antoinette, Hooning, Maartje J, Hopper, John L, Howell, Anthony, Huang, Guanmengqian, Hulick, Peter J, Imyanitov, Evgeny N, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Isaacs, Claudine, Iwasaki, Motoki, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, James, Paul A, Janavicius, Ramunas, Jankowitz, Rachel C, John, Esther M, Johnson, Nichola, Jones, Michael E, Jukkola-Vuorinen, Arja, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Karlan, Beth Y, Keeman, Renske, Kerin, Michael J, Khusnutdinova, Elza, Kiiski, Johanna I, Kirk, Judy, Kitahara, Cari M, Ko, Yon-Dschun, Konstantopoulou, Irene, Kosma, Veli-Matti, Koutros, Stella, Kubelka-Sabit, Katerina, Kwong, Ava, Kyriacou, Kyriacos, Laitman, Yael, Lambrechts, Diether, Lee, Eunjung, Leslie, Goska, Lester, Jenny, Lesueur, Fabienne, Lindblom, Annika, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Loud, Jennifer T, Lubiński, Jan, MacInnis, Robert J, Maishman, Tom, Makalic, Enes, Mannermaa, Arto, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Maria Elena, Matsuo, Keitaro, Maurer, Tabea, Mavroudis, Dimitrios, Mayes, Rebecca, McGuffog, Lesley, McLean, Catriona, Mebirouk, Noura, Meindl, Alfons, Miller, Austin, Miller, Nicola, Montagna, Marco, Moreno, Fernando, Muir, Kenneth, Mulligan, Anna Marie, Muñoz-Garzon, Victor M, Muranen, Taru A, Narod, Steven A, Nassir, Rami, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Nielsen, Finn C, Nikitina-Zake, Liene, Norman, Aaron, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Olsson, Håkan, Orr, Nick, Osorio, Ana, Pankratz, V Shane, Papp, Janos, Park, Sue K, Park-Simon, Tjoung-Won, Parsons, Michael T, Paul, James, Pedersen, Inge Sokilde, Peissel, Bernard, Peshkin, Beth, Peterlongo, Paolo, Peto, Julian, Plaseska-Karanfilska, Dijana, Prajzendanc, Karolina, Prentice, Ross, Presneau, Nadege, Prokofyeva, Darya, Pujana, Miquel Angel, Pylkäs, Katri, Radice, Paolo, Ramus, Susan J, Rantala, Johanna, Rau-Murthy, Rohini, Rennert, Gad, Risch, Harvey A, Robson, Mark, Romero, Atocha, Rossing, Maria, Saloustros, Emmanouil, Sánchez-Herrero, Estela, Sandler, Dale P, Santamariña, Marta, Saunders, Christobel, Sawyer, Elinor J, Scheuner, Maren T, Schmidt, Daniel F, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, Schöttker, Ben, Schürmann, Peter, Scott, Christopher, Scott, Rodney J, Senter, Leigha, Seynaeve, Caroline M, Shah, Mitul, Sharma, Priyanka, Shen, Chen-Yang, Shu, Xiao-Ou, Singer, Christian F, Slavin, Thomas P, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Spurdle, Amanda B, Stone, Jennifer, Stoppa-Lyonnet, Dominique, Sutter, Christian, Swerdlow, Anthony J, Tamimi, Rulla M, Tan, Yen Yen, Tapper, William J, Taylor, Jack A, Teixeira, Manuel R, Tengström, Maria, Teo, Soo Hwang, Terry, Mary Beth, Teulé, Alex, Thomassen, Mads, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A, Truong, Thérèse, Tung, Nadine, Tzardi, Maria, Ulmer, Hans-Ulrich, Vachon, Celine M, Van Asperen, Christi J, Van Der Kolk, Lizet E, Van Rensburg, Elizabeth J, Vega, Ana, Viel, Alessandra, Vijai, Joseph, Vogel, Maartje J, Wang, Qin, Wappenschmidt, Barbara, Weinberg, Clarice R, Weitzel, Jeffrey N, Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yannoukakos, Drakoulis, Zhang, Yan, Zheng, Wei, Hunter, David, Pharoah, Paul DP, Chang-Claude, Jenny, García-Closas, Montserrat, Schmidt, Marjanka K, Milne, Roger L, Kristensen, Vessela N, French, Juliet D, Edwards, Stacey L, Antoniou, Antonis C, Chenevix-Trench, Georgia, Simard, Jacques, Easton, Douglas F, Kraft, Peter, and Dunning, Alison M
Subjects: Quantitative Trait Loci, Chromosome Mapping, Bayes Theorem, Breast Neoplasms, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide, Linkage Disequilibrium, 3. Good health, Risk Factors, Biomarkers, Tumor, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

30. Common variants in breast cancer risk loci predispose to distinct tumor subtypes

Author: Ahearn, Thomas U, Zhang, Haoyu, Michailidou, Kyriaki, Milne, Roger L, Bolla, Manjeet K, Dennis, Joe, Dunning, Alison M, Lush, Michael, Wang, Qin, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Auer, Paul L, Augustinsson, Annelie, Baten, Adinda, Becher, Heiko, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bojesen, Stig E, Bonanni, Bernardo, B��rresen-Dale, Anne-Lise, Brauch, Hiltrud, Brenner, Hermann, Brooks-Wilson, Angela, Br��ning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Clarke, Christine L, NBCS Collaborators, Coll��e, J Margriet, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, D��rk, Thilo, Dwek, Miriam, Eccles, Diana M, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Floris, Giuseppe, Gago-Dominguez, Manuela, Gapstur, Susan M, Garc��a-S��enz, Jos�� A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Gonz��lez-Neira, Anna, Aln��s, Grethe I Grenaker, Grip, Mervi, Gu��nel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Harkness, Elaine F, Heemskerk-Gerritsen, Bernadette AM, Holleczek, Bernd, Hollestelle, Antoinette, Hooning, Maartje J, Hoover, Robert N, Hopper, John L, Howell, Anthony, ABCTB Investigators, KConFab/AOCS Investigators, Jakimovska, Milena, Jakubowska, Anna, John, Esther M, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Kauppila, Saila, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Koutros, Stella, Kristensen, Vessela N, Kr��ger, Ute, Kubelka-Sabit, Katerina, Kurian, Allison W, Kyriacou, Kyriacos, Lambrechts, Diether, Lee, Derrick G, Lindblom, Annika, Linet, Martha, Lissowska, Jolanta, Llaneza, Ana, Lo, Wing-Yee, MacInnis, Robert J, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Martinez, Maria Elena, McLean, Catriona, Meindl, Alfons, Menon, Usha, Nevanlinna, Heli, Newman, William G, Nodora, Jesse, Offit, Kenneth, Olsson, H��kan, Orr, Nick, Park-Simon, Tjoung-Won, Patel, Alpa V, Peto, Julian, Pita, Guillermo, Plaseska-Karanfilska, Dijana, Prentice, Ross, Punie, Kevin, Pylk��s, Katri, Radice, Paolo, Rennert, Gad, Romero, Atocha, R��diger, Thomas, Saloustros, Emmanouil, Sampson, Sarah, Sandler, Dale P, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Sch��ttker, Ben, Sherman, Mark E, Shu, Xiao-Ou, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Torres, Diana, Troester, Melissa A, Vachon, Celine M, Van Deurzen, Carolien HM, Van Veen, Elke M, Wagner, Philippe, Weinberg, Clarice R, Wendt, Camilla, Wesseling, Jelle, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Couch, Fergus J, Simard, Jacques, Kraft, Peter, Easton, Douglas, Pharoah, Paul, Schmidt, Marjanka K, Garc��a-Closas, Montserrat, and Chatterjee, Nilanjan
Subjects: Common breast cancer susceptibility variants, Breast cancer, Genetic predisposition, Etiologic heterogeneity, 3. Good health, Research Article
Abstract: Funder: Genome Canada and the Canadian Institutes of Health Research, Funder: G��nome Qu��bec; doi: http://dx.doi.org/10.13039/100013062, Funder: Foundation for the National Institutes of Health; doi: http://dx.doi.org/10.13039/100000009, Funder: Center for Inherited Disease Research, Funder: Cancer Research UK, Funder: Odense University Hospital Research Foundation, Funder: National R&D Program for Cancer Control��Ministry of Health and Welfare, Funder: Italian Association for Cancer Research, Funder: Carol M. Baldwin Breast Cancer Research Fund; doi: http://dx.doi.org/10.13039/100002645, Funder: National Health and Medical Research Council, Funder: Deutsche Kinderkrebsstiftung; doi: http://dx.doi.org/10.13039/501100007311, Funder: European Union, Funder: National Institutes of Health; doi: http://dx.doi.org/10.13039/100000002, Funder: National Cancer Institute, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Susan G. Komen for the Cure, Komen Wyoming Affiliate; doi: http://dx.doi.org/10.13039/100005987, Funder: Ovarian Cancer Research Fund; doi: http://dx.doi.org/10.13039/100001282, Funder: National Cancer Institute (NCI), BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

31. Comparative validation of the BOADICEA and Tyrer-Cuzick breast cancer risk models incorporating classical risk factors and polygenic risk in a population-based prospective cohort of women of European ancestry

Author: Pal Choudhury, Parichoy, Brook, Mark N., Hurson, Amber N., Lee, Andrew, Mulder, Charlotta V., Coulson, Penny, Schoemaker, Minouk J., Jones, Michael E., Swerdlow, Anthony J., Chatterjee, Nilanjan, Antoniou, Antonis C., and Garcia-Closas, Montserrat
Subjects: Breast cancer, Tyrer-Cuzick, Model validation, Short Report, IBIS, BOADICEA, Absolute risk, Prospective cohort, Risk prediction, 3. Good health
Abstract: Background: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. Methods: Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study. Results: The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women. Conclusion: The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.

32. Comparative validation of the BOADICEA and Tyrer-Cuzick breast cancer risk models incorporating classical risk factors and polygenic risk in a population-based prospective cohort of women of European ancestry

Author: Pal Choudhury, Parichoy, Brook, Mark N, Hurson, Amber N, Lee, Andrew, Mulder, Charlotta V, Coulson, Penny, Schoemaker, Minouk J, Jones, Michael E, Swerdlow, Anthony J, Chatterjee, Nilanjan, Antoniou, Antonis C, and Garcia-Closas, Montserrat
Subjects: Adult, Multifactorial Inheritance, Tyrer-Cuzick, Model validation, Breast Neoplasms, Absolute risk, Prospective cohort, Middle Aged, Models, Theoretical, Risk Assessment, Risk prediction, White People, 3. Good health, Young Adult, Breast cancer, Risk Factors, Population Surveillance, IBIS, Humans, BOADICEA, Female, Genetic Predisposition to Disease, Algorithms, Aged
Abstract: BACKGROUND: The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. METHODS: Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23-75 years from the Generations Study. RESULTS: The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 - 1.86) for women younger than 50 years and 1.09 (0.66 - 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 - 2.92) for younger and 1.73 (1.03 - 2.90) for older women. CONCLUSION: The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.

33. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W., Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E., Bolla, Manjeet K., Brenner, Hermann, Canzian, Federico, Castelao, Jose E., Chang-Claude, Jenny, Chanock, Stephen J., Couch, Fergus J., Czene, Kamila, Daly, Mary B., Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M., Easton, Douglas F., Ekici, Arif B., Eliassen, A. Heather, Fasching, Peter A., Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A., Geisler, Jürgen, Giles, Graham G., Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M., Heemskerk-Gerritsen, Bernadette A. M., Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L., Hunter, David J., Jacot, William, Jakubowska, Anna, John, Esther M., Jung, Audrey Y., Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B., Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N., Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A., Nevanlinna, Heli, Olshan, Andrew F., Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V., Peterlongo, Paolo, Pharoah, Paul D. P., Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S., Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J., Schmutzler, Rita K., Schoemaker, Minouk J., Scott, Christopher, Southey, Melissa C., Surowy, Harald, Swerdlow, Anthony J., Tamimi, Rulla M., Teras, Lauren R., Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A., Vachon, Celine M., Wang, Qin, Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, Michailidou, Kyriaki, Chenevix-Trench, Georgia, Bachelot, Thomas, and Schmidt, Marjanka K.
Subjects: 631/67/322, 631/67/68, article, 631/67/1347, skin and connective tissue diseases, 3. Good health
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

34. CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

Author: Johnson, Nichola, Maguire, Sarah, Morra, Anna, Kapoor, Pooja Middha, Tomczyk, Katarzyna, Jones, Michael E., Schoemaker, Minouk J., Gilham, Clare, Bolla, Manjeet K., Wang, Qin, Dennis, Joe, Ahearn, Thomas U., Andrulis, Irene L., Anton-Culver, Hoda, Antonenkova, Natalia N., Arndt, Volker, Aronson, Kristan J., Augustinsson, Annelie, Baynes, Caroline, Freeman, Laura E. Beane, Beckmann, Matthias W., Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Boeckx, Bram, Bogdanova, Natalia V., Bojesen, Stig E., Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Campa, Daniele, Canzian, Federico, Castelao, Jose E., Chanock, Stephen J., Chenevix-Trench, Georgia, Clarke, Christine L., Conroy, Don M., Couch, Fergus J., Cox, Angela, Cross, Simon S., Czene, Kamila, Dörk, Thilo, Eliassen, A. Heather, Engel, Christoph, Evans, D. Gareth, Fasching, Peter A., Figueroa, Jonine, Floris, Giuseppe, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M., García-Closas, Montserrat, Gaudet, Mia M., Giles, Graham G., Goldberg, Mark S., González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hamann, Ute, Harrington, Patricia A., Hart, Steven N., Hooning, Maartje J., Hopper, John L., Howell, Anthony, Hunter, David J., Jager, Agnes, Jakubowska, Anna, John, Esther M., Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M., Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N., Kurian, Allison W., Lambrechts, Diether, Le Marchand, Loic, Linet, Martha, Lubiński, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Martens, John W. M., Mavroudis, Dimitrios, Mayes, Rebecca, Meindl, Alfons, Milne, Roger L., Neuhausen, Susan L., Nevanlinna, Heli, Newman, William G., Nielsen, Sune F., Nordestgaard, Børge G., Obi, Nadia, Olshan, Andrew F., Olson, Janet E., Olsson, Håkan, Orban, Ester, Park-Simon, Tjoung-Won, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Rennert, Hedy S., Ruddy, Kathryn J., Saloustros, Emmanouil, Sandler, Dale P., Sawyer, Elinor J., Schmutzler, Rita K., Scott, Christopher, Shu, Xiao-Ou, Simard, Jacques, Smichkoska, Snezhana, Sohn, Christof, Southey, Melissa C., Spinelli, John J., Stone, Jennifer, Tamimi, Rulla M., Taylor, Jack A., Tollenaar, Rob A. E. M., Tomlinson, Ian, Troester, Melissa A., Truong, Thérèse, Vachon, Celine M., Van Veen, Elke M., Wang, Sophia S., Weinberg, Clarice R., Wendt, Camilla, Wildiers, Hans, Winqvist, Robert, Wolk, Alicja, Zheng, Wei, Ziogas, Argyrios, Dunning, Alison M., Pharoah, Paul D. P., Easton, Douglas F., Howie, A. Forbes, Peto, Julian, Dos-Santos-Silva, Isabel, Swerdlow, Anthony J., Chang-Claude, Jenny, Schmidt, Marjanka K., Orr, Nick, Fletcher, Olivia, Børresen-Dale, Anne-Lise, Alnæs, Grethe I. Grenaker, Sahlberg, Kristine K., Ottestad, Lars, Kåresen, Rolf, Schlichting, Ellen, Holmen, Marit Muri, Sauer, Toril, Haakensen, Vilde, Engebråten, Olav, Naume, Bjørn, Fosså, Alexander, Kiserud, Cecile E., Reinertsen, Kristin V., Helland, Åslaug, Riis, Margit, Geisler, Jürgen, Bowtell, David D. L., DeFazio, Anna, Webb, Penelope M., Clarke, Christine, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Carpenter, Jane, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Amor, David, Andrews, Lesley, Antill, Yoland, Balleine, Rosemary, Beesley, Jonathan, Bennett, Ian, Bogwitz, Michael, Botes, Leon, Brennan, Meagan, Brown, Melissa, Buckley, Michael, Burke, Jo, Butow, Phyllis, Caldon, Liz, Campbell, Ian, Chauhan, Deepa, Chauhan, Manisha, Christian, Alice, Cohen, Paul, Colley, Alison, Crook, Ashley, Cui, James, Cummings, Margaret, Dawson, Sarah-Jane, Delatycki, Martin, Dickson, Rebecca, Dixon, Joanne, Edkins, Ted, Edwards, Stacey, Farshid, Gelareh, Fellows, Andrew, Fenton, Georgina, Field, Michael, Flanagan, James, Fong, Peter, Forrest, Laura, Fox, Stephen, French, Juliet, Friedlander, Michael, Gaff, Clara, Gattas, Mike, George, Peter, Greening, Sian, Harris, Marion, Hart, Stewart, Hayward, Nick, Hopper, John, Hoskins, Cass, Hunt, Clare, James, Paul, Jenkins, Mark, Kidd, Alexa, Kirk, Judy, Koehler, Jessica, Kollias, James, Lakhani, Sunil, Lawrence, Mitchell, Lindeman, Geoff, Lipton, Lara, Lobb, Liz, Mann, Graham, McLachlan, Sue Anne, Meiser, Bettina, Milne, Roger, Nightingale, Sophie, O’Connell, Shona, O’Sullivan, Sarah, Ortega, David Gallego, Pachter, Nick, Patterson, Briony, Pearn, Amy, Phillips, Kelly, Pieper, Ellen, Rickard, Edwina, Robinson, Bridget, Saleh, Mona, Salisbury, Elizabeth, Saunders, Christobel, Saunus, Jodi, Scott, Clare, Sexton, Adrienne, Shelling, Andrew, Southey, Melissa, Spurdle, Amanda, Taylor, Jessica, Taylor, Renea, Thorne, Heather, Trainer, Alison, Tucker, Kathy, Visvader, Jane, Walker, Logan, Williams, Rachael, Winship, Ingrid, and Young, Mary Ann
Subjects: 631/67/68, article, 631/67/2324, 631/67/1347, 3. Good health
Abstract: Funder: Breast Cancer Now (BCN); doi: https://doi.org/10.13039/100009794, Funder: Cancer Research UK (CRUK); doi: https://doi.org/10.13039/501100000289, Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: U.S. Department of Health & Human Services | National Institutes of Health (NIH), Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011199; Grant(s): HEALTH-F2-2009-223175, HEALTH-F2-2009-223175, Funder: Genome Canada (Génome Canada); doi: https://doi.org/10.13039/100008762, Funder: Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada); doi: https://doi.org/10.13039/501100000024, Funder: Quebec Breast cancer Foundation Genome Quebec, Funder: U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (NLM); doi: https://doi.org/10.13039/100000092, Funder: EC | EC Seventh Framework Programm | FP7 Ideas: European Research Council (FP7-IDEAS-ERC - Specific Programme: "Ideas" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)), Funder: European Union’s Horizon 2020, Funder: Deutsche Krebshilfe (German Cancer Aid); doi: https://doi.org/10.13039/501100005972, Funder: BCAST - European Union’s Horizon 2020, Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913, Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (−49.2%, 95% CI −56.1% to −41.1%, P = 3.1 × 10–18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82–0.91, P = 6.9 × 10–8). Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.

35. Search for new loci and low-frequency variants influencing glioma risk by exome-array analysis

Author: Kinnersley, Ben, Kamatani, Yoichiro, Labussière, Marianne, Wang, Yufei, Galan, Pilar, Mokhtari, Karima, Delattre, Jean-Yves, Gousias, Konstantinos, Schramm, Johannes, Schoemaker, Minouk J, Swerdlow, Anthony, Fleming, Sarah J, Herms, Stefan, Heilmann, Stefanie, Nöthen, Markus M, Simon, Matthias, Sanson, Marc, Lathrop, Mark, and Houlston, Richard S
Subjects: BRCA2 Protein, Male, Genetics & Heredity, 0604 Genetics, Genotyping Techniques, Brain Neoplasms, Glioma, Middle Aged, Polymorphism, Single Nucleotide, Article, Isocitrate Dehydrogenase, Amino Acyl-tRNA Synthetases, Genetic Loci, Case-Control Studies, Humans, Exome, Female, Algorithms
Abstract: © 2016 Macmillan Publishers Limited.To identify protein-altering variants (PAVs) for glioma, we analysed Illumina HumanExome BeadChip exome-array data on 1882 glioma cases and 8079 controls from three independent European populations. In addition to single-variant tests we incorporated information on the predicted functional consequences of PAVs and analysed sets of genes with a higher likelihood of having a role in glioma on the basis of the profile of somatic mutations documented by large-scale sequencing initiatives. Globally there was a strong relationship between effect size and PAVs predicted to be damaging (P=2.29 × 10 -49); however, these variants which are most likely to impact on risk, are rare (MAFT, p.(Lys3326Ter), which has been shown to influence breast and lung cancer risk (odds ratio (OR)=2.3, P=4.00 × 10 -4 for glioblastoma (GBM)) and IDH2:c.782G>A, p.(Arg261His) (OR=3.21, P=7.67 × 10 -3, for non-GBM). Additionally, gene burden tests revealed a statistically significant association for HARS2 and risk of GBM (P=2.20 × 10 -6). Genome scans of low-frequency PAVs represent a complementary strategy to identify disease-causing variants compared with scans based on tagSNPs. Strategies to lessen the multiple testing burden by restricting analysis to PAVs with higher priors affords an opportunity to maximise study power.

36. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, Maria, Canisius, Sander, Keeman, Renske, Beesley, Jonathan, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Bermisheva, Marina, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Canzian, Federico, Castelao, Jose E, Chang-Claude, Jenny, Chanock, Stephen J, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dunning, Alison M, Easton, Douglas F, Ekici, Arif B, Eliassen, A Heather, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Geisler, Jürgen, Giles, Graham G, Grip, Mervi, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartikainen, Jaana M, Heemskerk-Gerritsen, Bernadette AM, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hunter, David J, Jacot, William, Jakubowska, Anna, John, Esther M, Jung, Audrey Y, Kaaks, Rudolf, Khusnutdinova, Elza, Koppert, Linetta B, Kraft, Peter, Kristensen, Vessela N, Kurian, Allison W, Lambrechts, Diether, Le Marchand, Loic, Lindblom, Annika, Luben, Robert N, Lubiński, Jan, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mavroudis, Dimitrios, Muranen, Taru A, Nevanlinna, Heli, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Patel, Alpa V, Peterlongo, Paolo, Pharoah, Paul DP, Punie, Kevin, Radice, Paolo, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Roylance, Rebecca, Rüdiger, Thomas, Ruebner, Matthias, Saloustros, Emmanouil, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Christopher, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Teras, Lauren R, Thomas, Emilie, Tomlinson, Ian, Troester, Melissa A, Vachon, Celine M, Wang, Qin, Winqvist, Robert, Wolk, Alicja, Ziogas, Argyrios, KConFab/AOCS Investigators, Michailidou, Kyriaki, Chenevix-Trench, Georgia, Bachelot, Thomas, and Schmidt, Marjanka K
Subjects: Germ Cells, Cancer Survivors, Biomarkers, Tumor, Genetic Variation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Kaplan-Meier Estimate, skin and connective tissue diseases, Polymorphism, Single Nucleotide, Germ-Line Mutation, 3. Good health
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.

37. Two truncating variants in FANCC and breast cancer risk

Author: Dörk, Thilo, Peterlongo, Paolo, Mannermaa, Arto, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Behrens, Sabine, Bermisheva, Marina, Blomqvist, Carl, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Canzian, Federico, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Choi, Ji-Yeob, Christiansen, Hans, Clarke, Christine L, Couch, Fergus J, Czene, Kamila, Daly, Mary B, Dos-Santos-Silva, Isabel, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, Gao, Chi, Gapstur, Susan M, García-Closas, Montserrat, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Goldberg, Mark S, Goldgar, David E, Guénel, Pascal, Haeberle, Lothar, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hein, Alexander, Hillemanns, Peter, Hogervorst, Frans BL, Hooning, Maartje J, Hopper, John L, Howell, Tony, Huo, Dezheng, Ito, Hidemi, Iwasaki, Motoki, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Khusnutdinova, Elza, Kim, Sung-Won, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kwong, Ava, Lambrechts, Diether, Marchand, Loic Le, Li, Jingmei, Lindström, Sara, Linet, Martha, Lo, Wing-Yee, Long, Jirong, Lophatananon, Artitaya, Lubiński, Jan, Manoochehri, Mehdi, Manoukian, Siranoush, Margolin, Sara, Martinez, Elena, Matsuo, Keitaro, Mavroudis, Dimitris, Meindl, Alfons, Menon, Usha, Milne, Roger L, Mohd Taib, Nur Aishah, Muir, Kenneth, Mulligan, Anna Marie, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Newman, William G, Offit, Kenneth, Olopade, Olufunmilayo I, Olshan, Andrew F, Olson, Janet E, Olsson, Håkan, Park, Sue K, Park-Simon, Tjoung-Won, Peto, Julian, Plaseska-Karanfilska, Dijana, Pohl-Rescigno, Esther, Presneau, Nadege, Rack, Brigitte, Radice, Paolo, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Romero, Atocha, Ruebner, Matthias, Saloustros, Emmanouil, Schmidt, Marjanka K, Schmutzler, Rita K, Schneider, Michael O, Schoemaker, Minouk J, Scott, Christopher, Shen, Chen-Yang, Shu, Xiao-Ou, Simard, Jacques, Slager, Susan, Smichkoska, Snezhana, Southey, Melissa C, Spinelli, John J, Stone, Jennifer, Surowy, Harald, Swerdlow, Anthony J, Tamimi, Rulla M, Tapper, William J, Teo, Soo H, Terry, Mary Beth, Toland, Amanda E, Tollenaar, Rob AEM, Torres, Diana, Torres-Mejía, Gabriela, Troester, Melissa A, Truong, Thérèse, Tsugane, Shoichiro, Untch, Michael, Vachon, Celine M, Ouweland, Ans MW Van Den, Veen, Elke M Van, Vijai, Joseph, Wendt, Camilla, Wolk, Alicja, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Ziv, Elad, ABCTB Investigators, NBCS Collaborators, Dunning, Alison M, Pharoah, Paul DP, Schindler, Detlev, Devilee, Peter, and Easton, Douglas F
Subjects: BRCA2 Protein, Fanconi Anemia, BRCA1 Protein, Case-Control Studies, Fanconi Anemia Complementation Group C Protein, Genetic Variation, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, 3. Good health, Sequence Deletion
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

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

Author: Johnson, Nichola, Dudbridge, Frank, Orr, Nick, Gibson, Lorna, Jones, Michael E, Schoemaker, Minouk J, Folkerd, Elizabeth J, Haynes, Ben P, Hopper, John L, Southey, Melissa C, Dite, Gillian S, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Atsma, Femke, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Renner, Stefan P, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Therese, Cordina, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Bernstein, Leslie, Anton-Culver, Hoda, Ziogas, Argyrios, Clarke Dur, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Dieffenbach, Aida Karina, Meindl, Alfons, Heil, Joerg, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, GENICA (Gene Environment Interaction And Breast Cancer In Germany) Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Dörk, Thilo, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, Beesley, Jonathan, KConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Van Den Berg, David, Tseng, Chiu-Chen, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Pensotti, Valeria, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Haiman, Chris, Simard, Jacques, Goldberg, Mark S, Labrèche, France, Dumont, Martine, Soucy, Penny, Teo, Soo, Yip, Cheng Har, Phuah, Sze Yee, Cornes, Belinda K, Kristensen, Vessela N, Grenaker Alnæs, Grethe, Børresen-Dale, Anne-Lise, Zheng, Wei, Winqvist, Robert, Pylkäs, Katri, Jukkola-Vuorinen, Arja, Grip, Mervi, Andrulis, Irene L, Knight, Julia A, Glendon, Gord, Mulligan, Anna Marie, Devillee, Peter, Figueroa, Jonine, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Hall, Per, Schoof, Nils, Hooning, Maartje, Hollestelle, Antoinette, Oldenburg, Rogier A, Tilanus-Linthorst, Madeleine, Liu, Jianjun, Cox, Angie, Brock, Ian W, Reed, Malcolm WR, Cross, Simon S, Blot, William, Signorello, Lisa B, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Kang, Daehee, Noh, Dong-Young, Park, Sue K, Choi, Ji-Yeob, Hartman, Mikael, Miao, Hui, Lim, Wei Yen, Tang, Anthony, Hamann, Ute, Försti, Asta, Rüdiger, Thomas, Ulmer, Hans Ulrich, Jakubowska, Anna, Lubinski, Jan, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Sangrajrang, Suleeporn, Gaborieau, Valerie, Brennan, Paul, McKay, James, Slager, Susan, Toland, Amanda E, Vachon, Celine, Yannoukakos, Drakoulis, Shen, Chen-Yang, Yu, Jyh-Cherng, Huang, Chiun-Sheng, Hou, Ming-Feng, González-Neira, Anna, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Luccarini, Craig, Dennis, Joe, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Jean, Easton, Douglas F, García-Closas, Montserrat, Dowsett, Mitch, Ashworth, Alan, Swerdlow, Anthony J, Peto, Julian, Dos Santos Silva, Isabel, and Fletcher, Olivia
Subjects: Adult, Menarche, Genotype, Age Factors, Breast Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, White People, 3. Good health, 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 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 later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.

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

Author: Lynne J. Hocking, Caterina Barbieri, Jenny Chang-Claude, David Karasik, Dieter Flesch-Janys, James F. Wilson, Mark S. Goldberg, Henry Voelzke, Archie Campbell, Stig E. Bojesen, David R. Weir, Ailith Pirie, Megan L. Grove, Melissa Wellons, Georg Homuth, Corrado Masciullo, Jennifer A. Brody, Hermann Brenner, Paolo Gasparini, Andrew D. Johnson, Patrick Neven, Graham G. Giles, Peter Kraft, André G. Uitterlinden, Wei Zheng, Alkes L. Price, Anja Rudolph, Arto Mannermaa, Nicholas G. Martin, Christopher A. Haiman, Massimo Mangino, Melissa C. Southey, Daniela Ruggiero, Toshiko Tanaka, Kathryn L. Lunetta, Julie E. Buring, John R. B. Perry, Robert Winqvist, Laufey Tryggvadottir, Angela Cox, Serena Sanna, Nicola Pirastu, Anna Jakubowska, Paul D.P. Pharoah, David J. Porteous, Dragana Vuckovic, Andrea D. Coviello, Giorgia Girotto, Sara Lindstroem, Patrick Sulem, Astrid Petersmann, Xin Li, Maartje J. Hooning, Lili Milani, Sven Bergmann, Marek Zygmunt, Javier Benitez, Vilmundur Gudnason, Fernando Rivadeneira, Volker Arndt, Marina Ciullo, Caroline Hayward, Sheila Ulivi, Janet E. Olson, Hoda Anton-Culver, Maria Kabisch, Sara Margolin, Vessela N. Kristensen, Patrick F. McArdle, Tanguy Corre, Nora Franceschini, Veli-Matti Kosma, Hiltrud Brauch, Roger L. Milne, Eric Boerwinkle, Matthias W. Beckmann, Charles Kooperberg, Qin Wang, Jessica D. Faul, Stephen J. Chanock, Alexander Teumer, Mark O. Goodarzi, Unnur Thorsteinsdottir, R Maegi, Paul M. Ridker, Antonis C. Antoniou, Ozren Polasek, Daniel F. Gudbjartsson, Barbara McKnight, Melissa E. Garcia, Manjeet K. Bolla, Alanna C. Morrison, Paolo Radice, Xiuqing Guo, Lude L. Franke, Michela Traglia, Marjanka K. Schmidt, Heli Nevanlinna, Teresa Nutile, Cinzia Sala, Pascal Guénel, Jennifer E. Huffman, Stephen T. Turner, Anna Murray, Carl Blomqvist, Margaux F. Keller, Samuel E. Jones, Montserrat Garcia-Closas, Ivana Kolcic, Anne B. Newman, Jan Lubinski, Albert Hofman, Isabel dos-Santos-Silva, Hilary K. Finucane, Anne Lise Børresen-Dale, Alexander P. Reiner, Tim D. Spector, Gonneke Willemsen, John D. Eicher, Douglas F. Easton, Claudia Langenberg, Anthony J. Swerdlow, Natalia Bogdanova, Alison M. Dunning, Giorgio Pistis, Tõnu Esko, Behrooz Z. Alizadeh, Martina Mueller-Nurasyid, Eleonora Porcu, Laura M. Yerges-Armstrong, Leslie J. Raffel, Laura Crisponi, Gonçalo R. Abecasis, Jerome I. Rotter, Yii-Der Ida Chen, Antonietta Robino, Katri Pylkaes, Ken K. Ong, Thibaud Boutin, Elinor J. Sawyer, Daniel I. Chasman, Brian E. Henderson, Frank B. Hu, Leslie Bernstein, Drakoulis Yannoukakos, Tamara B. Harris, Dorret I. Boomsma, Katherine S. Ruth, Jie Yao, Keith Humphreys, Jennifer A. Smith, Elisabeth Altmaier, Ulrike Peters, Doris Stoeckl, Eva Albrecht, Tatijana Zemunik, Jenny A. Visser, Minouk J. Schoemaker, Diego Vozzi, Thilo Doerk, J. Ross Chapman, Irene L. Andrulis, Joanne M. Murabito, Alan F. Wright, Lisette Stolk, Jonathan Marten, Alice M. Arnold, Paolo Peterlongo, Harry Campbell, Natalia Pervjakova, Jingmei Li, Jennifer Kriebel, Alicia Beeghly-Fadiel, Immaculata De Vivo, Jouke-Jan Hottenga, Kari Stefansson, Cornelia M. van Duijn, Brendan Bulik-Sullivan, Evelin Mihailov, Chunyan He, Joe Dennis, Nicholas J. Wareham, Yongmei Liu, Sharon L.R. Kardia, Lynda M. Rose, Felix R. Day, Georgia Chenevix-Trench, Albert V. Smith, David J. Hunter, Sandosh Padmanabhan, Christian Gieger, Konstantin Strauch, Igor Rudan, Jacques Simard, Jian'an Luan, Robert A. Scott, Kyriaki Michailidou, Bruce M. Psaty, Per Hall, Suzette J. Bielinski, Rita K. Schmutzler, Julian Peto, Ellen W. Demerath, Ursula M. Schick, Rossella Sorice, Wei Zhao, Børge G. Nordestgaard, Andres Metspalu, Jonine D. Figueroa, Julia A. Knight, Barbara Burwinkel, Thomas Bruening, Judith Manz, Anna González-Neira, Ilaria Gandin, Ian Tomlinson, Thérèse Truong, Kent D. Taylor, Amanda E. Toland, Deborah J. Thompson, Alfons Meindl, Caroline M. Seynaeve, Benjamin M. Neale, Fergus J. Couch, Mike A. Nalls, Ute Hamann, Kamila Czene, John L. Hopper, Bruce H. R. Wolffenbuttel, Grant W. Montgomery, Hatef Darabi, Daniela Toniolo, Jinyan Huang, Peter Devilee, Cathy E. Elks, David Schlessinger, Luigi Ferrucci, Frank Schmidt, Peter A. Fasching, Diether Lambrechts, Najaf Amin, Day, Felix R, Ruth, Katherine S, Thompson, Deborah J, Lunetta, Kathryn L, Pervjakova, Natalia, Chasman, Daniel I, Stolk, Lisette, Finucane, Hilary K, Sulem, Patrick, Bulik Sullivan, Brendan, Esko, Tõnu, Johnson, Andrew D, Elks, Cathy E, Franceschini, Nora, He, Chunyan, Altmaier, Elisabeth, Brody, Jennifer A, Franke, Lude L, Huffman, Jennifer E, Keller, Margaux F, Mcardle, Patrick F, Nutile, Teresa, Porcu, Eleonora, Robino, Antonietta, Rose, Lynda M, Schick, Ursula M, Smith, Jennifer A, Teumer, Alexander, Traglia, Michela, Vuckovic, Dragana, Yao, Jie, Zhao, Wei, Albrecht, Eva, Amin, Najaf, Corre, Tanguy, Hottenga, Jouke Jan, Mangino, Massimo, Smith, Albert V, Tanaka, Toshiko, Abecasis, Gonçalo R, Andrulis, Irene L, Anton Culver, Hoda, Antoniou, Antonis C, Arndt, Volker, Arnold, Alice M, Barbieri, CATERINA MARIA, Beckmann, Matthias W, Beeghly Fadiel, Alicia, Benitez, Javier, Bernstein, Leslie, Bielinski, Suzette J, Blomqvist, Carl, Boerwinkle, Eric, Bogdanova, Natalia V, Bojesen, Stig E, Bolla, Manjeet K, Borresen Dale, Anne Lise, Boutin, Thibaud S, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thoma, Burwinkel, Barbara, Campbell, Archie, Campbell, Harry, Chanock, Stephen J, Chapman, J. Ro, Chen, Yii Der Ida, Chenevix Trench, Georgia, Couch, Fergus J, Coviello, Andrea D, Cox, Angela, Czene, Kamila, Darabi, Hatef, De Vivo, Immaculata, Demerath, Ellen W, Dennis, Joe, Devilee, Peter, Dörk, Thilo, Dos Santos Silva, Isabel, Dunning, Alison M, Eicher, John D, Fasching, Peter A, Faul, Jessica D, Figueroa, Jonine, Flesch Janys, Dieter, Gandin, Ilaria, Garcia, Melissa E, García Closas, Montserrat, Giles, Graham G, Girotto, Giorgia, Goldberg, Mark S, González Neira, Anna, Goodarzi, Mark O, Grove, Megan L, Gudbjartsson, Daniel F, Guénel, Pascal, Guo, Xiuqing, Haiman, Christopher A, Hall, Per, Hamann, Ute, Henderson, Brian E, Hocking, Lynne J, Hofman, Albert, Homuth, Georg, Hooning, Maartje J, Hopper, John L, Hu, Frank B, Huang, Jinyan, Humphreys, Keith, Hunter, David J, Jakubowska, Anna, Jones, Samuel E, Kabisch, Maria, Karasik, David, Knight, Julia A, Kolcic, Ivana, Kooperberg, Charle, Kosma, Veli Matti, Kriebel, Jennifer, Kristensen, Vessela, Lambrechts, Diether, Langenberg, Claudia, Li, Jingmei, Li, Xin, Lindström, Sara, Liu, Yongmei, Luan, Jian'An, Lubinski, Jan, Mägi, Reedik, Mannermaa, Arto, Manz, Judith, Margolin, Sara, Marten, Jonathan, Martin, Nicholas G, Masciullo, Corrado, Meindl, Alfon, Michailidou, Kyriaki, Mihailov, Evelin, Milani, Lili, Milne, Roger L, Müller Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M, Nevanlinna, Heli, Neven, Patrick, Newman, Anne B, Nordestgaard, Børge G, Olson, Janet E, Padmanabhan, Sandosh, Peterlongo, Paolo, Peters, Ulrike, Petersmann, Astrid, Peto, Julian, Pharoah, Paul D. P, Pirastu, Nicola, Pirie, Ailith, Pistis, Giorgio, Polasek, Ozren, Porteous, David, Psaty, Bruce M, Pylkäs, Katri, Radice, Paolo, Raffel, Leslie J, Rivadeneira, Fernando, Rudan, Igor, Rudolph, Anja, Ruggiero, Daniela, Sala, Cinzia F, Sanna, Serena, Sawyer, Elinor J, Schlessinger, David, Schmidt, Marjanka K, Schmidt, Frank, Schmutzler, Rita K, Schoemaker, Minouk J, Scott, Robert A, Seynaeve, Caroline M, Simard, Jacque, Sorice, Rossella, Southey, Melissa C, Stöckl, Dori, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D, Thorsteinsdottir, Unnur, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Tryggvadottir, Laufey, Turner, Stephen T, Vozzi, Diego, Wang, Qin, Wellons, Melissa, Willemsen, Gonneke, Wilson, James F, Winqvist, Robert, Wolffenbuttel, Bruce B. H. R, Wright, Alan F, Yannoukakos, Drakouli, Zemunik, Tatijana, Zheng, Wei, Zygmunt, Marek, Bergmann, Sven, Boomsma, Dorret I, Buring, Julie E, Ferrucci, Luigi, Montgomery, Grant W, Gudnason, Vilmundur, Spector, Tim D, van Duijn, Cornelia M, Alizadeh, Behrooz Z, Ciullo, Marina, Crisponi, Laura, Easton, Douglas F, Gasparini, Paolo, Gieger, Christian, Harris, Tamara B, Hayward, Caroline, Kardia, Sharon L. R, Kraft, Peter, Mcknight, Barbara, Metspalu, Andre, Morrison, Alanna C, Reiner, Alex P, Ridker, Paul M, Rotter, Jerome I, Toniolo, Daniela, Uitterlinden, André G, Ulivi, Sheila, Völzke, Henry, Wareham, Nicholas J, Weir, David R, Yerges Armstrong, Laura M, Price, Alkes L, Stefansson, Kari, Visser, Jenny A, Ong, Ken K, Chang Claude, Jenny, Murabito, Joanne M, Perry, John R. B, Murray, Anna, Internal Medicine, Epidemiology, Medical Oncology, Clinical Genetics, Biological Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Lifestyle, Overweight and Diabetes, PRACTICAL Consortium, kConFab Investigators, AOCS Investigators, EPIC-InterAct Consortium, LifeLines Cohort Study, Generation, Scotland, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Lifestyle Medicine (LM), Life Course Epidemiology (LCE), Center for Liver, Digestive and Metabolic Diseases (CLDM), Stem Cell Aging Leukemia and Lymphoma (SALL), and Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET)
Subjects: Netherlands Twin Register (NTR), Aging, DNA Repair, LOCI, Genome-wide association study, BLOOD-PRESSURE, Disease, CHROMOSOMAL INSTABILITY, Bioinformatics, HOMOLOGOUS RECOMBINATION, PREMATURE OVARIAN FAILURE, Genotype, BRCA2 MUTATION CARRIERS, WIDE ASSOCIATION, Gene Regulatory Networks, NATURAL MENOPAUSE, Genetics, education.field_of_study, menopause, DDR, BODY-MASS INDEX, CELL-TYPES, BRCA1 Protein, Reproduction, BRCA1-mediated DNA repair, Age Factors, Obstetrics and Gynecology, General Medicine, Genomics, Middle Aged, 3. Good health, Menopause, Phenotype, Female, medicine.symptom, Signal Transduction, Delayed puberty, Adult, DNA repair, Population, Hypothalamus, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Lower risk, DDR, Article, Breast cancer, SDG 3 - Good Health and Well-being, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, Allele, education, Genetic association, Models, Genetic, business.industry, Genetic Variation, medicine.disease, Aging/genetics, BRCA1 Protein/genetics, Breast Neoplasms/genetics, Gene Regulatory Networks/genetics, Genetic Predisposition to Disease/genetics, Genome-Wide Association Study/methods, Genomics/methods, Hypothalamus/metabolism, Menopause/genetics, Reproduction/genetics, Signal Transduction/genetics, business, Genome-Wide Association Study
Abstract: Menopause timing has a major impact on infertility and risk of disease. Younger age at natural (nonsurgical) menopause (ANM) is associated with a higher risk of osteoporosis, cardiovascular disease, and type 2 diabetes and a lower risk of breast cancer. Late menopause is associated with a higher risk of breast cancer. It is well known that the age at which women go through menopause is partly determined by genes, but the underlying mechanisms are poorly understood. Genome-wide association studies have identified 18 common genetic variants associated with ANM. These variants explain less than 5% of the variation in ANM compared with the 21% explained by all common variants on genome-wide association study arrays. This genome-wide association study was the collaborative effort of researchers from 177 institutions worldwide. The study was designed to investigate genetic variants associated with timing of menopause among a population of approximately 70,000 women of European ancestry. A dual strategy was used to identify both common and, for the first time, low-frequency coding variants associated with ANM. The causal relationship between ANM and breast cancer was investigated using a Mendelian randomization approach. Combined analysis identified 1208 single-nucleotide polymorphisms (SNPs) of a total of approximately 2.6 million that reached the genome-wide significance threshold for association with ANM. Forty-four regions with common variants were identified; among these 44 loci were 2 rare low-frequency missense alleles of large effect. A majority of ANM SNPs were enriched in DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal relationship between delayed ANM and breast cancer risk; there was approximately 6% increase in risk per year; P = 3 × 10-14); increased risk with delayed menopause appeared to be mediated primarily by prolonged sex hormone exposure in a woman’s lifetime, not DDR mechanisms. This is the first study to confirm the link between early and late menopause and breast cancer risk using genetic information. Age at natural menopause genetic variants influence breast cancer risk primarily through variation in menopause timing. Although carrying higher numbers of ANM-increasing variants and enrichment in DDR genes are associated with a modest increase in breast cancer risk, the major mechanism for increased risk appears to be prolonged estrogen and/or progesterone exposure due to delayed menopause.
Published: 2015

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