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1. Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Author

Elinor Sawyer, Rebecca Roylance, Christos Petridis, Mark N Brook, Salpie Nowinski, Efterpi Papouli, Olivia Fletcher, Sarah Pinder, Andrew Hanby, Kelly Kohut, Patricia Gorman, Michele Caneppele, Julian Peto, Isabel Dos Santos Silva, Nichola Johnson, Ruth Swann, Miriam Dwek, Katherine-Anne Perkins, Cheryl Gillett, Richard Houlston, Gillian Ross, Paolo De Ieso, Melissa C Southey, John L Hopper, Elena Provenzano, Carmel Apicella, Jelle Wesseling, Sten Cornelissen, Renske Keeman, Peter A Fasching, Sebastian M Jud, Arif B Ekici, Matthias W Beckmann, Michael J Kerin, Federick Marme, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Therese Truong, Pierre Laurent-Puig, Pierre Kerbrat, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, Primitiva Menéndez, Javier Benitez, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Alfons Meindl, Peter Lichtner, Rita K Schmutzler, Magdalena Lochmann, Hiltrud Brauch, Hans-Peter Fischer, Yon-Dschun Ko, GENICA Network, Heli Nevanlinna, Taru A Muranen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M Hartikainen, Georgia Chenevix-Trench, KConFab Investigators, Diether Lambrechts, Caroline Weltens, Erik Van Limbergen, Sigrid Hatse, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Graham G Giles, Gianluca Severi, Laura Baglietto, Catriona A McLean, Christopher A Haiman, Brian E Henderson, Fredrick Schumacher, Loic Le Marchand, Jacques Simard, Mark S Goldberg, France Labrèche, Martine Dumont, Vessela Kristensen, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Saila Kauppila, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Peter Devillee, Rob A E M Tollenaar, Caroline M Seynaeve, Mieke Kriege, Jonine Figueroa, Stephen J Chanock, Mark E Sherman, Maartje J Hooning, Antoinette Hollestelle, Ans M W van den Ouweland, Carolien H M van Deurzen, Jingmei Li, Kamila Czene, Keith Humphreys, Angela Cox, Simon S Cross, Malcolm W R Reed, Mitul Shah, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Anthony Swerdlow, Alan Ashworth, Nicholas Orr, Minouk Schoemaker, Fergus J Couch, Emily Hallberg, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Daniel C Tessier, Daniel Vincent, Francois Bacot, Manjeet K Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Alison M Dunning, Per Hall, Doug Easton, Paul Pharoah, Marjanka K Schmidt, Ian Tomlinson, and Montserrat Garcia-Closas

Subjects
Genetics, QH426-470
Abstract

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P

Published
2014
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2. Comparison of 6q25 breast cancer hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author

Rebecca Hein, Melanie Maranian, John L Hopper, Miroslaw K Kapuscinski, Melissa C Southey, Daniel J Park, Marjanka K Schmidt, Annegien Broeks, Frans B L Hogervorst, H Bas Bueno-de-Mesquita, Kenneth R Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A Fasching, Alexander Hein, Arif B Ekici, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E Bojesen, Børge G Nordestgaard, Henrik Flyger, Roger L Milne, Jose Ignacio Arias Perez, M Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R Bartram, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V Bogdanova, Iosif V Zalutsky, Natalia N Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, Kconfab Investigators, AOCS Group, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J Couch, Janet E Olson, Xianshu Wang, Zachary Fredericksen, Graham G Giles, Laura Baglietto, Catriona A McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L Andrulis, Julia A Knight, Gord Glendon, Anna Marie Mulligan, Jonine D Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E Sherman, Maartje Hooning, John W M Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W Brock, Simon S Cross, Malcolm W R Reed, Shahana Ahmed, Maya Ghoussaini, Paul D P Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A Newcomb, Linda Titus, Kathleen M Egan, Georgia Chenevix-Trench, Antonis C Antoniou, Manjeet K Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F Easton, and Alison M Dunning

Subjects
Medicine, Science
Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.

Published
2012
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3. Correction: Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC).

Author

Rebecca Hein, Melanie Maranian, John L. Hopper, Miroslaw K. Kapuscinski, Melissa C. Southey, Daniel J. Park, Marjanka K. Schmidt, Annegien Broeks, Frans B. L. Hogervorst, H. Bas Bueno-de-Mesquit, Kenneth R. Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E. Bojesen, Børge G. Nordestgaard, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, M. Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, Shan Wang-Gohrke, Thilo Dörk, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomäki, Carl Blomqvist, Natalia V. Bogdanova, Iosif V. Zalutsky, Natalia N. Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen, Xiaoqing Chen, Jonathan Beesley, kConFab Investigators, Diether Lambrechts, Hui Zhao, Patrick Neven, Hans Wildiers, Stefan Nickels, Dieter Flesch-Janys, Paolo Radice, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Graham G. Giles, Laura Baglietto, Catriona A. McLean, Gianluca Severi, Kenneth Offit, Mark Robson, Mia M. Gaudet, Joseph Vijai, Grethe Grenaker Alnæs, Vessela Kristensen, Anne-Lise Børresen-Dale, Esther M. John, Alexander Miron, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Jonine D. Figueroa, Montserrat García-Closas, Jolanta Lissowska, Mark E. Sherman, Maartje Hooning, John W. M. Martens, Caroline Seynaeve, Margriet Collée, Per Hall, Keith Humpreys, Kamila Czene, Jianjun Liu, Angela Cox, Ian W. Brock, Simon S. Cross, Malcolm W. R. Reed, Shahana Ahmed, Maya Ghoussaini, Paul DP. Pharoah, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Anna Jakubowska, Katarzyna Jaworska, Katarzyna Durda, Elżbieta Złowocka, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Chen-Yang Shen, Jyh-Cherng Yu, Huan-Ming Hsu, Ming-Feng Hou, Nick Orr, Minouk Schoemaker, Alan Ashworth, Anthony Swerdlow, Amy Trentham-Dietz, Polly A. Newcomb, Linda Titus, Kathleen M. Egan, Georgia Chenevix-Trench, Antonis C. Antoniou, Manjeet K. Humphreys, Jonathan Morrison, Jenny Chang-Claude, Douglas F. Easton, and Alison M. Dunning

Subjects
Medicine, Science
Published
2012
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4. What to do when the parathyroid gland is not found during a transcervical exploration?

Author

Georgina Planas, Mauro Guarino, José Belda, Esther Cladellas, Elisabeth Martínez-Téllez, Antonio Moral, Jose Ignacio Arias Perez, and Juan Carlos Trujillo-Reyes

Subjects
Pulmonary and Respiratory Medicine, Adenoma, medicine.medical_specialty, medicine.medical_treatment, Thoracic, Video-assisted thoracic surgery, Parathyroid hormone, 030218 nuclear medicine & medical imaging, Parathyroid Glands, 03 medical and health sciences, Basal (phylogenetics), 0302 clinical medicine, Ectopic parathyroid, medicine, Humans, Parathyroid adenoma, Parathyroidectomy, business.industry, Mediastinum, medicine.disease, Thymectomy, Parathormone, Surgery, Mediastinal disease, medicine.anatomical_structure, Parathyroid Neoplasms, 030220 oncology & carcinogenesis, Parathyroid gland, Cardiology and Cardiovascular Medicine, business, Mediastinal Diseases, Primary hyperparathyroidism
Abstract

The most frequent cause of suboptimal results in a parathyroid adenoma resection is an ectopic location, mainly in the anterior mediastinum. These cases may not always be resected through a traditional cervical access. We present 2 cases of primary hyperparathyroidism who underwent an unsuccessful bilateral cervical exploration due to parathyroid tissue located inside the thymic gland. A video-assisted thoracoscopic surgery thymectomy with intraoperative determination of blood parathormone levels was performed. A 50% reduction of intraoperatory parathyroid hormone blood from the highest basal level at 5 and 10 min after resection was obtained. Final pathological results showed an intra-thymic parathyroid adenoma in the first patient and an intra-thymic focus of parathyroid hyperplasia in the second patient. In conclusion, video-assisted thoracoscopic surgery thymectomy could be the optimal approach to resect ectopic parathyroid adenomas located in the anterior mediastinum.

Published
2020

5. LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies

Author

Eugenia Mato, Francisco Blanco-Vaca, Rosa Corcoy, Giovanna Revilla, Lídia Cedó, Srivinasa T. Reddy, Antonio Moral, Jose Ignacio Arias Perez, Mireia Tondo, Joan Carles Escolà-Gil, Enrique Lerma, and Victoria Fuste

Subjects
0301 basic medicine, Cancer Research, HDL, Carcinogenesis, LDL, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Endocrine Gland Neoplasms, medicine, Animals, Humans, Scavenger receptor, Thyroid cancer, Cancer, Cholesterol, business.industry, Cholesterol, HDL, Cholesterol, LDL, medicine.disease, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, LDL receptor, Cancer research, lipids (amino acids, peptides, and proteins), Endocrine, Ovarian cancer, business, Lipoprotein, Hormone
Abstract

Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies.

Published
2020

6. 18F-Fluorocholine PET/CT in patients with primary Hyperparathyroidism and negative or inconclusive 99mTc-MIBI parathyroid scan: clinico-pathological correlations

Author

Inka Miñambres, Eulalia Ballester, Antonio Moral, Montserrat Estorch, Jose Ignacio Arias Perez, Montserrat Clos, Judit Amigo Farran, Ana Chico, and Diego Alfonso Lopez

Subjects
medicine.medical_specialty, PET-CT, business.industry, medicine, Clinico pathological, In patient, Radiology, medicine.disease, business, 18F-fluorocholine, Primary hyperparathyroidism, Parathyroid scan
Published
2019

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

Author

Wing-Yee Lo, Dhanya Ramachandran, Christos Petridis, Fernando Salvador Moreno, Tongguang Cheng, Bernardo Bonanni, Ann Smeets, Susan E. Hankinson, Caroline Seynaeve, Suet-Feung Chin, Vessela N. Kristensen, Christopher G. Scott, Javier Benitez, William T. Newman, Brigitte Rack, Marjanka K. Schmidt, Diether Lambrechts, Alfons Meindl, Maria Escala-Garcia, Hoda Anton-Culver, Veli-Matti Kosma, Nadege Presneau, Daniel F. Schmidt, Douglas F. Easton, Ans M.W. van den Ouweland, Emmanouil Saloustros, Antoinette Hollestelle, Darya Prokofieva, Elinor J. Sawyer, Louise A. Brinton, Manuela Gago-Dominguez, Minouk J. Schoemaker, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Eva Galle, Catriona McLean, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Per Hall, Jaana M. Hartikainen, Leslie Bernstein, Jose Ignacio Arias Perez, Flavio Lejbkowicz, Qi Guo, Brian D. Carter, Martha S. Linet, Fredrick R. Schumacher, Yan Zhang, Mikael Eriksson, Hiltrud Brauch, Janet A. Dunn, Gord Glendon, Bernd Holleczek, William J. Tapper, Marike Gabrielson, Keith Humphreys, Rodney J. Scott, Tabea Kühl, Lorraine Durcan, David J. Hunter, Pascal Guénel, Tom Maishman, Mary B. Daly, Rami Nassir, Andreas Schneeweiss, Kamila Czene, Jonine D. Figueroa, Grethe I. Grenaker Alnæs, Julia A. Knight, Angel Carracedo, Susan M. Gapstur, Manuel R. Teixeira, Guanmengqian Huang, Paul L. Auer, Sara Y. Brucker, Johanna I. Kiiski, Adam R. Brentnall, Simon S. Cross, Joe Dennis, Nicola Miller, Walter C. Willett, Melissa C. Southey, Christoph Engel, Niclas Håkansson, Diana Eccles, John L. Hopper, Elaine F. Harkness, Audrey Y. Jung, Trinidad Caldés, Steven N. Hart, Sara Lindström, Michael P. Lux, Julie Lecarpentier, Lian Li, Robert Winqvist, Peter Kraft, Stephen J. Chanock, Thilo Dörk, Melanie Maierthaler, Rudolf Kaaks, Angela Cox, Maartje J. Hooning, José A. García-Sáenz, Christi J. van Asperen, Mervi Grip, Enes Makalic, Mia M. Gaudet, David E. Goldgar, Ross L. Prentice, Carolina Ellberg, Sune F. Nielsen, Federico Canzian, Rebecca Roylance, Aline Talhouk, Vassilios Georgoulias, Eunjung Lee, Siranoush Manoukian, Sara Margolin, Paul D.P. Pharoah, Hedy S. Rennert, Mitul Shah, Matthias W. Beckmann, Anthony Howell, Anne Lise Børresen-Dale, Christopher A. Haiman, V. Shane Pankratz, Anna González-Neira, Kathrin Thöne, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Ute Krüger, Mehdi Manoochehri, Arja Jukkola-Vuorinen, Loic Le Marchand, Katri Pylkäs, Peter Hillemanns, Dieter Flesch-Janys, Volker Arndt, Peter A. Fasching, Christine L. Clarke, Louise Hiller, Eric Hahnen, Jan Lubinski, Jose E. Castelao, Roger L. Milne, Linetta B. Koppert, Peter Devilee, Rob A. E. M. Tollenaar, Ian W. Brock, Claire Mulot, Mila Pinchev, Carlos Caldas, Michael Untch, Gadi Rennert, Aaron D. Norman, Per Broberg, Anthony J. Swerdlow, Lothar Haeberle, Heli Nevanlinna, Arto Mannermaa, Irene L. Andrulis, Angela George, Montserrat Garcia-Closas, Jolanta Lissowska, Jonathan Beesley, Paolo Peterlongo, Cari M. Kitahara, Rulla M. Tamimi, Annika Lindblom, Sabine Behrens, Nick Orr, David G. Cox, D. Gareth Evans, Jacques Simard, Diana Torres, Constance Turman, Celine M. Vachon, Qin Wang, Hans-Ulrich Ulmer, Maria Kabisch, Maria Elena Martinez, Paolo Radice, Maria Tengström, Dimitrios Mavroudis, Jean Abraham, Helena M. Earl, Alice S. Whittemore, Hermann Brenner, Rita K. Schmutzler, Børge G. Nordestgaard, Barbara Burwinkel, Michael Jones, Esther M. John, Patricia Harrington, Daniele Campa, Elke M. van Veen, Clara Pérez-Barrios, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Elza Khusnutdinova, Michael J. Kerin, Miriam Dwek, Sibylle Loibl, Manjeet K. Bolla, Carl Blomqvist, Sander Canisius, Graham G. Giles, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Emilie Cordina-Duverger, Arif B. Ekici, Yon-Dschun Ko, Pooja Middha, Alison M. Dunning, Katarzyna Kaczmarek, Bram Boeckx, Mary Beth Terry, Jenny Chang-Claude, Karoliona Prajzendanc, Renske Keeman, Camilla Wendt, Atocha Romero, Stig E. Bojesen, Robert J. MacInnis, Clare Turnbull, Lukas Schwentner, Xiaohong R. Yang, Henrik Flyger, Håkan Olsson, Wolfgang Janni, Sofia Khan, Clinicum, Department of Oncology, University of Helsinki, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, HUS Comprehensive Cancer Center, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, Cancer Research, PROGNOSIS, Genome-wide association study, PATHWAY, Prognostic markers, Breast cancer, 0302 clinical medicine, Epidemiology of cancer, Cancer genetics, RISK, Hazard ratio, SINGLE-NUCLEOTIDE POLYMORPHISMS, GENETIC-VARIATION, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, SURVIVAL, TUMOR SUBTYPES, Female, Chromosomes, Human, Pair 7, EXPRESSION, medicine.medical_specialty, CLINICAL-OUTCOMES, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Article, White People, NBCS Collaborators, RC0254, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, Proportional Hazards Models, business.industry, Proportional hazards model, Genetic Variation, Cancer, Bayes Theorem, medicine.disease, business, Genome-Wide Association Study
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

8. Cholesterol and 27-hydroxycholesterol promote thyroid carcinoma aggressiveness

Author

Giovanna Revilla, Ana Cenarro, Eugenia Mato, Gerard Sabé, Victoria Fuste, Rosa Corcoy, Cintia Gonzalez, David Santos, Annabel García-León, Marcelo Magalhães, Antonio Moral, Lucía Baila-Rueda, Jose Ignacio Arias Perez, Roman Blanco, Alberto de Leiva, Joan Carles Escolà-Gil, Enrique Lerma, Manuel dos Santos Faria, and Monica de Pablo Pons

Subjects
Male, 0301 basic medicine, Apolipoprotein B, endocrine system diseases, lcsh:Medicine, Thyroid Carcinoma, Anaplastic, Phosphatidylinositol 3-Kinases, chemistry.chemical_compound, 0302 clinical medicine, Cell Movement, lcsh:Science, Aged, 80 and over, Multidisciplinary, biology, TOR Serine-Threonine Kinases, Thyroid, Middle Aged, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 27-Hydroxycholesterol, Cholestanetriol 26-Monooxygenase, Female, lipids (amino acids, peptides, and proteins), Adult, Adolescent, MAP Kinase Signaling System, Lipoproteins, Cytochrome P450 Family 7, Article, Thyroid cancer, Thyroid carcinoma, Young Adult, 03 medical and health sciences, Cell Line, Tumor, Biomarkers, Tumor, medicine, Humans, Thyroid Neoplasms, Aged, Cell Proliferation, business.industry, Cholesterol, Endometrial cancer, lcsh:R, Cholesterol, LDL, medicine.disease, Carcinoma, Papillary, Hydroxycholesterols, 030104 developmental biology, Receptors, LDL, chemistry, Steroid Hydroxylases, LDL receptor, biology.protein, Cancer research, lcsh:Q, Hydroxymethylglutaryl CoA Reductases, business, 030217 neurology & neurosurgery, Lipoprotein
Abstract

Cholesterol mediates its proliferative and metastatic effects via the metabolite 27-hydroxycholesterol (27-HC), at least in breast and endometrial cancer. We determined the serum lipoprotein profile, intratumoral cholesterol and 27-HC levels in a cohort of patients with well-differentiated papillary thyroid carcinoma (PTC; low/intermediate and high risk), advanced thyroid cancers (poorly differentiated, PDTC and anaplastic thyroid carcinoma, ATC) and benign thyroid tumors, as well as the expression of genes involved in cholesterol metabolism. We investigated the gene expression profile, cellular proliferation, and migration in Nthy-ori 3.1 and CAL-62 cell lines loaded with human low-density lipoprotein (LDL). Patients with more aggressive tumors (high-risk PTC and PDTC/ATC) showed a decrease in blood LDL cholesterol and apolipoprotein B. These changes were associated with an increase in the expression of the thyroid’s LDL receptor, whereas 3-hydroxy-3-methylglutaryl-CoA reductase and 25-hydroxycholesterol 7-alpha-hydroxylase were downregulated, with an intratumoral increase of the 27-HC metabolite. Furthermore, LDL promoted proliferation in both the Nthy-ori 3.1 and CAL-62 thyroid cellular models, but only in ATC cells was its cellular migration increased significantly. We conclude that cholesterol and intratumoral accumulation of 27-HC promote the aggressive behavior process of PTC. Targeting cholesterol metabolism could be a new therapeutic strategy in thyroid tumors with poor prognosis.

Published
2019

9. Publisher Correction: Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation

Author

Maya Ghoussaini, Stacey L. Edwards, Kyriaki Michailidou, Silje Nord, Richard Cowper-Sal·lari, Kinjal Desai, Siddhartha Kar, Kristine M. Hillman, Susanne Kaufmann, Dylan M. Glubb, Jonathan Beesley, Joe Dennis, Manjeet K. Bolla, Qin Wang, Ed Dicks, Qi Guo, Marjanka K. Schmidt, Mitul Shah, Robert Luben, Judith Brown, Kamila Czene, Hatef Darabi, Mikael Eriksson, Daniel Klevebring, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Diether Lambrechts, Bernard Thienpont, Patrick Neven, Hans Wildiers, Annegien Broeks, Laura J. Van’t Veer, Emiel J. Th Rutgers, Fergus J. Couch, Janet E. Olson, Emily Hallberg, Celine Vachon, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Julian Peto, Isabel dos-Santos-Silva, Lorna Gibson, Heli Nevanlinna, Taru A. Muranen, Kristiina Aittomäki, Carl Blomqvist, Per Hall, Jingmei Li, Jianjun Liu, Keith Humphreys, Daehee Kang, Ji-Yeob Choi, Sue K. Park, Dong-Young Noh, Keitaro Matsuo, Hidemi Ito, Hiroji Iwata, Yasushi Yatabe, Pascal Guénel, Thérèse Truong, Florence Menegaux, Marie Sanchez, Barbara Burwinkel, Frederik Marme, Andreas Schneeweiss, Christof Sohn, Anna H. Wu, Chiu-chen Tseng, David Van Den Berg, Daniel O. Stram, Javier Benitez, M Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Xiao-Ou Shu, Wei Lu, Yu-Tang Gao, Qiuyin Cai, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Sandrine Tchatchou, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Annika Lindblom, Sara Margolin, Soo Hwang Teo, Cheng Har Yip, Daphne S. C. Lee, Tien Y. Wong, Maartje J. Hooning, John W. M. Martens, J. Margriet Collée, Carolien H. M. van Deurzen, John L. Hopper, Melissa C. Southey, Helen Tsimiklis, Miroslav K. Kapuscinski, Chen-Yang Shen, Pei-Ei Wu, Jyh-Cherng Yu, Shou-Tung Chen, Grethe Grenaker Alnæs, Anne-Lise Borresen-Dale, Graham G. Giles, Roger L. Milne, Catriona McLean, Kenneth Muir, Artitaya Lophatananon, Sarah Stewart-Brown, Pornthep Siriwanarangsan, Mikael Hartman, Hui Miao, Shaik Ahmad Bin Syed Buhari, Yik Ying Teo, Peter A. Fasching, Lothar Haeberle, Arif B. Ekici, Matthias W. Beckmann, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Christa Stegmaier, Anthony Swerdlow, Alan Ashworth, Nick Orr, Minouk J. Schoemaker, Montserrat García-Closas, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Jacques Simard, Mark S. Goldberg, France Labrèche, Martine Dumont, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Koto, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Sara Volorio, Thilo Dörk, Natalia V. Bogdanova, Sonja Helbig, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Peter Devilee, Robert A. E. M. Tollenaar, Caroline Seynaeve, Christi J. Van Asperen, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Susan Slager, Amanda E. Toland, Christine B. Ambrosone, Drakoulis Yannoukakos, Suleeporn Sangrajrang, Valerie Gaborieau, Paul Brennan, James McKay, Ute Hamann, Diana Torres, Wei Zheng, Jirong Long, Hoda Anton-Culver, Susan L. Neuhausen, Craig Luccarini, Caroline Baynes, Shahana Ahmed, Mel Maranian, Catherine S. Healey, Anna González-Neira, Guillermo Pita, M Rosario Alonso, Nuria Álvarez, Daniel Herrero, Daniel C. Tessier, Daniel Vincent, Francois Bacot, Ines de Santiago, Jason Carroll, Carlos Caldas, Melissa A. Brown, Mathieu Lupien, Vessela N. Kristensen, Paul D. P. Pharoah, Georgia Chenevix-Trench, Juliet D. French, Douglas F. Easton, and Alison M. Dunning

Subjects
Oncology, medicine.medical_specialty, Multidisciplinary, business.industry, Published Erratum, MEDLINE, General Physics and Astronomy, Locus (genetics), General Chemistry, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, medicine, 030212 general & internal medicine, business
Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology., Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Published
2018

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

Author

Vesa Kataja, Aida Karina Dieffenbach, Chia-Ni Hsiung, Catherine S. Healey, Gie Hooi Tan, Soo Hwang Teo, Domenico Palli, Frederik Marme, Katri Pylkäs, Roger L. Milne, Jaana M. Hartikainen, Gord Glendon, Susan L. Slager, Chen-Yang Shen, Fredrick R. Schumacher, Daniel F. Schmidt, Suleeporn Sangrajrang, Kee Seng Chia, Lorna Gibson, Pascal Guénel, Alice S. Whittemore, Jenny Chang-Claude, Yu Tang Gao, Hidemi Ito, Simon S. Cross, Sofia Khan, Marie Sanchez, Daniel Vincent, Daniel Herrero, Nicola Miller, Antoinette Hollestelle, Caroline M. Seynaeve, Christopher A. Haiman, Hermann Brenner, Kay-Tee Khaw, Loris Bernard, Habibul Ahsan, Melissa C. Southey, David Van Den Berg, Martha J. Shrubsole, Daniel O. Stram, William Blot, Mel Maranian, Robert Winqvist, Keitaro Matsuo, John W. M. Martens, Heli Nevanlinna, Mia M. Gaudet, Anna Jakubowska, Christine D. Berg, Paul D.P. Pharoah, Jacques Simard, Manjeet K. Bolla, Dieter Flesch-Janys, Mark S. Goldberg, Paul Brennan, Ching Wan Chan, Sune F. Nielsen, Sara Lindström, Mitul Shah, Matthias W. Beckmann, Craig Luccarini, Jonathan Beesley, Kyriaki Michailidou, Paolo Peterlongo, Marc J. Gunter, Anna González-Neira, Ji Yeob Choi, Per Hall, Sarah Stewart-Brown, Keith Humphreys, Hui Cai, Kathleen E. Malone, Elinor J. Sawyer, Louise A. Brinton, Marjanka K. Schmidt, Xiao-Ou Shu, Barbara Perkins, Lotte Maxild Mortensen, Chiu-Chen Tseng, Hanne Meijers-Heijboer, Minouk J. Schoemaker, Keun-Young Yoo, Julia A. Knight, Alan Ashworth, Stig E. Bojesen, Kamila Czene, Artitaya Lophatananon, Graham G. Giles, S. Ahmed, Kazuo Tajima, Douglas F. Easton, Maria Kabisch, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Irene L. Andrulis, Clare Turnbull, Caroline Baynes, Christine B. Ambrosone, Jan Lubinski, Muriel A. Adank, A. Meindl, Taru A. Muranen, Siranoush Manoukian, Susan M. Gapstur, Natalia Bogdanova, Alexander Hein, Annika Lindblom, Nazneen Rahman, Annegien Broeks, Lothar Haeberle, Federico Canzian, G Pita, Ming-Feng Hou, Hiroji Iwata, Drakoulis Yannoukakos, Diana Torres, Vessela N. Kristensen, Peter Devilee, Qiuyin Cai, Christi J Asperen, John L. Hopper, Diether Lambrechts, Michael Lush, Hans Wildiers, Joe Dennis, Sandra L. Halverson, Carl Blomqvist, Erik Van Limbergen, Malin Sund, Daehee Kang, Grethe I. Grenaker Alnæs, Marilie D. Gammon, Ursula Eilber, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Kirsimari Aaltonen, Olivia Fletcher, Jonine D. Figueroa, Angela Cox, Pei Ei Wu, Maartje J. Hooning, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Malcolm W.R. Reed, Emily Hallberg, Sara Margolin, Volker Arndt, Montserrat Garcia-Closas, Francois Bacot, Rita K. Schmutzler, Julian Peto, David J. Hunter, Thomas Brüning, Katarzyna Jaworska, Christof Sohn, Børge G. Nordestgaard, Enes Makalic, Hatef Darabi, Barbara Burwinkel, Petra P.H. Peeters, J. Margriet Collée, Rongxi Yang, Robert N. Hoover, Eiliv Lund, Fergus J. Couch, Ute Hamann, Jirong Long, Wei Zheng, Sabine Behrens, Giske Ursin, Muhammad G. Kibriya, Claire Mulot, Laure Dossus, Helen Tsimiklis, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Alison M. Dunning, Lisa B. Signorello, Valerie Gaborieau, Kenneth Muir, Anthony J. Swerdlow, Javier Benitez, Judith S. Brand, Sander Canisius, Hoda Anton-Culver, Veli-Matti Kosma, Thilo Dörk, Sten Cornelissen, Christa Stegmaier, Cheng Har Yip, Brian E. Henderson, Harald Surowy, Jingmei Li, Nur Aishah Taib, W. Ryan Diver, Carmel Apicella, Janet E. Olson, Kristiina Aittomäki, Celine M. Vachon, Regina M. Santella, Dimitrios Trichopoulos, Jianjun Liu, Nick Orr, Martine Dumont, Christian Sutter, Sue K. Park, Mikael Hartman, Susan L. Neuhausen, Hui Miao, M. Pilar Zamora, Anna H. Wu, Rob B. van der Luijt, Isabel dos-Santos-Silva, Graham Casey, Henrik Flyger, M. Rosario Alonso, Nuria Álvarez, Michael J. Kerin, Loic Le Marchand, Jose Ignacio Arias Perez, Mikael Eriksson, Esther M. John, Quinten Waisfisz, Qin Wang, Daniel C. Tessier, Paolo Radice, Robert A.E.M. Tollenaar, James McKay, Silje Nord, Hiltrud Brauch, José María Huerta, Stephen J. Chanock, Mervi Grip, Patrick Neven, Senno Verhoef, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Cardiothoracic Surgery, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, and CCA - Oncogenesis

Subjects
Breast Neoplasms, Single-nucleotide polymorphism, Genome-wide association study, Biology, Research Support, Polymorphism, Single Nucleotide, N.I.H, Cohort Studies, brca1, Breast cancer, Research Support, N.I.H., Extramural, Meta-Analysis as Topic, SDG 3 - Good Health and Well-being, common variants, Journal Article, estrogen, chek2-asterisk-1100delc, Genetics, medicine, Humans, Genetic Predisposition to Disease, 1000 Genomes Project, Non-U.S. Gov't, genotype imputation, risk, Genetic association, Research Support, Non-U.S. Gov't, Chromatin binding, Extramural, Cancer, Microarray Analysis, confer susceptibility, medicine.disease, 3. Good health, ovarian-cancer, Genetic Loci, Case-Control Studies, alleles, Female, Imputation (genetics), Genome-Wide Association Study, metaanalysis
Abstract

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1. ispartof: Nature Genetics vol:47 issue:4 pages:373-80 ispartof: location:United States status: published

Published
2015

11. Performance of automated scoring of ER, PR, HER2, CK5/6 and EGFR in breast cancer tissue microarrays in the Breast Cancer Association Consortium

Author

Fiona M. Blows, Sarah-Jane Dawson, Jelle Wesseling, Ian W. Brock, William J. Howat, Wilma E. Mesker, Veli-Matti Kosma, Penny Coulson, Leigh-Anne McDuffus, Rainer Fagerholm, Sarah E Pinder, Carolien H.M. van Deurzen, Angela Cox, Lorna Morris, Malcolm W.R. Reed, Arto Mannermaa, Louise Jones, Carl Blomqvist, Reijo Sironen, Daniel W. Visscher, Vesa Kataja, Annegien Broeks, Janet E. Olson, Simon S. Cross, Patrycja Gazinska, Mark E. Sherman, Marjanka K. Schmidt, Joyce Sanders, Manjeet K. Bolla, Jonine D. Figueroa, Caroline M. Seyaneve, Paul D.P. Pharoah, Elena Provenzano, Douglas F. Easton, Päivi Heikkilä, Mark N. Brook, Elinor J. Sawyer, Jose Ignacio Arias Perez, Javier Benítez, Heli Nevanlinna, Montserrat Garcia-Closas, Peter Devillee, Jolanta Lissowska, Primitiva Menéndez, Carlos Caldas, Louise A. Brinton, Nicola Johnson, Jodi Miller, Frances Daley, Fergus J. Couch, H. Raza Ali, and Antoinette Hollestelle

Subjects
Oncology, medicine.medical_specialty, Pathology, Estrogen receptor, Breast tumor, Pathology and Forensic Medicine, 03 medical and health sciences, Cytokeratin, 0302 clinical medicine, Breast cancer, Internal medicine, Progesterone receptor, medicine, 030212 general & internal medicine, Epidermal growth factor receptor, 030304 developmental biology, 0303 health sciences, Tissue microarray, biology, business.industry, Digital pathology, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, 030221 ophthalmology & optometry, biology.protein, Immunohistochemistry, business
Abstract

Breast cancer risk factors and clinical outcomes vary by tumour marker expression. However, individual studies often lack the power required to assess these relationships, and large-scale analyses are limited by the need for high throughput, standardized scoring methods. To address these limitations, we assessed whether automated image analysis of immunohistochemically stained tissue microarrays can permit rapid, standardized scoring of tumour markers from multiple studies. Tissue microarray sections prepared in nine studies containing 20 263 cores from 8267 breast cancers stained for two nuclear (oestrogen receptor, progesterone receptor), two membranous (human epidermal growth factor receptor 2 and epidermal growth factor receptor) and one cytoplasmic (cytokeratin 5/6) marker were scanned as digital images. Automated algorithms were used to score markers in tumour cells using the Ariol system. We compared automated scores against visual reads, and their associations with breast cancer survival. Approximately 65-70% of tissue microarray cores were satisfactory for scoring. Among satisfactory cores, agreement between dichotomous automated and visual scores was highest for oestrogen receptor (Kappa = 0.76), followed by human epidermal growth factor receptor 2 (Kappa = 0.69) and progesterone receptor (Kappa = 0.67). Automated quantitative scores for these markers were associated with hazard ratios for breast cancer mortality in a dose-response manner. Considering visual scores of epidermal growth factor receptor or cytokeratin 5/6 as the reference, automated scoring achieved excellent negative predictive value (96-98%), but yielded many false positives (positive predictive value = 30-32%). For all markers, we observed substantial heterogeneity in automated scoring performance across tissue microarrays. Automated analysis is a potentially useful tool for large-scale, quantitative scoring of immunohistochemically stained tissue microarrays available in consortia. However, continued optimization, rigorous marker-specific quality control measures and standardization of tissue microarray designs, staining and scoring protocols is needed to enhance results.

Published
2014

12. Association analysis identifies 65 new breast cancer risk loci

Author

Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P

Published
2017

13. Investigation of gene-environment interactions between 47 newly identified breast cancer susceptibility loci and environmental risk factors

Author

Manuela Gago-Dominguez, Catriona McLean, Georgia Chenevix-Trench, Malcolm W.R. Reed, Doug Easton, Ellen G. Engelhardt, Keith Humphreys, Judith S. Brand, Laura Baglietto, Sune F. Nielsen, Stephen J. Chanock, Børge G. Nordestgaard, Qin Wang, Simon S. Cross, Arif B. Ekici, Yon-Dschun Ko, Jolanta Lissowska, A.K. Dieffenbach, Javier Benitez, Montserrat Garcia-Closas, Thomas Brüning, Henrik Flyger, Betül T. Yesilyurt, Vesa Kataja, Lothar Häberle, Fergus J. Couch, Jenny Chang-Claude, Dieter Flesch-Janys, Veli-Matti Kosma, Manjeet K. Bolla, Celine M. Vachon, Florence Menegaux, Giuseppe Floris, John L. Hopper, Christa Stegmaier, J. Esteban Castelao, Stig E. Bojesen, Peter A. Fasching, Hannah Munday, Mitul Shah, Matthias W. Beckmann, Jose Ignacio Arias Perez, Elena Provenzano, Mikael Eriksson, Diether Lambrechts, Alison M. Dunning, Marjanka K. Schmidt, Sabine Behrens, Jaana M. Hartikainen, Melissa C. Southey, Gord Glendon, Anthony J. Swerdlow, Emilie Cordina-Duverger, Ursula Eilber, Emiel J. Th. Rutgers, Paul D.P. Pharoah, Angela Cox, Volker Arndt, Karin Leunen, Pascal Guénel, Minouk J. Schoemaker, Jingmei Li, Carmel Apicella, Annegien Broeks, María Dolores Torres, Mark E. Sherman, Irene L. Andrulis, Emily Hallberg, Janet E. Olson, Roger L. Milne, Joe Dennis, Nick Orr, Ute Hamann, Hatef Darabi, Amanda B. Spurdle, Kamila Czene, Anja Rudolph, Arto Mannermaa, Anna González-Neira, Thérèse Truong, Anna Marie Mulligan, Per Hall, Hermann Brenner, Julia A. Knight, Petra Seibold, Alan Ashworth, Graham G. Giles, and Angel Carracedo

Subjects
Oncology, Genetics, Cancer Research, medicine.medical_specialty, Single-nucleotide polymorphism, Genome-wide association study, Biology, medicine.disease, Breast cancer, Polymorphism (computer science), Internal medicine, medicine, Genetic predisposition, SNP, Risk factor, Gene–environment interaction
Abstract

A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint )

Published
2014

14. Identification of new genetic susceptibility loci for breast cancer through consideration of gene-environment interactions

Author

Pascal Guénel, Gord Glendon, Roger L. Milne, Celine M. Vachon, Kamila Czene, Núria Malats, Jaana M. Hartikainen, Georgia Chenevix-Trench, Per Hall, Hermann Brenner, Gianluca Severi, Alexandra J. van den Broek, Jonine D. Figueroa, Julia A. Knight, Patrick Neven, Petra Seibold, Alan Ashworth, Thérèse Truong, Sabine Behrens, John L. Hopper, Anna Marie Mulligan, Jose Ignacio Arias Perez, Marjanka K. Schmidt, Javier Benitez, Femke Atsma, Olivia Fletcher, Irene L. Andrulis, Jolanta Lissowska, Anja Schoeps, Amanda B. Spurdle, Peter A. Fasching, Isabel dos Santos Silva, Lothar Häberle, Diether Lambrechts, Aida Karina Dieffenbach, Janet E. Olson, Anja Rudolph, Hiltrud Brauch, Florence Menegaux, Arto Mannermaa, Fergus J. Couch, Ute Hamann, Stephen J. Chanock, Nick Orr, Veli-Matti Kosma, Anthony J. Swerdlow, Martine Dumont, Laura Baglietto, Linde M. Braaf, Vesa Kataja, Dan Connley, Nichola Johnson, Montserrat Garcia-Closas, Kristen S. Purrington, Jacques Simard, Hans Wildiers, Jingmei Li, Helen Cramp, Angela Cox, Daniel F. Schmidt, Volker Arndt, Enes Makalic, Hatef Darabi, Julian Peto, Christa Stegmaier, Børge G. Nordestgaard, Arif B. Ekici, Matthieu Moisse, Alison M. Dunning, Michael Jones, Yon-Dschun Ko, Graham G. Giles, Emilie Cordina-Duverger, Stig E. Bojesen, Jenny Chang-Claude, Dieter Flesch-Janys, Matthias W. Beckmann, Melissa C. Southey, Paul D.P. Pharoah, Henrik Flyger, and Douglas F. Easton

Subjects
Aging, Linkage disequilibrium, Chromosomes, Human, Pair 21, Epidemiology, Linkage Disequilibrium, Body Mass Index, breast cancer risk, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Gene–environment interaction, Genetics (clinical), Cancer, 2. Zero hunger, Genetics, 0303 health sciences, Research Support, Non-U.S. Gov't, Confounding, Case-control study, Single Nucleotide, Middle Aged, 3. Good health, Postmenopause, Parity, 030220 oncology & carcinogenesis, Public Health and Health Services, Chromosomes, Human, Pair 6, Female, Pair 6, Body mass index, Breast cancer risk, Gene-environment interaction, Polymorphisms, Adolescent, Body Height, Breast Neoplasms, European Continental Ancestry Group, Genetic Loci, Genetic Predisposition to Disease, Humans, Menarche, Polymorphism, Single Nucleotide, Gene-Environment Interaction, Human, case-control study, Single-nucleotide polymorphism, Biology, Population stratification, Article, White People, Chromosomes, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, Clinical Research, Breast Cancer, Journal Article, Genetic predisposition, medicine, Genetic Testing, Polymorphism, 030304 developmental biology, Prevention, Human Genome, Research Support, N.I.H., Intramural, medicine.disease, Pair 21, polymorphisms, Research Support, U.S. Gov't, Non-P.H.S
Abstract

Item does not contain fulltext Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G x E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 x 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 x 10(-05)). Our findings confirm comparable power of the recent methods for detecting G x E interaction and the utility of using G x E interaction analyses to identify new susceptibility loci.

Published
2014

15. 11q13 is a susceptibility locus for hormone receptor positive breast cancer

Author

Dong Young Noh, Pascal Guénel, Graeme Elliott, Vesa Kataja, Shamil Gancev, Xianshu Wang, Shan Wang-Gohrke, Annegien Broeks, Florence Menegaux, Hans Wildiers, Richard van Hien, Natalia Bogdanova, Jean Wang, Puttisak Puttawibul, Betül T. Yesilyurt, Peter Devilee, Gord Glendon, Katri Pylkäs, Mark E. Sherman, Jenny Chang-Claude, Federik Marme, Michael Bremer, Katarzyna Durda, Sarah Schott, Vessela N. Kristensen, Paolo Radice, Teresa Selander, Kamila Czene, Alfons Meindl, Gianluca Severi, Angela Cox, Maartje J. Hooning, Claus R. Bartram, John L. Hopper, Ursel Eilber, Michael Jones, M. Pilar Zamora, Stephen J. Chanock, Laura Baglietto, Caroline M. Seynaeve, Daehee Kang, Thilo Dörk, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Loris Bernard, Stig E. Bojesen, Barbara Burwinkel, Douglas F. Easton, Arif B. Ekici, kConFab Investigators, Mervi Grip, Robert A.E.M. Tollenaar, Argyrios Ziogas, Jonathan Beesley, Paolo Peterlongo, Volker Arndt, Xiaoqing Chen, Nichola Johnson, Jaana M. Hartikainen, Ming-Feng Hou, Diether Lambrechts, Ruediger Schulz-Wendtland, Jan Lubinski, Taru A. Muranen, Heli Nevanlinna, Esther M. John, Graham G. Giles, Chen-Yang Shen, Jolanta Lissowska, Ian W. Brock, Grethe I. Grenaker Alnæs, Gillian S. Dite, Charlotte Lanng, Hiltrud Brauch, Anthony J. Swerdlow, MC Southey, Christina Justenhoven, Manjeet K. Humphreys, Keun-Young Yoo, Elinor J. Sawyer, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Fergus J. Couch, Peter Schürmann, Stefan Nickels, Jianjun Liu, Marjanka K. Schmidt, Zachary S. Fredericksen, Yuri I. Rogov, Ute Hamann, Elza Khusnutdinova, Hermann Brenner, Sara Margolin, Natalia Antonenkova, Peter A. Fasching, Matthias W. Beckmann, Johann H. Karstens, Montserrat Garcia-Closas, Patrick Neven, Thomas Brüning, Carl Blomqvist, Heiko Müller, Jyh Cherng Yu, Katarzyna Jaworska, Yon Ko, Pei Ei Wu, Arto Mannermaa, Rebecca Hein, Darya Prokofieva, Melissa C. Southey, Andreas Schneeweiss, Irene L. Andrulis, Christa Stegmaier, Robert Winqvist, Annika Lindblom, Anna Jakubowska, Paul D.P. Pharoah, Peter Hillemanns, Alexander Miron, Roger L. Milne, Marina Bermisheva, Dieter Flesch-Janys, Christof Sohn, Nicola Miller, Georgia Chenevix-Trench, Kristiina Aittomäki, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Siranoush Manoukian, Robert Paridaens, Anne Lise Børresen-Dale, Suthee Rattanamongkongul, Olivia Fletcher, Simon S. Cross, Artitaya Lophatananon, Isabel dos Santos Silva, Janet E. Olson, Nick Orr, Per Hall, Alan Ashworth, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Alison M. Dunning, Kenneth Muir, Sten Cornelissen, Carmel Apicella, Arja Jukkola-Vuorinen, Michael J. Kerin, ~, and Medical Oncology

Subjects
Oncology, hormone receptor status, Estrogen receptor, Genome-wide association study, 0302 clinical medicine, Risk Factors, Genotype, Receptors, single-nucleotide polymorphisms, common variants, Pair 11, Progesterone, Genetics (clinical), Genetics, 0303 health sciences, repair genes, Single Nucleotide, identifies 5, 11q13, Breast cancer susceptibility, Genome-wide association, Hormone receptor status, Polymorphisms, Risk factors, Breast Neoplasms, Chromosomes, Human, Pair 11, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, 3. Good health, ovarian-cancer, 030220 oncology & carcinogenesis, Human, brca1 mutations, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Polymorphism, 030304 developmental biology, breast cancer susceptibility, Odds ratio, tumor characteristics, medicine.disease, confer susceptibility, Estrogen, genome-wide association, family registry, Ovarian cancer, polymorphisms
Abstract

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

Published
2016

16. Breast cancer risk variants at 6q25 display different phenotype associations and regulate ESR1, RMND1 and CCDC170

Author

Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] Latvian Biomed Res & Study Ctr, Riga, Latvia [ 113 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 114 ] Univ Pretoria, Dept Genet, ZA-0002 Pretoria, South Africa [ 115 ] Beckman Res Inst City Hope, Dept Populat Sci, Duarte, CA USA [ 116 ] Copenhagen Univ Hosp, Rigshosp, Dept Oncol, Copenhagen, Denmark [ 117 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, Copenhagen, Denmark [ 118 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain [ 119 ] Biomed Network Rare Dis CIBERER, Madrid, Spain [ 120 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid, Spain [ 121 ] City Hope Clin Canc Genom Community Res Network, Duarte, CA USA [ 122 ] City Hope Natl Med Ctr, Clin Canc Genet, Duarte, CA USA [ 123 ] Ist Europeo Oncol, Div Canc Prevent & Genet, Milan, Italy [ 124 ] Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Dept Prevent & Predict Med, Unit Med Genet, Via Venezian 1, I-20133 Milan, Italy [ 125 ] Univ Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst Human Genet, D-48149 Munster, Germany [ 137 ] Univ Lyon 1, CNRS UMR 5286, INSERM U1052, Ctr Rech Cancerol Lyon, F-69365 Lyon, France [ 138 ] Inst Curie, Dept Tumour Biol, Paris, France [ 139 ] Univ Paris 05, Sorbonne Paris Cite, Paris, France [ 140 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitutionnelle Canc Frequent, Lyon, France [ 141 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA [ 142 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 143 ] Hosp Clin San Carlos, IdISSC, Mol Oncol Lab, Madrid, Spain [ 144 ] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland [ 145 ] Univ Helsinki, Cent Hosp, Helsinki, Finland [ 146 ] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands [ 147 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, Rotterdam, Netherlands [ 148 ] Netherlands Canc Inst, Dept Epidemiol, Amsterdam, Netherlands [ 149 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China [ 150 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 151 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary [ 152 ] Vall dHebron Univ Hosp, VHIO, Oncogenet Lab, Barcelona, Spain [ 153 ] Catalan Inst Oncol, IDIBGI, Hereditary Canc Program, Genet Counseling Unit, Girona, Spain [ 154 ] Catalan Inst Oncol, IDIBELL Bellvitge Biomed Res Inst, Breast Canc & Syst Biol Unit, Barcelona, Spain [ 155 ] Univ Iceland, Fac Med, Landspitali Univ Hosp, Dept Pathol, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital University of Iceland [ 156 ] Univ Iceland, Fac Med, Biomed Ctr BMC, Reykjavik, Iceland [ 157 ] Ctr Hosp Univ Quebec, Div Med Genet, Quebec City, PQ, Canada [ 158 ] Univ Laval, Quebec City, PQ, Canada [ 159 ] Ctr Hosp Univ Quebec, Quebec City, PQ, Canada [ 160 ] IRCCS, IOV, Immunol & Mol Oncol Unit, Padua, Italy [ 161 ] Portuguese Oncol Inst, Dept Genet, Oporto, Portugal [ 162 ] Univ Porto, Biomed Sci Inst ICBAS, Rua Campo Alegre 823, P-4100 Oporto, Portugal [ 163 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA [ 164 ] McGill Univ, Program Canc Genet, Montreal, PQ, Canada [ 165 ] Masaryk Univ, Masaryk Mem Canc Inst, Brno, Czech Republic [ 166 ] Masaryk Univ, Fac Med, Brno, Czech Republic [ 167 ] Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA [ 168 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, Vienna, Austria [ 169 ] Univ S Florida, H Lee Moffitt Canc Ctr, Dept Canc Epidemiol, Tampa, FL 33682 USA [ 170 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, US NIH, Rockville, MD USA [ 171 ] Carmel Hosp, Dept Community Med & Epidemiol, Haifa, Israel [ 172 ] Technion Israel Inst Technol, Bruce Rappaport Fac Med, POB 9649, IL-31096 Haifa, Israel [ 173 ] Clalit Natl Israeli Canc Control Ctr, Haifa, Israel [ 174 ] NN Petrov Oncol Res Inst, St Petersburg, Russia [ 175 ] NorthShore Univ Hlth Syst, Ctr Med Genet, Evanston, IL USA [ 176 ] Peter MacCallum Canc Ctr, Div Canc Med, East Melbourne, Vic, Australia [ 177 ] Roswell Pk Canc Inst, Stat & Data Management Ctr, NRG Oncol, Buffalo, NY 14263 USA [ 178 ] Univ Hlth Network, Lab Med Program, Toronto, ON, Canada [ 179 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada [ 180 ] Vejle Hosp, Dept Clin Genet, Vejle, Denmark [ 181 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark [ 182 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, Pisa, Italy [ 183 ] Univ Hosp Pisa, Pisa, Italy [ 184 ] Univ Malaya, Univ Malaya Med Ctr, Fac Med, Univ Malaya Canc Res Inst, Kuala Lumpur, Malaysia [ 185 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 186 ] Lund Univ, Dept Oncol, Lund, Sweden [ 187 ] Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden [ 188 ] Univ Lund Hosp, Dept Clin Genet, S-22185 Lund, Sweden [ 189 ] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden [ 190 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 191 ] Univ Calif Los Angeles, Sch Med, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 192 ] Univ Calif Los Angeles, Sch Publ Hlth, Johnsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, Los Angeles, CA USA [ 193 ] Univ Calif San Francisco, Dept Med & Genet, San Francisco, CA 94143 USA [ 194 ] Univ Penn, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA [ 195 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 196 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic, Australia [ 197 ] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Melbourne, Vic, Australia [ 198 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 199 ] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA [ 200 ] Dalhousie Univ, Dept Obstet Gynaecol & Pediat, Halifax, NS, Canada [ 201 ] Univ Western Australia, Ctr Genet Origins Hlth & Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England

Subjects
0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract

To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund

Published
2016

17. Associations of Breast Cancer Risk Factors With Tumor Subtypes: A Pooled Analysis From the Breast Cancer Association Consortium Studies

Author

Gillian S. Dite, Brian E. Henderson, U Hamann, Rulla M. Tamimi, Agnes Jager, Laurence N. Kolonel, J Heinz, Hans Wildiers, Celine M. Vachon, Päivi Heikkilä, Chen-Yang Shen, Laura J. Van 'T Veer, Pasi Hirvikoski, Suleeporn Sangrajrang, James McKay, Päivi Auvinen, Michael Bremer, Ann Smeets, Kamila Czene, William J. Tapper, Peter Hillemanns, Fergus J. Couch, John L. Hopper, Douglas F. Easton, Jose Ignacio Arias Perez, Roger L. Milne, Helen Tsimiklis, Carmel Apicella, Antoinette Hollestelle, Zachary S. Fredericksen, Argyrios Ziogas, Helen Cramp, Melissa C. Southey, Malcolm W.R. Reed, Tjoung Won Park-Simon, Janet E. Olson, Primitiva Menéndez Rodríguez, Robert Winqvist, Fabrice Odefrey, Bohdan Górski, Caroline Seynaeve, Matthew L. Kosel, Valerie Gaborieau, Mia M. Gaudet, Diether Lambrechts, Anna Jakubowska, Paul D.P. Pharoah, Fleur Hammet, Amanda B. Spurdle, Stig E. Bojesen, Thilo Dörk, Victoria Cafourek, Julia A. Knight, Frances P O'Malley, Daniel Connley, Letitia D. Smith, David L. Wachter, Flora E. van Leeuwen, David Dynnes Ørsted, Helene Holland, Sabapathy P. Balasubramanian, Aysun Ay, Tuomas Heikkinen, Jaana M. Kauppinen, Diljit Kaur-Knudsen, Børge G. Nordestgaard, Gord Glendon, Paul Brennan, Jacek Gronwald, Mervi Grip, Elinor J. Sawyer, Kristy Driver, Jan Lubinski, Hoda Anton-Culver, Louise A. Brinton, Veli-Matti Kosma, Mieke Kriege, P. E.A. Huijts, Irene L. Andrulis, P. Zamora, S. Chanock, Pei Ei Wu, Tomasz Byrski, Arja Jukkola-Vuorinen, Peter A. Fasching, Tomasz Huzarski, Hatef Darabi, Andreas Meyer, Raem Tollenaar, Fiona M. Blows, Ian Tomlinson, Xiaohong R. Yang, Dallas R. English, Diana Eccles, Ans M.W. van den Ouweland, Johann H. Karstens, Montserrat Garcia-Closas, Alina Vrieling, Graham G. Giles, Michael J. Kerin, Show Lin Yang, Nicola Miller, Sue Gerty, Thomas Brüning, Christopher A. Haiman, Kari Mononen, Loic Le Marchand, Jyh Cherng Yu, Anna Marie Mulligan, Jenny Chang-Claude, Christian R. Loehberg, Matthias W. Beckmann, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Susan E. Hankinson, Gianluca Severi, Angela M. Jones, Heli Nevanlinna, Caroline Weltens, Jolanta Lissowska, Hiltrud Brauch, Giu Cheng Hsu, Sebastian M. Jud, Per Hall, Hans Fischer, Arto Mannermaa, Christina Justenhoven, Laura Baglietto, Katri Pylkäs, Kristiina Aittomäki, Sara Margolin, T. Vandorpe, M. Barile, Ylermi Soini, Beate Pesch, Ellen L. Goode, Nayana Weerasooriya, Peter Devilee, Carl Blomqvist, Margriet Collée, Vesa Kataja, Arndt Hartmann, Manjeet K. Humphreys, Siranoush Manoukian, Annika Lindblom, Marjanka K. Schmidt, Yon Ko, Patrick Neven, Chia-Ni Hsiung, Xianshu Wang, Keith Humphreys, Dieter Flesch-Janys, Niall M. McInerney, Javier Benítez, Esther M. John, Jianjun Liu, Peter Sinn, Reijo Sironen, Annegien Broeks, Rebecca Hein, Shou Tung Chen, Paolo Radice, Simon S. Cross, Mark E. Sherman, Robert Paridaens, Shan Wang-Gohrke, Sebastian B. Weihbrecht, Jonine D. Figueroa, Catriona McLean, Georgia Chenevix-Trench, David J. Hunter, Henrik Flyger, Beata Peplonska, VU University medical center, EMGO - Quality of care, Virology, Medical Oncology, Clinical Genetics, Surgery, and University of Groningen

Subjects
Oncology, Cancer Research, Receptor, ErbB-2, Estrogen receptor, Body Mass Index, ErbB-2, 0302 clinical medicine, Risk Factors, Receptors, Odds Ratio, EPITHELIAL OVARIAN-CANCER, Progesterone, REPAIR GENES, 2. Zero hunger, 0303 health sciences, education.field_of_study, Tumor, Medicine (all), Age Factors, SINGLE-NUCLEOTIDE POLYMORPHISMS, Articles, 3. Good health, ErbB Receptors, Parity, ESTROGEN, Receptors, Estrogen, POSTMENOPAUSAL WOMEN, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Receptor, Receptor, erbB-2, medicine.medical_specialty, SUSCEPTIBILITY LOCI, Oncology and Carcinogenesis, Population, Breast Neoplasms, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Biomarkers, Tumor, medicine, Humans, Oncology & Carcinogenesis, Obesity, Risk factor, education, 030304 developmental biology, Menarche, HORMONE-RECEPTOR, DIFFERENT HISTOPATHOLOGIC TYPES, Epidermal Growth Factor, business.industry, Parturition, Case-control study, Case-Control Studies, Keratin-5, Logistic Models, Receptor, Epidermal Growth Factor, Cancer, Odds ratio, BASAL-LIKE SUBTYPE, medicine.disease, Endocrinology, PROGESTERONE-RECEPTOR STATUS, business, Biomarkers
Abstract

BACKGROUND: Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. METHODS: We pooled tumor marker and epidemiological risk factor data from 35,568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. RESULTS: In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR(-) than PR(+) tumors (P = .001). Nulliparity (P = 3 × 10(-6)) and increasing age at first birth (P = 2 × 10(-9)) were less frequent in ER(-) than in ER(+) tumors. Obesity (body mass index [BMI] ≥ 30 kg/m(2)) in younger women (≤50 years) was more frequent in ER(-)/PR(-) than in ER(+)/PR(+) tumors (P = 1 × 10(-7)), whereas obesity in older women (>50 years) was less frequent in PR(-) than in PR(+) tumors (P = 6 × 10(-4)). The triple-negative (ER(-)/PR(-)/HER2(-)) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6(+) and/or epidermal growth factor receptor [EGFR](+)) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER(+) or PR(+) tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P = .61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P = .34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P = .09) or CBP tumors. CONCLUSIONS: This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.

Published
2010

18. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

Author

S. Lindstrom, Javier Benitez, Natalia Bogdanova, Christine B. Ambrosone, Judith S. Brand, Joe Dennis, Hoda Anton-Culver, Carl Blomqvist, Katarzyna Durda, Loic Le Marchand, Hiltrud Brauch, Aida Karina Dieffenbach, Veli-Matti Kosma, Heli Nevanlinna, Caroline Seynaeve, Drakoulis Yannoukakos, Gord Glendon, Stephen Burgess, Kyriaki Michailidou, Jolanta Lissowska, Thilo Dörk, Paolo Peterlongo, Helen Tsimiklis, J Lubinski, Melissa C. Southey, Robert Winqvist, Kamila Czene, Sune F. Nielsen, Anja Rudolph, Vessela N. Kristensen, Alison M. Dunning, Catherine S. Healey, Diether Lambrechts, Christi J. van Asperen, M. Rosario Alonso, C. Stegmaier, Giuseppe Floris, Per Hall, Jaana M. Hartikainen, Chun Li, Malcolm W.R. Reed, Nuria Álvarez, Anna Jakubowska, Paul D.P. Pharoah, Sara Margolin, John L. Hopper, Barbara Perkins, Francois Bacot, Michael Jones, Jacques Simard, Katarzyna Jaworska-Bieniek, Fredrick R. Schumacher, Angela Cox, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Arja Jukkola-Vuorinen, Arif B. Ekici, Mervi Grip, Rongxi Yang, Esther M. John, Kathleen E. Malone, Vesa Kataja, Qin Wang, Fergus J. Couch, Keith Humphreys, Katja van den Hurk, Michael J. Kerin, Anna González-Neira, Jenny Chang-Claude, Daniel Vincent, Wei Zheng, Ian Tomlinson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Amanda E. Toland, Xiao-Ou Shu, Dieter Flesch-Janys, Volker Arndt, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Craig Luccarini, Børge G. Nordestgaard, Grethe I. Grenaker Alnæs, Alice S. Whittemore, Olivia Fletcher, Guillermo Pita, Matti A. Rookus, Barbara Burwinkel, Lothar Haeberle, Hermann Brenner, John W. M. Martens, Mitul Shah, Marilie D. Gammon, Patrick Neven, Emilie Cordina-Duverger, Jose Ignacio Arias Perez, Ben Zhang, Martine Dumont, Mel Maranian, Annika Lindblom, Habibul Ahsan, Susan L. Neuhausen, Mikael Eriksson, Jingmei Li, Carmel Apicella, Frederik Marmé, Peter Kraft, Hatef Darabi, Ulrike Peters, Hans Wildiers, Arto Mannermaa, J. Margriet Collée, Pascal Guénel, Peter Devilee, M.J. Hooning, Daniel C. Tessier, Shahana Ahmed, Paolo Radice, Montserrat Garcia-Closas, Elinor J. Sawyer, Louise A. Brinton, Susan L. Slager, Bernardo Bonanni, Peter A. Fasching, Simon S. Cross, Thérèse Truong, Matthias W. Beckmann, Catriona McLean, Douglas F. Easton, Georgia Chenevix-Trench, David J. Hunter, Kristiina Aittomäki, Janet E. Olson, Henrik Flyger, Chenjie Zeng, Nick Orr, Siranoush Manoukian, Antonenkova Nn, Stig E. Bojesen, Wan-Qing Wen, Jirong Long, Nicola Miller, Brandon L. Pierce, Ryan J. Delahanty, Anthony J. Swerdlow, Brian E. Henderson, Harald Surowy, Yon-Dschun Ko, Celine M. Vachon, Daniel Herrero, Christopher A. Haiman, Sandrine Tchatchou, Florence Menegaux, Katri Pylkäs, Taru A. Muranen, Roger L. Milne, Thomas Brüning, Marjanka K. Schmidt, Manjeet K. Bolla, M. Pilar Zamora, Irene L. Andrulis, Caroline Baynes, Emily Hallberg, D. Seminara, Isabel dos-Santos-Silva, Diana Torres, Wim L. A. M. de Kort, Nichola Johnson, Public and occupational health, Clinical Genetics, Virology, Medical Oncology, Surgery, and Landsteiner Laboratory

Subjects
Oncology, Cancer Research, medicine.medical_specialty, Pathology, coronary-artery-disease, prospective cohort, Genome-wide association study, Breast Neoplasms, Article, different anatomic sites, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, common variants, Mendelian randomization, Odds Ratio, Medicine, Humans, Prospective Studies, Risk factor, Prospective cohort study, Evidence-Based Medicine, business.industry, body-fat distribution, Mendelian Randomization Analysis, multiple genetic-variants, Odds ratio, medicine.disease, susceptibility loci, Body Height, interleukin-6 receptor, adult human height, Relative risk, genome-wide association, Female, business
Abstract

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer.

Published
2015

19. Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer

Author

Melissa C. Southey, Fredrick R. Schumacher, Robert Winqvist, Simon S. Cross, Katarzyna Durda, Anna Jakubowska, Paul D.P. Pharoah, Judith S. Brand, Christi J. van Asperen, Javier Benitez, Isabel dos-Santos-Silva, Douglas F. Easton, Roger L. Milne, Justo Lorenzo Bermejo, Hermann Brenner, Patrick Neven, Frederik Marmé, Marie Sanchez, Peter Bugert, Maria Kabisch, Anja Rudolph, Arto Mannermaa, Thilo Dörk, Diether Lambrechts, Anna González-Neira, Hoda Anton-Culver, Thomas Dünnebier, Matthias Ruebner, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Veli-Matti Kosma, Christopher A. Haiman, Dieter Flesch-Janys, Martha J. Shrubsole, Florence Menegaux, Catriona McLean, Olivia Fletcher, Kamila Czene, Mark S. Goldberg, Per Hall, Jacques Simard, Keith Humphreys, Qin Wang, Georgia Chenevix-Trench, Katarzyna Jaworska-Bieniek, Jan Lubinski, Loic Le Marchand, Katri Pylkäs, Barbara Perkins, Kristen S. Purrington, Daniel C. Tessier, Paolo Radice, Craig Luccarini, Sune F. Nielsen, Paolo Peterlongo, Nicola Miller, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, John L. Hopper, Annegien Broeks, Kristiina Aittomäki, Mieke Kriege, Sandrine Tchatchou, Frans B. L. Hogervorst, Jenny Chang-Claude, Robert A.E.M. Tollenaar, Angela Cox, Maartje J. Hooning, Brian E. Henderson, Seth W. Slettedahl, Montserrat Garcia-Closas, Thomas Brüning, Malcolm W.R. Reed, Francois Bacot, Alison M. Dunning, kConFab Investigators, Julian Peto, Børge G. Nordestgaard, Linetta B. Koppert, Volker Arndt, Rongxi Yang, Celine M. Vachon, Peter Devilee, Qiuyin Cai, Caroline Weltens, Hiltrud Brauch, Heli Nevanlinna, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Stig E. Bojesen, Giulietta Scuvera, Kyriaki Michailidou, Jolanta Lissowska, Marjanka K. Schmidt, Fergus J. Couch, Barbara Burwinkel, Ute Hamann, Jaana M. Hartikainen, Janet E. Olson, Natalia Bogdanova, Irene L. Andrulis, M. Pilar Zamora, Caroline Baynes, Gord Glendon, Wei Zheng, Taru A. Muranen, Drakoulis Yannoukakos, Caroline Seynaeve, Aida Karina Dieffenbach, Stefano Fortuzzi, Mel Maranian, Arif B. Ekici, Nick Orr, Annika Lindblom, Nichola Johnson, Arja Jukkola-Vuorinen, Anthony J. Swerdlow, Peter A. Fasching, Sten Cornelissen, Martine Dumont, Diana Torres, Helen Tsimiklis, Yon-Dschun Ko, Vesa Kataja, Shibo Ying, Jingmei Li, Carmel Apicella, Vessela N. Kristensen, Hatef Darabi, Christa Stegmaier, Stéphanie Peeters, Michael J. Kerin, Graham G. Giles, Elinor J. Sawyer, Minouk J. Schoemaker, Manjeet K. Bolla, Carl Blomqvist, Xianshu Wang, Joe Dennis, Stephen J. Chanock, Mervi Grip, Jose Ignacio Arias Perez, Mikael Eriksson, Daniel Vincent, Antoinette Hollestelle, Pascal Guénel, Shahana Ahmed, Henrik Flyger, Clinical Genetics, Medical Oncology, and Surgery

Subjects
Risk, Cancer Research, Candidate gene, kinase, Chromosomal Proteins, Non-Histone, Survivin, European Continental Ancestry Group, Estrogen receptor, cytokinesis, Original Manuscript, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Cell Cycle Proteins, Biology, metaphase, Polymorphism, Single Nucleotide, White People, Inhibitor of Apoptosis Proteins, Breast cancer, SDG 3 - Good Health and Well-being, Medizinische Fakultät, cleavage furrow, Genotype, medicine, Aurora Kinase B, Humans, Genetic Predisposition to Disease, ddc:610, Allele, skin and connective tissue diseases, 3' Untranslated Regions, mitosis, Genetics, INCENP, aurora-b, General Medicine, medicine.disease, segregation, mammaglobin, Receptors, Estrogen, midbody, Case-Control Studies, Female, Genome-Wide Association Study
Abstract

The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixedeffects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007 and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. © The Author 2015.

Published
2015

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

Author

Suleeporn Sangrajrang, James McKay, Jirong Long, Gord Glendon, Qi Guo, Malcolm W.R. Reed, Yon Dschun Koto, Sara Margolin, Francois Bacot, Julian Peto, Shaik Ahmad Buhari, Fredrick R. Schumacher, Jose Ignacio Arias Perez, Børge G. Nordestgaard, Kamila Czene, Barbara Burwinkel, Mikael Eriksson, Lorna Gibson, Mitul Shah, Matthias W. Beckmann, Shahana Ahmed, Anthony J. Swerdlow, Frederik Marmé, Pascal Guénel, Hidemi Ito, Mark S. Goldberg, Laura J. van't Veer, John W.M. Martens, Wei Zheng, John L. Hopper, Susanne Kaufmann, Carlos Caldas, Jonathan Beesley, Paolo Peterlongo, Ji Yeob Choi, Daniel O. Stram, Sarah Stewart-Brown, Elinor J. Sawyer, Craig Luccarini, Anja Rudolph, Qin Wang, Javier Benitez, Marie Sanchez, Daniel Herrero, Catherine S. Healey, Arto Mannermaa, Daniel C. Tessier, Paolo Radice, David Van Den Berg, Jacques Simard, Hoda Anton-Culver, Stephen J. Chanock, Christopher A. Haiman, Ines de Santiago, Minouk J. Schoemaker, Irene L. Andrulis, Veli-Matti Kosma, Isabel dos-Santos-Silva, Caroline Baynes, Douglas F. Easton, Stacey L. Edwards, Florence Menegaux, Hatef Darabi, Kyriaki Michailidou, Anna H. Wu, Carolien H.M. van Deurzen, Annegien Broeks, Paul Brennan, Sonja Helbig, Melissa C. Southey, Daniel Klevebring, Loic Le Marchand, Katri Pylkäs, J. Margriet Collée, Ed Dicks, Robert A.E.M. Tollenaar, Henrik Flyger, Jenny Chang-Claude, Annika Lindblom, Christine B. Ambrosone, Lothar Haeberle, Janet E. Olson, Sune F. Nielsen, Robert Winqvist, M. Pilar Zamora, Emily Hallberg, Vessela N. Kristensen, Hermann Brenner, Diana Torres, Valerie Gaborieau, Keitaro Matsuo, Yu-Tang Gao, Yik Ying Teo, Anna Jakubowska, Paul D.P. Pharoah, Patrick Neven, Vesa Kataja, Fergus J. Couch, Robert Luben, Ute Hamann, Katarzyna Jaworska-Bieniek, Dylan M. Glubb, Nick Orr, Christi J. van Asperen, Sara Volorio, Tien Yin Wong, Keith Humphreys, Jianjun Liu, Helen Tsimiklis, Thilo Dörk, Jaana M. Hartikainen, Guillermo Pita, Daniel Vincent, Roger L. Milne, M. Rosario Alonso, Nuria Álvarez, Chiu-Chen Tseng, Daehee Kang, Martine Dumont, Richard Cowper-Sal-lari, Mathieu Lupien, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Xiao-Ou Shu, Brian E. Henderson, Miroslav Kapuscinski, Hui Miao, Angela Cox, Caroline Seynaeve, Stig E. Bojesen, Jason S. Carroll, Nicola Miller, Marjanka K. Schmidt, Taru A. Muranen, Celine M. Vachon, Manjeet K. Bolla, Hans Wildiers, Carl Blomqvist, Maartje J. Hooning, Sandrine Tchatchou, Maya Ghoussaini, Cheng Har Yip, Artitaya Lophatananon, Graham G. Giles, Penny Webb, Yasushi Yatabe, Aida Karina Dieffenbach, Mikael Hartman, Volker Arndt, Simon S. Cross, Per Hall, Soo Hwang Teo, Arif B. Ekici, Joe Dennis, Heli Nevanlinna, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Jolanta Lissowska, Kinjal Desai, Alan Ashworth, Jan Lubinski, Primitiva Menéndez, Pei Ei Wu, Natalia Bogdanova, Kristine M. Hillman, Juliet D. French, Andreas Schneeweiss, Drakoulis Yannoukakos, Montserrat Garcia-Closas, Catriona McLean, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Thomas Brüning, Kristiina Aittomäki, Silje Nord, Jyh Cherng Yu, Hiltrud Brauch, Peter Devilee, Anne Lise Børresen-Dale, Susan L. Slager, Melissa A. Brown, Qiuyin Cai, Hiroji Iwata, Diether Lambrechts, Bernardo Bonanni, Katarzyna Durda, Emiel J. Th. Rutgers, Grethe I. Grenaker Alnæs, Anna de Fazio, Siddhartha Kar, Mel Maranian, Susan L. Neuhausen, Judith E. Brown, Christof Sohn, Sue K. Park, Christa Stegmaier, Shou Tung Chen, Dong-Young Noh, Bernard Thienpont, Alison M. Dunning, Kenneth Muir, Daphne S.C. Lee, Michael J. Kerin, Dieter Flesch-Janys, Jingmei Li, Chen-Yang Shen, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Pathology, Cardiothoracic Surgery, International Institute of Social Studies, Ghoussaini, Maya [0000-0002-2415-2143], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Dicks, Ed [0000-0002-0617-0401], Luben, Robert [0000-0002-5088-6343], Carroll, Jason [0000-0003-3643-0080], Caldas, Carlos [0000-0003-3547-1489], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
General Physics and Astronomy, Genome-wide association study, in-vivo, Genotype, phase, cyclin d1 expression, Promoter Regions, Genetic, CYCLIN D1 EXPRESSION, IN-VIVO, Genetics, Multidisciplinary, FACTOR-BINDING PROTEIN-5, foxa1, ASSOCIATION, Chromatin, 3. Good health, Multidisciplinary Sciences, Chromosomes, Human, Pair 2, functional variants, MCF-7 Cells, Science & Technology - Other Topics, GROWTH, Female, Hepatocyte Nuclear Factor 3-alpha, growth, PHASE, Breast Neoplasms, Locus (genetics), Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Breast cancer, SDG 3 - Good Health and Well-being, Cell Line, Tumor, medicine, Humans, SNP, Genetic Predisposition to Disease, RNA, Messenger, FUNCTIONAL VARIANTS, Gene, Science & Technology, association, Correction, General Chemistry, medicine.disease, CELLS, factor-binding protein-5, cells, FOXA1, Insulin-Like Growth Factor Binding Protein 5
Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology. ispartof: Nature communications vol:5 pages:4999- ispartof: location:England status: published

Published
2014

21. The proteomic 2D-DIGE approach reveals the protein voltage-dependent anion channel 2 as a potential therapeutic target in epithelial thyroid tumours

Author

Alberto de Leiva, Cintia González, Laia Selva, Irene Orera, Enrique Lerma, Jose Ignacio Arias Perez, Eugenia Mato, Antonio Moral, Silvia Barceló-Batllori, Olga Bell, and Martina Corra

Subjects
Sorafenib, Adult, Male, Niacinamide, Proteomics, Voltage-dependent anion channel, Adolescent, Biochemistry, Two-Dimensional Difference Gel Electrophoresis, Young Adult, Endocrinology, Downregulation and upregulation, Cell Line, Tumor, Gene expression, medicine, Humans, Neoplasms, Glandular and Epithelial, Thyroid Neoplasms, Molecular Biology, Aged, bcl-2-Associated X Protein, Aged, 80 and over, Gene knockdown, biology, Voltage-Dependent Anion Channel 2, Phenylurea Compounds, Thyroid, Middle Aged, Molecular biology, Up-Regulation, medicine.anatomical_structure, bcl-2 Homologous Antagonist-Killer Protein, Cell culture, biology.protein, Female, VDAC2, medicine.drug
Abstract

We investigated the role of VDAC2 in human epithelial thyroid tumours using proteomic 2D-DIGE analysis and qRT-PCR. We found a significant up-regulation of VDAC2 in thyroid tumours and in thyroid tumour cell lines (TPC-1 and CAL-62). We did not detect overexpression of VDAC2 in a normal thyroid cell line (Nthy-ori 3-1). Silico analysis revealed that two proteins, BAK1 and BAX, had a strong relationship with VDAC2. BAK1 gene expression showed down-regulation in thyroid tumours (follicular and papillary tumours) and in TPC-1 and CAL-62 cell lines. Transient knockdown of VDAC2 in TPC-1 and CAL-62 promoted upregulation of the BAK1 gene and protein expression, and increased susceptibility to sorafenib treatment. Overexpression of the BAK1 gene in CAL-62 showed lower sorafenib sensitivity than VDAC2 knockdown cells. We propose the VDAC2 gene as a novel therapeutic target in these tumours.

Published
2014

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

Author

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

Subjects
Physiology, chemistry.chemical_compound, 610 Medical sciences Medicine, 0302 clinical medicine, Risk Factors, Medizinische Fakultät, Genotype, Cytochrome P-450 CYP3A, Age of Onset, Reproductive History, Medicine(all), 0303 health sciences, Age Factors, twins, Middle Aged, 3. Good health, steroid-hormones, 030220 oncology & carcinogenesis, loci, Menarche, Veterinary (all), Female, Research Article, Adult, medicine.medical_specialty, premenopausal women, Breast Neoplasms, Estrone, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, White People, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, estradiol, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetic Association Studies, Aged, 030304 developmental biology, Gynecology, business.industry, Case-control study, medicine.disease, Clinical research, Premenopause, chemistry, sex-hormone levels, Cancer and Oncology, genome-wide association, Age of onset, business, serum
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 (Ptrend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (Ptrend = 0.005) but not cases (Ptrend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (Phet = 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 (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; Ptrend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; Ptrend = 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.

Published
2014

23. Functional Variants at the 11q13 Risk Locus for Breast Cancer Regulate Cyclin D1 Expression through Long-Range Enhancers

Author

Yu Tang Gao, Senno Verhoef, Sofia Khan, Brian E. Henderson, M. Pilar Zamora, Roger L. Milne, Qin Wang, Jaana M. Hartikainen, Joshua A. Betts, Montserrat Garcia-Closas, Gianluca Severi, Shahana Ahmed, Katarzyna Durda, Pascal Guénel, Hidemi Ito, Manjeet K. Bolla, Francois Bacot, Gord Glendon, Hermann Brenner, Chen-Yang Shen, Suleeporn Sangrajrang, James McKay, Fergus J. Couch, Nicholas W. Knoblauch, Vernon S. Pankratz, Dieter Flesch-Janys, Henrik Flyger, Pierre Laurent-Puig, Isabel dos Santos Silva, Heiko Müller, Nichola Johnson, Alfons Meindl, Nicola Miller, Christian R. Loehberg, Mark S. Goldberg, Mikael Hartman, Daniel C. Tessier, Paolo Radice, Ann Smeets, Ute Hamann, Xueling Sim, Irene L. Andrulis, Caroline Baynes, Annika Lindblom, Craig Luccarini, Laura Baglietto, Kristiina Aittomäki, Nils Schoof, Ana-Teresa Maia, Andrew K. Godwin, David Van Den Berg, Katri Pylkäs, Caroline M. Seynaeve, Madeleine M.A. Tilanus-Linthorst, Chiu-Chen Tseng, Angela Cox, Jirong Long, Stacey L. Edwards, Kerstin B. Meyer, Daniel R. Barnes, Per Hall, Melissa C. Southey, Wei Zheng, Stig E. Bojesen, Maartje J. Hooning, Daniel Herrero, William Blot, Don M. Conroy, Alison M. Dunning, John W.M. Martens, Artitaya Lophatananon, Christopher A. Haiman, Frederik Marmé, Sabapathy P. Balasubramanian, Florence Menegaux, Peter Kraft, Sarah Stewart-Brown, Julian Peto, Volker Arndt, Kenneth Muir, Daniel Klevebring, Robert Winqvist, Jose Ignacio Arias Perez, Joe Dennis, Sune F. Nielsen, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Valerie Gaborieau, Børge G. Nordestgaard, Anthony J. Swerdlow, Mitul Shah, M. Rosario Alonso, Keitaro Matsuo, Daniel O. Stram, Hui Cai, Anja Rudolph, Arto Mannermaa, Hiroji Iwata, Matthias W. Beckmann, Eranga N. Vithana, Elinor J. Sawyer, Anna Jakubowska, Paul D.P. Pharoah, Barbara Burwinkel, Annegien Broeks, Julia A. Knight, Alan Ashworth, Diether Lambrechts, Zoe Aitken, Marjanka K. Schmidt, Peter Bailey, Catherine S. Healey, Chia-Ni Hsiung, Anna González-Neira, Lisa B. Signorello, Thilo Dörk, Keun-Young Yoo, Maya Ghoussaini, J. H. Sng, J. Margriet Collée, Sten Cornelissen, Aiko Sueta, Melissa A. Brown, Nick Orr, Peter Lichtner, Hiltrud Brauch, Douglas F. Easton, Jonine D. Figueroa, Anna H. Wu, Kristine M. Hillman, Domenico Sardella, Dong Young Noh, Minouk J. Schoemaker, Fredrick R. Schumacher, Martine Dumont, Jianjun Liu, Kyriaki Michailidou, Stephen J. Chanock, Rita K. Schmutzler, Vesa Kataja, Kamila Czene, Natalia Antonenkova, Mervi Grip, Heli Nevanlinna, Georgia Chenevix-Trench, Peter Devilee, Qiuyin Cai, Pornthep Siriwanarangsan, Jolanta Lissowska, Christine B. Ambrosone, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Jenny Chang-Claude, Kirsimari Aaltonen, John L. Hopper, Bruce A.J. Ponder, Giuseppe Floris, Christa Stegmaier, Xianshu Wang, Cheng Har Yip, Christina Justenhoven, Vessela N. Kristensen, Jingmei Li, Shou Tung Chen, Karen A. Pooley, Jonathan Tyrer, Bernardo Bonanni, Sara Margolin, Päivi Heikkilä, Keith Humphreys, Martin O'Reilly, Sandra Deming-Halverson, Thomas L. Carroll, Pei Ei Wu, Soo Hwang Teo, Hui Miao, Stéphanie Peeters, Christof Sohn, Constance Chen, Jacques Simard, Jan Lubinski, Daehee Kang, Natalia Bogdanova, Juliet D. French, Christoph Engel, Adam M. Lee, Katarzyna Jaworska-Bieniek, Drakoulis Yannoukakos, Andreas Schneeweiss, Mel Maranian, Michael J. Kerin, Loic Le Marchand, Martha J. Shrubsole, Carl Blomqvist, Char Hong Ng, Daniel Vincent, Jonathan Beesley, Paolo Peterlongo, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Ed Dicks, Arif B. Ekici, Andrew H. Beck, Xiao-Ou Shu, Graham G. Giles, Stefan Nickels, Clinical Genetics, Obstetrics & Gynecology, Medical Oncology, Surgery, and Cardiothoracic Surgery

Subjects
Messenger, Electrophoretic Mobility Shift Assay, Enhancer RNAs, Genome-wide association study, Medical and Health Sciences, prostate-cancer, 0302 clinical medicine, 2.1 Biological and endogenous factors, Genetics(clinical), Cyclin D1, Aetiology, RNA, Small Interfering, Pair 11, Promoter Regions, Genetic, Luciferases, Genetics (clinical), Cancer, estrogen-receptor, Genetics & Heredity, Genetics, Regulation of gene expression, 0303 health sciences, Tumor, Silencer Elements, Reverse Transcriptase Polymerase Chain Reaction, Single Nucleotide, Biological Sciences, Chromatin, Gene Expression Regulation, Neoplastic, Enhancer Elements, Genetic, 030220 oncology & carcinogenesis, kConFab Investigators, Female, Transcriptional, GENICA Network, Human, Chromatin Immunoprecipitation, Enhancer Elements, Breast Neoplasms, GATA3 Transcription Factor, Biology, Small Interfering, Real-Time Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Article, Chromosomes, Cell Line, multiple loci, Promoter Regions, 03 medical and health sciences, down-regulation, Genetic, SDG 3 - Good Health and Well-being, Cell Line, Tumor, Binding Sites, Case-Control Studies, Chromosomes, Human, Pair 11, Humans, RNA, Messenger, Silencer Elements, Transcriptional, ets-Domain Protein Elk-4, Breast Cancer, Polymorphism, Enhancer, Transcription factor, 030304 developmental biology, Neoplastic, gene-expression, susceptibility loci, growth-factor receptor-2, cell-cycle, Gene Expression Regulation, genome-wide association, Cancer research, RNA, mammary-gland, Chromatin immunoprecipitation
Abstract

Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1. © 2013 The American Society of Human Genetics.

Published
2013

24. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Author

Michael Lush, Hans Wildiers, Christopher A. Haiman, Nils Schoof, Per Hall, Beatrice Melin, Hiltrud Brauch, Liisa M. Pelttari, Angela Brooks-Wilson, Laima Tihomirova, Ingo B. Runnebaum, Hui Cai, Kenneth Offit, Michael P. Lux, Robert Edwards, Julia A. Knight, Ignace Vergote, Arto Leminen, Alan Ashworth, Kyriaki Michailidou, Martha J. Shrubsole, Sophie Giraud, Nadeem Siddiqui, Katri Pylkäs, Sune F. Nielsen, Vernon S. Pankratz, Lenka Foretova, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Andreas du Bois, Christi J. van Asperen, Nuria Álvarez, M. Pilar Zamora, Theo A. Mvan Os, Susan J. Ramus, Olivia Fletcher, Usha Menon, Olivier Caron, Dieter Flesch-Janys, Sara H. Olson, Ellen L. Goode, Yael Laitman, Jingmei Li, Lynne R. Wilkens, Carmel Apicella, Brooke L. Fridley, Robert Luben, Mark S. Goldberg, Mary Anne Rossing, Dominique Stoppa-Lyonnet, Jonathan Beesley, Jan Lubinski, Paolo Peterlongo, Phuong L. Mai, Henrik Flyger, Thilo Dörk, Douglas A. Levine, Rob B. van der Luijt, Stig E. Bojesen, Javier Benitez, Natalia Bogdanova, Stephen J. Chanock, Andrew K. Godwin, Sharon E. Johnatty, Helga B. Salvesen, Juliet D. French, Daphne Gschwantler Kaulich, Rod Karevan, Arif B. Ekici, Marc Frenay, Taru A. Muranen, Jirong Long, Catherine S. Healey, Craig Luccarini, Chen-Yang Shen, Lorna Gibson, Pascal Guénel, Hidemi Ito, Nicholas T. Woods, Drakoulis Yannoukakos, Thomas Hansen, Francesca Damiola, Valérie Bonadona, Satoyo Hosono, Marion Piedmonte, Steve Ellis, Suleeporn Sangrajrang, Aleksandra Gentry-Maharaj, James McKay, Olga M. Sinilnikova, Jennifer A. Doherty, Xiao-Ou Shu, Curtis Olswold, Nhu D. Le, Michael J. Kerin, Malcolm C. Pike, Jenny Chang-Claude, Gianluca Severi, Michael Jones, Linda E. Kelemen, Loic Le Marchand, Maureen E. Hoatlin, Fredrick R. Schumacher, Dieter Niederacher, Michael E. Carney, Angela Cox, Attila Teoman, Hannah P. Yang, Graham G. Giles, Jianjun Liu, Xiaoqing Chen, Elisa V. Bandera, Tanja Pejovic, Galina Lurie, Karoline Kuchenbaecker, Mariusz Bidziński, Chanel E. Smart, Maartje J. Hooning, Jose Ignacio Arias Perez, Anne-Marie Gerdes, L. Rogmann, Christoph Engel, Harvey A. Risch, Ignacio Blanco, Isabel dos Santos Silva, Hoda Anton-Culver, Camilla Krakstad, Volker Arndt, Foluso O. Ademuyiwa, Frans B. L. Hogervorst, Stacey L. Edwards, Florian Heitz, Veli-Matti Kosma, Beth Y. Karlan, Robert A. Vierkant, Irene L. Andrulis, Agnieszka Dansonka-Mieszkowska, Hanne Meijers-Heijboer, Alison M. Dunning, Sabapathy P. Balasubramanian, Penny Soucy, Edwin S. Iversen, Heli Nevanlinna, Celeste Leigh Pearce, Melissa C. Southey, Howard C. Shen, Kenneth Muir, Jolanta Lissowska, Clareann H. Bunker, Judy Garber, David Van Den Berg, Yin Ling Woo, Brigitte Bressac-de Paillerets, Rebecca Hein, Norbert Arnold, Saila Kauppila, Lisa Walker, Cezary Cybulski, Estrid Høgdall, Anthony J. Swerdlow, Robert Winqvist, Susanne K. Kjaer, Christa Stegmaier, Kazuo Tajima, Caroline Baynes, Valerie Gaborieau, Keitaro Matsuo, Ed Dicks, Irene Orlow, Torben A Kruse, Rachel Palmieri Weber, David E. Goldgar, Anna Jakubowska, Honglin Song, Antonis C. Antoniou, Paul D.P. Pharoah, Katja K.H. Aben, Lambertus A. Kiemeney, Laurence Faivre, Stefan Nickels, Joellen M. Schildkraut, Yu Tang Gao, Valerie McGuire, Charles L. Shapiro, Sebastian M. Armasu, Katherine L. Nathanson, Marjanka K. Schmidt, Susan L. Neuhausen, Jolanta Kupryjanczyk, Janet E. Olson, Nicolas Wentzensen, Dong Young Noh, Maya Ghoussaini, Ian G. Campbell, Annegien Broeks, Gustavo C. Rodriguez, Rebecca L. Johnston, Shan Wang-Gohrke, Monica Barile, Vesa Kataja, Melanie Maranian, Shahana Ahmed, Christof Sohn, Julie M. Cunningham, Weiva Sieh, Shani Shimon Paluch, Riccardo Dolcetti, John W.M. Martens, Manjeet K. Bolla, Shelley S. Tworoger, Robert S. Brown, Allan Jensen, Hui Miao, Boris Winterhoff, Mari K. Halle, Arndt Hartmann, Loris Bernard, Brian E. Henderson, Els Wauters, Carl Blomqvist, Daniel O. Stram, Karen A. Pooley, Roberta B. Ness, James Paul, Hilda A. Pickett, Wei Zheng, Sandra Deming-Halverson, Soo Hwang Teo, Andrew Lee, Thomas A. Sellers, Philip Iau, D. Gareth Evans, Françis Bacot, Sunil R. Lakhani, Qin Wang, Nick Orr, Celine M. Vachon, Edith Olah, Gong Yang, Svend Aage Engelholm, Martine Dumont, Linda S. Cook, Daniel C. Tessier, Evgeny N. Imyanitov, Paolo Radice, Mikael Hartman, Annika Lindblom, John R. McLaughlin, Radka Platte, Jenny Permuth-Wey, Keun-Young Yoo, Andrew Berchuck, Roger R. Reddel, M. John Kennedy, Toru Nakanishi, Allison F. Vitonis, Melissa C. Larson, Anna H. Wu, Helmut Deissler, Giuseppe Giannini, Barbara Wappenschmidt, Tomasz Byrski, M. Kamran Ikram, Natalia Antonenkova, Banu Arun, Peter Hillemanns, William Blot, Siti Zawiah Omar, Sue Healey, Trevor Cole, Cheng Har Yip, Matthias Dürst, Mark E. Robson, Roger L. Milne, Timothy R. Rebbeck, Jaana M. Hartikainen, Mieke Kriege, C. Ellen van der Schoot, Hansjoerg Plendl, Yasushi Yatabe, Jan C. Oosterwijk, Claus Høgdall, Rob A. E. M. Tollenaar, Jacek Gronwald, Yi Lu, Kate Lawrenson, Michael D. Stutz, Chia-Ni Hsiung, Alvaro N.A. Monteiro, Maren Weischer, Philipp Harter, Nicola Miller, Lisa B. Signorello, Katarzyna Durda, Peter Lichtner, Ritu Salani, Alfons Meindl, Montserrat Garcia-Closas, George Fountzilas, Uffe Birk Jensen, Thomas Brüning, Laura Baglietto, Anne M. van Altena, Kristine M. Hillman, Bernard Peissel, Trinidad Caldés, Rosemarie Davidson, Julian Barwell, Peter Devilee, Jenny Lester, Qiuyin Cai, Heiko Müller, Jyh Cherng Yu, Kerstin Rhiem, Muy Kheng Tea, Sharon A. Savage, Åke Borg, Daniel Vincent, Antoinette Hollestelle, Katarzyna Jaworska, Mat Adenan Noor Azmi, Yon Ko, Kimberly R. Kalli, Debra Frost, Martin Gore, Chiu-Chen Tseng, Georgia Chenevix-Trench, Pornthep Siriwanarangsan, Evelyn Despierre, Fergus J. Couch, Vijayalakshmi Shridhar, Artitaya Lophatananon, Amanda B. Spurdle, Joe Dennis, Ute Hamann, Vessela N. Kristensen, Frederik Marmé, Jonathan Tyrer, Arja Jukkola-Vuorinen, Wei Lu, Peter A. Fasching, Bruno Buecher, Kristiina Aittomäki, Kirsten B. Moysich, Lesley McGuffog, Mine S. Cicek, Guillermo Pita, Arjen R. Mensenkamp, Agnes Jager, Catherine M. Phelan, Jacques Simard, Ming-Feng Hou, Hiroji Iwata, James M. Flanagan, Elena Fineberg, Susan M. Domchek, Csilla Szabo, Diether Lambrechts, Anja Rudolph, Daehee Kang, Gottfried E. Konecny, Eitan Friedman, Argyrios Ziogas, Arto Mannermaa, Susan Peock, Matti A. Rookus, Christian F. Singer, Claire Mulot, Siranoush Manoukian, Johanna Rantala, Helen Tsimiklis, Gord Glendon, Pierre Laurent-Puig, Barbara Brouwers, Filomena Ficarazzi, Jonine D. Figueroa, Anne-Bine Skytte, Caroline Seynaeve, Christian Sutter, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Kathryn L. Terry, Børge G. Nordestgaard, Simon A. Gayther, Barbara Burwinkel, Ira Schwaab, Steven A. Narod, Elisabeth Wik, Ralf Bützow, Marco Montagna, Mark H. Greene, Linde M. Braaf, Janusz Menkiszak, Kamila Czene, Sarah Stewart-Brown, Kees E. P. van Roozendaal, Andreas Schneeweiss, Daniel Barrowdale, Elinor J. Sawyer, Alice S. Whittemore, Marc T. Goodman, Judith E. Brown, Kunle Odunsi, John L. Hopper, Nina Ditsch, Leon F.A.G. Massuger, Hermann Brenner, Joaquin J. Garcia, Xianshu Wang, Susan L. Slager, Aleksandra Tołoczko-Grabarek, Sylvie Mazoyer, Diana Eccles, Yik Ying Teo, Iwona K. Rzepecka, Bernardo Bonanni, Sara Margolin, Daniela Zaffaroni, Yew Ching Teh, Ans M Wvan Den Ouweland, Bent Ejlertsen, Maria Soller, Mitul Shah, Matthias W. Beckmann, Elizabeth M. Poole, J. Margriet Collée, Lorna Rodriguez-Rodriguez, Sandrina Lambrechts, Daniel W. Cramer, Douglas F. Easton, Virginie Caux-Moncoutier, Mads Thomassen, Keith Humphreys, ~, Landsteiner Laboratory, Clinical Haematology, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Human Genetics, MUMC+: DA KG Lab Centraal Lab (9), Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Human genetics, CCA - Oncogenesis, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Clinical Genetics, Cardiothoracic Surgery, and Medical Oncology

Subjects
Telomerase, Messenger, Càncer d'ovari, Estrogen receptor, Aetiology, screening and detection [ONCOL 5], 0302 clinical medicine, Breast cancer, Risk Factors, Alternative Splicing, Biomarkers, Tumor, Breast Neoplasms, Case-Control Studies, Chromatin, DNA Methylation, Female, Gene Expression Profiling, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Luciferases, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Polymorphism, Single Nucleotide, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Telomere, Genetics, BUCCAL CELLS, 0303 health sciences, Tumor, Telòmer, GENETIC-VARIATION, COMMON VARIANTS, Single Nucleotide, tert-clptm1l locus, genome-wide association, genetic-variation, susceptibility loci, buccal cells, fibroblasts, common variants, carcinoma, reverse-transcriptase htert, metaanalysis, Aetiology, screening and detection Immune Regulation [ONCOL 5], 3. Good health, Tumor Markers, Biological, 030220 oncology & carcinogenesis, FIBROBLASTS, SUSCEPTIBILITY LOCI, CARCINOMA, Single-nucleotide polymorphism, Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, medicine, Polymorphism, Allele, GENOME-WIDE ASSOCIATION, METAANALYSIS, 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Breast cancer susceptibility, Hereditary cancer and cancer-related syndromes [ONCOL 1], Translational research Genomic disorders and inherited multi-system disorders [ONCOL 3], medicine.disease, Molecular biology, TERT-CLPTM1L LOCUS, Minor allele frequency, RNA, Biomarkers, REVERSE-TRANSCRIPTASE HTERT
Abstract

Journal article TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant. European Commission Seventh Framework Programme (agreement 223175-HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10118 and C1287/A12014) peer-reviewed

Published
2013

25. Confirmation of 5p12 As a Susceptibility Locus for Progesterone-Receptor-Positive, Lower Grade Breast Cancer

Author

Peter Hillemanns, Roger L. Milne, Chiun-Sheng Huang, Jan Lubinski, Arif B. Ekici, Rita K. Schmutzler, Julian Peto, Qin Wang, Rob A. E. M. Tollenaar, Børge G. Nordestgaard, Chen-Yang Shen, Paolo Radice, Nicola Miller, Barbara Burwinkel, Suleeporn Sangrajrang, Núria Malats, James McKay, Gianluca Severi, Ian Tomlinson, Dong-Young Noh, Irene L. Andrulis, Xiaoqing Chen, Esther M. John, Katarzyna Durda, Anna Marie Mulligan, Anne Lise Børrensen-Dale, Frederik Marmé, Simon S. Cross, Elza Khusnutdinova, Joerg Heil, Gillian S. Dite, Melissa C. Southey, Thilo Dörk, Peter Kraft, Monica Barile, Graeme Elliot, Olivia Fletcher, Yuri I. Rogov, Arto Mannermaa, Nazneen Rahman, Annegien Broeks, Susan E. Hankinson, Xianshu Wang, Natalia Bogdanova, Mark E. Sherman, Volker Harth, Johann H. Karstens, Montserrat Garcia-Closas, Robert Winqvist, Alfons Meindl, Rebecca Hein, Laura J. van't Veer, Stefan Nickels, Manjeet K. Humphreys, Valerie Gaborieau, Lorna Gibson, Jose Ignacio Arias Perez, Giuseppe Floris, Christa Stegmaier, Gord Glendon, Heiko Müller, Marjanka K. Schmidt, Jonine D. Figueroa, Julia A. Knight, Graham G. Giles, Siranoush Manoukian, Ming-Feng Hou, Albina Farahtdinova, Gilles Thomas, Diether Lambrechts, Anna Jakubowska, Paul D.P. Pharoah, Alexander Miron, Michael J. Kerin, Iosif V. Zalutsky, Ian W. Brock, Laura Baglietto, Argyrios Ziogas, Claus R. Bartram, John L. Hopper, Marina Bermisheva, Grethe I. Grenaker Alnæs, Jaana M. Hartikainen, Sei Hyun Ahn, Hermann Brenner, Paul Brennan, Dieter Flesch-Janys, Stephen J. Chanock, Robert N. Hoover, Fergus J. Couch, Georgia Chenevix-Trench, Anthony Renwick, Sheila Seal, Mervi Grip, Matthias W. Beckmann, Karin Leunen, Javier Benitez, Peter Schürmann, Vesa Kataja, Arja Jukkola-Vuorinen, Peter A. Fasching, David J. Hunter, Christian M. Bayer, Rogier A. Oldenburg, Karen A. Pooley, Antoinette Hollestelle, Hoda Anton-Culver, Veli-Matti Kosma, P. Zamora, Jonathan Beesley, Paolo Peterlongo, Darya Prokofieva, Keun-Young Yoo, Isabel dos Santos Silva, Katarzyna Jaworska, Janet E. Olson, Carmel Apicella, U Hamann, Jyh-Cherng Yu, Shan Wang-Gohrke, Natalia Antonenkova, Sara Lindström, Andreas Schneeweiss, Katri Pylkäs, Douglas F. Easton, Charlotte Lanng, Alison M. Dunning, Vessela N. Kristensen, Daehee Kang, Elinor J. Sawyer, Jolanta Lissowska, Christina Justenhoven, Zachary S. Fredericksen, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Volker Arndt, Christof Sohn, Betül T. Yesilyurt, Jenny Chang-Claude, Ellen L. Goode, Stig E. Bojesen, Clare Turnbull, Medical Oncology, Clinical Genetics, and Surgery

Subjects
Oncology, Epidemiology, Estrogen receptor, Noninfiltrating, Cohort Studies, 0302 clinical medicine, Risk Factors, Ductal, Receptors, common variants, Breast, Progesterone, risk, 0303 health sciences, subtypes, Carcinoma, Ductal, Breast, Breast Neoplasms, Carcinoma, Intraductal, Noninfiltrating, Case-Control Studies, Chromosomes, Human, Pair 5, Female, Follow-Up Studies, Humans, Neoplasm Grading, Polymorphism, Single Nucleotide, Prognosis, Receptors, Estrogen, Receptors, Progesterone, Genetic Predisposition to Disease, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, alleles, Pair 5, Human, medicine.medical_specialty, Intraductal, Biology, Article, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, medicine, Genetic predisposition, Carcinoma, Polymorphism, 030304 developmental biology, Gynecology, Case-control study, Ductal carcinoma, confer susceptibility, medicine.disease, Estrogen, genome-wide association, Histopathology
Abstract

Background: The single-nucleotide polymorphism (SNP) 5p12-rs10941679 has been found to be associated with risk of breast cancer, particularly estrogen receptor (ER)-positive disease. We aimed to further explore this association overall, and by tumor histopathology, in the Breast Cancer Association Consortium. Methods: Data were combined from 37 studies, including 40,972 invasive cases, 1,398 cases of ductal carcinoma in situ (DCIS), and 46,334 controls, all of white European ancestry, as well as 3,007 invasive cases and 2,337 controls of Asian ancestry. Associations overall and by tumor invasiveness and histopathology were assessed using logistic regression. Results: For white Europeans, the per-allele OR associated with 5p12-rs10941679 was 1.11 (95% CI = 1.08–1.14, P = 7 × 10−18) for invasive breast cancer and 1.10 (95% CI = 1.01–1.21, P = 0.03) for DCIS. For Asian women, the estimated OR for invasive disease was similar (OR = 1.07, 95%CI = 0.99–1.15, P = 0.09). Further analyses suggested that the association in white Europeans was largely limited to progesterone receptor (PR)-positive disease (per-allele OR = 1.16, 95% CI = 1.12–1.20, P = 1 × 10−18 vs. OR = 1.03, 95% CI = 0.99–1.07, P = 0.2 for PR-negative disease; Pheterogeneity = 2 × 10−7); heterogeneity by ER status was not observed (P = 0.2) once PR status was accounted for. The association was also stronger for lower grade tumors [per-allele OR (95% CI) = 1.20 (1.14–1.25), 1.13 (1.09–1.16), and 1.04 (0.99–1.08) for grade 1, 2, and 3/4, respectively; Ptrend = 5 × 10−7]. Conclusion: 5p12 is a breast cancer susceptibility locus for PR-positive, lower grade breast cancer. Impact: Multicenter fine-mapping studies of this region are needed as a first step to identifying the causal variant or variants. Cancer Epidemiol Biomarkers Prev; 20(10); 2222–31. ©2011 AACR.

Published
2011

26. Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Author

Graham G. Giles, Sandrine Tchatchou, Bart Claes, Fergus J. Couch, Douglas F. Easton, Simon S. Cross, Manjeet K. Humphreys, Irene L. Andrulis, Annika Lindblom, Paul Brennan, Bahar Ozturk, Marjanka K. Schmidt, Ute Hamann, Carlos Caldas, Thomas Löning, Alexander Hein, Peter Hillemanns, Roger L. Milne, Matti Eskelinen, Melissa C. Southey, Patrick Neven, Rob A. E. M. Tollenaar, Giu-Cheng Hsu, Päivi Heikkilä, Jonathan Beesley, Keith Humphreys, Malcolm W.R. Reed, Hiltrud Brauch, Valerie Gaborieau, Laurence N. Kolonel, Alison M. Dunning, Sabapathy P. Balasubramanian, Jianjun Liu, Diljit Kaur-Knudsen, Anna Jakubowska, Paul D.P. Pharoah, Geert J.L.H. van Leenders, Matthew L. Kosel, Angela Cox, Christopher A. Haiman, Aocs, Arif B. Ekici, Peter A. Fasching, Ruediger Schulz-Wendtland, Anne Lise Børresen-Dale, Loic Le Marchand, Maartje J. Hooning, Fleur Hammet, Christof Sohn, Gillian S. Dite, Yon-Dschun Ko, Sebastian M. Jud, Per Hall, Mark E. Sherman, Jaana M. Kauppinen, Bohdan Górski, Dieter Flesch-Janys, Fiona M. Blows, Sara Margolin, Jacek Gronwald, Jonine D. Figueroa, Amanda B. Spurdle, Thilo Dörk, Javier Benitez, Catriona McLean, Chia-Ni Hsiung, Matthias W. Beckmann, Ylermi Soini, kConFab, Frederik Marmé, Georgia Chenevix-Trench, David Dynnes Ørsted, Johann H. Karstens, Hoda Anton-Culver, Veli-Matti Kosma, Christi J. van Asperen, Montserrat Garcia-Closas, Annegien Broeks, Arto Mannermaa, Thomas Brüning, Jenny Chang-Claude, Xiaoqing Chen, Päivi Auvinen, Carl Blomqvist, David J. Hunter, Anna Marie Mulligan, Kristiina Aittomäki, Michael Bremer, Renate de Groot, Shou-Tung Chen, Kirsimari Aaltonen, Beate Pesch, Helene Holland, Susan E. Hankinson, Kamila Czene, Jan Lubinski, Mieke Kriege, Ming-Feng Hou, Vesa Kataja, John L. Hopper, Diether Lambrechts, Carmel Apicella, Petra E A Huijts, Brian E. Henderson, Laura Baglietto, Rebecca Hein, Helen Cramp, Frances P. O'Malley, Arndt Hartmann, Grethe I. Grenaker Alnæs, Louise A. Brinton, Jyh-Cherng Yu, Primitiva Menéndez Rodríguez, T. Vandorpe, Elena Provenzano, Peter Devilee, Tomasz Byrski, Heli Nevanlinna, Stig E. Bojesen, Tuomas Heikkinen, Jolanta Lissowska, Beata Peplonska, Argyrios Ziogas, Christina Justenhoven, Tomasz Huzarski, Zachary S. Fredericksen, Agnes Jager, Caroline Seynaeve, Chiun-Sheng Huang, Vessela N. Kristensen, Daniel Connley, Børge G. Nordestgaard, Barbara Burwinkel, Vincent T.H.B.M. Smit, Kristy Driver, Antoinette Hollestelle, Letitia D. Smith, Stephen J. Chanock, Hans-Peter Sinn, Chen-Yang Shen, Suleeporn Sangrajrang, Andreas Schneeweiss, Rogier A. Oldenburg, Jose Ignacio Arias Perez, Xiaohong R. Yang, Henrik Flyger, Hans-Peter Fischer, Pilar Zamora, Laura J. van't Veer, Xianshu Wang, Cezary Cybulski, Hans Wildiers, Shan Wang-Gohrke, Gianluca Severi, Medical Oncology, Clinical Genetics, and Pathology

Subjects
Oncology, Candidate gene, Receptor, ErbB-2, Estrogen receptor, Genome-wide association study, Penetrance, Bioinformatics, 0302 clinical medicine, ErbB-2, Risk Factors, Receptors, Odds Ratio, Asian Continental Ancestry Group, Biomarkers, Tumor, Breast Neoplasms, European Continental Ancestry Group, Female, Genetic Loci, Humans, Receptors, Estrogen, Receptors, Progesterone, Genetic Predisposition to Disease, Molecular Biology, Genetics, Genetics (clinical), Progesterone, 0303 health sciences, education.field_of_study, Tumor, Association Studies Articles, General Medicine, 3. Good health, Risk factors for breast cancer, 030220 oncology & carcinogenesis, Receptor, medicine.medical_specialty, Population, Biology, Auto-immunity, transplantation and immunotherapy [N4i 4], White People, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Asian People, Internal medicine, medicine, education, 030304 developmental biology, medicine.disease, Estrogen, TOX3, Biomarkers
Abstract

Contains fulltext : 96071.pdf (Publisher’s version ) (Closed access) Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 x 10(-18)), rs3803662 (16q12) (P = 3.7 x 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 x 10(-6) and P = 4.1 x 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P

Published
2011

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

Author

Malcolm W.R. Reed, Artitaya Lophatananon, M. Pilar Zamora, Chen-Yang Shen, Monica Barile, Suleeporn Sangrajrang, Nichola Johnson, James McKay, Ming-Feng Hou, Diether Lambrechts, Isabel dos Santos Silva, Paolo Radice, Thilo Dörk, Janet E. Olson, Grethe I. Grenaker Alnæs, Katarzyna Durda, Angela Cox, Javier Benitez, Maartje J. Hooning, Douglas F. Easton, Volker Arndt, Hui Zhao, Nick Orr, Heli Nevanlinna, Leslie Bernstein, Jose Ignacio Arias Perez, Hoda Anton-Culver, Nicola Miller, Jolanta Lissowska, Natalia Bogdanova, Frans B. L. Hogervorst, Manjeet K. Humphreys, Johann H. Karstens, Alfons Meindl, Veli-Matti Kosma, Mark E. Sherman, Montserrat Garcia-Closas, Pascal Guénel, Zachary S. Fredericksen, Alison M. Dunning, Kenneth Offit, Marjanka K. Schmidt, Katarzyna Jaworska, Yon Ko, Heiko Müller, Jyh Cherng Yu, Melissa C. Southey, Paul Brennan, Kenneth Muir, Maya Ghoussaini, Laura Baglietto, Antonis C. Antoniou, Sheila Seal, Robert Winqvist, Siranoush Manoukian, Peter Schürmann, Anne Lise Børresen-Dale, Rita K. Schmutzler, Julian Peto, Linda J. Titus, Ian W. Brock, Valerie Gaborieau, Miroslaw K. Kapuscinski, Iosif V. Zalutsky, Arja Jukkola-Vuorinen, Peter A. Fasching, Elza Khusnutdinova, Jaana M. Hartikainen, Børge G. Nordestgaard, Jianjun Liu, Barbara Burwinkel, Anthony J. Swerdlow, Suthee Rattanamongkongul, Florence Menegaux, Hermann Brenner, Mervi Grip, Michael J. Kerin, Rebecca Hein, Simon S. Cross, Mia M. Gaudet, Anna Jakubowska, Paul D.P. Pharoah, Alexander Miron, Keun-Young Yoo, Katri Pylkäs, Huan Ming Hsu, Per Hall, Christa Stegmaier, Patrick Neven, H. Bas Bueno-de-Mesquit, Dieter Flesch-Janys, Sara Margolin, Jonine D. Figueroa, Natalia Antonenkova, Peter Hillemanns, Elżbieta Złowocka, Matthias W. Beckmann, Julia A. Knight, Alan Ashworth, Catriona McLean, Georgia Chenevix-Trench, Mark E. Robson, Arto Mannermaa, Roger L. Milne, Dong Young Noh, Nazneen Rahman, Hiltrud Brauch, Carl Blomqvist, Darya Prokovieva, Vesa Kataja, Kristiina Aittomäki, Annegien Broeks, Keith Humpreys, Marina Bermisheva, Sarah Schott, Ian Tomlinson, Thérèse Truong, Anna Marie Mulligan, Irene L. Andrulis, Christof Sohn, Olivia Fletcher, Gord Glendon, Annika Lindblom, Graham G. Giles, Kamila Czene, Xiaoqing Chen, Esther M. John, Claus R. Bartram, John L. Hopper, Fergus J. Couch, Kathleen M. Egan, Ute Hamann, Stig E. Bojesen, Vessela N. Kristensen, Tuomas Heikkinen, Clare Turnbull, Alexander Hein, Emilie Cordina-Duverger, Stefan Nickels, Daehee Kang, Arif B. Ekici, Frederick Marmee, Elinor J. Sawyer, Minouk J. Schoemaker, Jenny Chang-Claude, Argyrios Ziogas, Caroline Seynaeve, Joseph Vijai, Anthony Renwick, Jonathan Beesley, Paolo Peterlongo, Jonathan J. Morrison, Henrik Flyger, Andreas Schneeweiss, John W.M. Martens, Xianshu Wang, Puttisak Puttawibul, Christina A. Clarke, Daniel J. Park, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Polly A. Newcomb, Hans Wildiers, Amy Trentham-Dietz, Albina Farahtdinova, Gianluca Severi, Margriet Collée, Clinical Genetics, Medical Oncology, Department of Obstetrics and Gynecology, Women's Health Research Program, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, and Genome-Scale Biology (GSB) Research Program

Subjects
Life Sciences & Biomedicine - Other Topics, Genetics and Molecular Biology (all), Oncology, Linkage disequilibrium, Epidemiology, susceptibility locus, Estrogen receptor, Genome-wide association study, chinese, Bioinformatics, Biochemistry, Linkage Disequilibrium, 0302 clinical medicine, Risk Factors, Receptors, SUSCEPTIBILITY LOCUS, 0303 health sciences, Multidisciplinary, Medicine (all), Cancer Risk Factors, Statistics, Obstetrics and Gynecology, WOMEN, Single Nucleotide, Genomics, 3. Good health, Europe, Multidisciplinary Sciences, Receptors, Estrogen, 030220 oncology & carcinogenesis, Genetic Epidemiology, Medicine, Science & Technology - Other Topics, Chromosomes, Human, Pair 6, Female, Pair 6, women, Cancer Epidemiology, Human, Research Article, medicine.medical_specialty, Asia, Breast Neoplasms, Haplotypes, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Genome-Wide Association Study, Biochemistry, Genetics and Molecular Biology (all), Agricultural and Biological Sciences (all), Science, education, Genetic Causes of Cancer, Single-nucleotide polymorphism, Biostatistics, Chromosomes, RC0254, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genome Analysis Tools, Internal medicine, Breast Cancer, medicine, Genome-Wide Association Studies, Genetics, Cancer Genetics, SNP, Polymorphism, Biology, Genetic Association Studies, 030304 developmental biology, Science & Technology, business.industry, Haplotype, Computational Biology, Human Genetics, Odds ratio, medicine.disease, Estrogen, Genetics of Disease, 3111 Biomedicine, business, CHINESE, Mathematics
Abstract

The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6×10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8×10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2×10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8×10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8×10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3×10(-7), p(heterogeneity) = 5.1×10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours. ispartof: PLoS One vol:7 issue:8 ispartof: location:United States status: published

Published
2012
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28. The role of genetic breast cancer susceptibility variants as prognostic factors

Author

Laura J. van't Veer, John W.M. Martens, Erik Van Limbergen, Jenny Chang-Claude, Alison M. Dunning, Sabapathy P. Balasubramanian, Janet E. Olson, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Malcolm W.R. Reed, Manjeet K. Humphreys, Mark E. Sherman, Douglas F. Easton, Graham G. Giles, Anne Sophie Dieudonne, Bernardo Bonanni, Marjanka K. Schmidt, Saila Kauppila, Thilo Dörk, Michael Bremer, Arja Jukkola-Vuorinen, Peter A. Fasching, Sara J. Schonfeld, Laura Baglietto, Annegien Broeks, Stig E. Bojesen, Stefan Nickels, Carl Blomqvist, Kamila Czene, Javier Benitez, Hilmi Ozcelik, John L. Hopper, Frederik Marmé, Paolo Peterlongo, Simon S. Cross, Melissa C. Southey, Maria Schiekel, Robert Winqvist, Paul D.P. Pharoah, Alexander Miron, Agnes Jager, Jose Ignacio Arias Perez, M. Pilar Zamora, Esther M. John, Matthew L. Kosel, Diether Lambrechts, Henrik Flyger, Sigrid Hatse, Tjoung Won Park-Simon, Per Hall, Petra E A Huijts, Jonine D. Figueroa, Irene L. Andrulis, Dario Greco, Hoda Anton-Culver, Veli-Matti Kosma, Kelly-Anne Phillips, Arto Mannermaa, Claudia Rauh, Fergus J. Couch, Andreas Schneeweiss, Flora E. van Leeuwen, Kristen N. Stevens, Annika Lindblom, Bernard Peissel, Georgia Chenevix-Trench, Arif B. Ekici, Preetha Rajaraman, Shan Wang-Gohrke, Dennis J. Slamon, Jianjun Liu, M.J. Hooning, Jaana M. Hartikainen, Montserrat Garcia-Closas, Katri Pylkäs, Roger L. Milne, Christof Sohn, Peter Devilee, Gianluca Severi, Ursula Eilber, Kristiina Aittomäki, Vesa Kataja, Børge G. Nordestgaard, Rob A. E. M. Tollenaar, Anna Marie Mulligan, Argyrios Ziogas, Barbara Burwinkel, Caroline Seynaeve, Bernard Loris, Mieke Kriege, Renate Udo, Gord Glendon, Carmel Apicella, Heli Nevanlinna, Thomas Karn, Jolanta Lissowska, Angela Cox, and Medical Oncology

Subjects
Genome-wide association study, 0302 clinical medicine, Risk Factors, Databases, Genetic, Receptors, Association Studies Article, Genetics (clinical), 0303 health sciences, education.field_of_study, Hazard ratio, Homozygote, General Medicine, Single Nucleotide, Middle Aged, Prognosis, 3. Good health, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Population, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Databases, Breast cancer, Genetic, SDG 3 - Good Health and Well-being, medicine, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, education, Molecular Biology, 030304 developmental biology, Genetic association, Proportional Hazards Models, Neoplastic, Proportional hazards model, medicine.disease, Estrogen, Genetics, Population, TOX3, Gene Expression Regulation, Genetic Loci, Cancer research
Abstract

Recent genome-wide association studies identified 11 single nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk. We investigated these and 62 other SNPs for their prognostic relevance. Confirmed BC risk SNPs rs17468277 (CASP8), rs1982073 (TGFB1), rs2981582 (FGFR2), rs13281615 (8q24), rs3817198 (LSP1), rs889312 (MAP3K1), rs3803662 (TOX3), rs13387042 (2q35), rs4973768 (SLC4A7), rs6504950 (COX11) and rs10941679 (5p12) were genotyped for 25 853 BC patients with the available follow-up; 62 other SNPs, which have been suggested as BC risk SNPs by a GWAS or as candidate SNPs from individual studies, were genotyped for replication purposes in subsets of these patients. Cox proportional hazard models were used to test the association of these SNPs with overall survival (OS) and BC-specific survival (BCS). For the confirmed loci, we performed an accessory analysis of publicly available gene expression data and the prognosis in a different patient group. One of the 11 SNPs, rs3803662 (TOX3) and none of the 62 candidate/GWAS SNPs were associated with OS and/or BCS at P

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