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1. 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
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2. Genome-Wide Analysis of Circulating Cell-Free DNA Copy Number Detects Active Melanoma and Predicts Survival

Author

Ian W. Brock, Shobha Silva, Sarah Danson, Fiona Taylor, Daniel Connley, David J. Hughes, James R. Bradford, Greg Wells, Abdulazeez Salawu, George J Burghel, Helen Cramp, Andrew J. G. McDonagh, Angela Cox, Nick Tiffin, and Dawn Teare

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, Percentile, Skin Neoplasms, DNA Copy Number Variations, Clinical Biochemistry, Disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Blood plasma, medicine, Humans, Melanoma, Survival analysis, Biochemistry, medical, business.industry, Proportional hazards model, Biochemistry (medical), Odds ratio, medicine.disease, Survival Analysis, Circulating Cell-Free DNA, 030104 developmental biology, 030220 oncology & carcinogenesis, Feasibility Studies, business, Cell-Free Nucleic Acids
Abstract

BACKGROUND A substantial number of melanoma patients develop local or metastatic recurrence, and early detection of these is vital to maximise benefit from new therapies such as inhibitors of BRAF and MEK, or immune checkpoints. This study explored the use of novel DNA copy-number profiles in circulating cell-free DNA (cfDNA) as a potential biomarker of active disease and survival. PATIENTS AND METHODS Melanoma patients were recruited from oncology and dermatology clinics in Sheffield, UK, and cfDNA was isolated from stored blood plasma. Using low-coverage whole-genome sequencing, we created copy-number profiles from cfDNA from 83 melanoma patients, 44 of whom had active disease. We used scoring algorithms to summarize copy-number aberrations and investigated their utility in multivariable logistic and Cox regression analyses. RESULTS The copy-number aberration score (CNAS) was a good discriminator of active disease (odds ratio, 3.1; 95% CI, 1.5–6.2; P = 0.002), and CNAS above or below the 75th percentile remained a significant discriminator in multivariable analysis for active disease (P = 0.019, with area under ROC curve of 0.90). Additionally, mortality was higher in those with CNASs above the 75th percentile than in those with lower scores (HR, 3.4; 95% CI, 1.5–7.9; P = 0.005), adjusting for stage of disease, disease status (active or resected), BRAF status, and cfDNA concentration. CONCLUSIONS This study demonstrates the potential of a de novo approach utilizing copy-number profiling of cfDNA as a biomarker of active disease and survival in melanoma. Longitudinal analysis of copy-number profiles as an early marker of relapsed disease is warranted.

Published
2018
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3. 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
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4. Assessing melanoma BRAF status through ddPCR of cfDNA

Author

Shobha Silva, Sarah Danson, Greg Wells, L. Passby, Ian W. Brock, and Angela Cox

Subjects
Oncology, medicine.medical_specialty, endocrine system diseases, business.industry, Concordance, medicine.medical_treatment, Melanoma, Disease progression, Significant difference, Cancer, Hematology, Amplicon, medicine.disease, digestive system diseases, Targeted therapy, Internal medicine, medicine, Stage (cooking), business, neoplasms
Abstract

Background Targeted therapy has revolutionised the systemic treatment of melanoma. Patients with stage III/IV melanoma with a mutation in BRAF are treated with BRAF inhibitors, with BRAF mutation status being assessed by tissue analysis. Cell-free DNA (cfDNA) released from tumours provides a method for detecting BRAF mutations. This project analysed BRAF status in cfDNA through digital droplet PCR (ddPCR). We aimed to assess the relationship between cfDNA BRAF status and disease relapse and progression. Methods Plasma from 100 patients with active or recently resected melanoma was obtained during previous work. 85 samples had cfDNA extracted. Tissue BRAF status was known for 57 samples. cfDNA was extracted from 1-2ml plasma with the QIAamp circulating nucleic acid kit (QIAGEN®) following manufacturer protocol, eluting cfDNA into 100µL. cfDNA was quantified with SYBR green quantitative real-time PCR (Life Technologies), based on an 87bp GAPDH gene amplicon. ddPCR™ was performed using the Bio-Rad QX200 Droplet Generator™ and Droplet Reader as per manufacturer protocol. Analysis was performed with Bio-Rad QuantaSoft Version 1.7.4. Results Median yield of cfDNA was 1.97ng/ml. This correlated well with other yields from this sample set (Pearson’s r = 0.6687, p 10,000 droplets and were included for analysis. 12 samples contained BRAF mutant positive droplets. Concordance rate between tissue BRAF status and the presence/absence of cfDNA BRAF mutant droplets was 74%. 7/18 tissue BRAF mutant samples were cfDNA BRAF mutant positive, in contrast to 2/32 tissue BRAF wild-type samples. The presence of BRAF mutant positive droplets in cfDNA was significantly different between tissue BRAF mutant and wild-type groups (p = 0.004). The presence of BRAF mutant droplets did not confer any significant difference in rate of relapse (p = 0.758) or mortality rate (p = 0.654). Conclusions A very low volume of cfDNA can be used to detect BRAF mutations in patients with melanoma through ddPCR. Having used small yields of cfDNA, it is possible that some samples fell below the limit of detection for ddPCR. Longitudinal study is warranted to monitor cfDNA BRAF status, and whether this correlates with relapse and disease progression. Legal entity responsible for the study The authors. Funding Weston Park Cancer Charity. Disclosure All authors have declared no conflicts of interest.

Published
2019
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5. 9q31.2-rs865686 as a susceptibility locus for estrogen receptor-positive breast cancer: evidence from the Breast Cancer Association Consortium

Author

Javier Benitez, Frederik Marmé, Nichola Johnson, Ian W. Brock, Fiona M. Blows, Natalia Bogdanova, Arto Mannermaa, Peter Hillemanns, Hoda Anton-Culver, Anthony J. Swerdlow, Roger L. Milne, Jonathan Beesley, Veli-Matti Kosma, Guzel Zinnatullina, Paolo Peterlongo, Irene L. Andrulis, Annika Lindblom, Dieter Flesch-Janys, Ann Smeets, Arif B. Ekici, Pascal Guénel, Vesa Kataja, Thomas Brüning, Graham G. Giles, Isabel dos-Santos-Silva, Douglas F. Easton, Yuriy Rogov, Ruediger Schulz-Wendtland, Pierre Laurent-Puig, Thilo Dörk, Malcolm W.R. Reed, Heiko Müller, Linda M. Braaf, Janet E. Olson, Cariona A. McLean, Leslie Bernstein, Elinor J. Sawyer, Jaana M. Hartikainen, Siranoush Manoukian, Robert Paridaens, Marina Bermisheva, Natalia Antonenkova, Ian Tomlinson, Thérèse Truong, Minouk J. Schoemaker, Anna Marie Mulligan, Elza Khusnutdinova, Xianshu Wang, Christof Sohn, Katri Pylkäs, Caroline M. Seynaeve, Christina Clarke Dur, Caroline Weltens, Sune F. Nielsen, Carl Blomqvist, Nick Orr, Hiltrud Brauch, Maryam Mahmoodi, Shan Wang-Gohrke, Melissa C. Southey, Fergus J. Couch, Olivia Fletcher, Mervi Grip, Nayana Weerasooriya, Georgia Chenevix-Trench, Rita K. Schmutzler, Julian Peto, Jenny Chang-Claude, Peter Schürmann, Frank Dudbridge, John W.M. Martens, Robert Winqvist, Surapon Wiangnon, Celine M. Vachon, Arkom Chaiwerawattana, Hermann Brenner, Artitaya Lophatananon, Arja Jukkola-Vuorinen, Peter A. Fasching, Børge G. Nordestgaard, Manjeet K. Humphreys, Barbara Burwinkel, Kristiina Aittomäki, Marjanka K. Schmidt, Argyrios Ziogas, Michael Bremer, Paul D.P. Pharoah, Loris Bernard, Alexander Miron, Sara Margolin, Kamila Czene, Diether Lambrechts, Claus R. Bartram, Annegien Broeks, Maya Ghoussaini, John L. Hopper, Simon S. Cross, Matthias W. Beckmann, Per Hall, Agnes Jager, Stig E. Bojesen, Michael Jones, Darya Prokofyeva, Julia A. Knight, Alan Ashworth, Taru A. Muranen, Xiaoqing Chen, Esther M. John, Claire Mulot, Alfons Meindl, Ursula Eilber, Laura Baglietto, José Ignacio Arias-Perez, Peter Devilee, Henrik Flyger, Sten Cornelissen, Jingmei Li, Katharina Buck, Carmel Apicella, Michael J. Kerin, Gianluca Severi, Alison M. Dunning, Kenneth Muir, Anne Langheinz, Andreas Schneeweiss, Heli Nevanlinna, Michael Golatta, Christina Justenhoven, Antoinette Hollestelle, Jianjun Liu, Helen R. Warren, Sabine Behrens, Madeleine M.A. Tilanus-Linthorst, Angela Cox, Maartje J. Hooning, Qin Wang, Paolo Radice, Volker Arndt, Robert A.E.M. Tollenaar, M. Pilar Zamora, Medical Oncology, Surgery, and Clinical Genetics

Subjects
Oncology, Pathology, Epidemiology, Estrogen receptor, population, Genome-wide association study, genetic risk, 0302 clinical medicine, Receptors, common variants, Progesterone, 0303 health sciences, education.field_of_study, identifies 2, Chromosome Mapping, Single Nucleotide, Middle Aged, 5p12, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, alleles, Female, Chromosomes, Human, Pair 9, Receptors, Progesterone, linkage, Human, Pair 9, medicine.medical_specialty, Population, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Chromosomes, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Genetic predisposition, Humans, Genetic Predisposition to Disease, Polymorphism, Allele, education, Aged, 030304 developmental biology, menarche, Case-control study, Cancer, medicine.disease, confer susceptibility, Estrogen, Case-Control Studies, genome-wide association, Genome-Wide Association Study
Abstract

Background: Our recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686). Methods: To further investigate the rs865686–breast cancer association, we conducted a replication study within the Breast Cancer Association Consortium, which comprises 37 case–control studies (48,394 cases, 50,836 controls). Results: This replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10−29] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (Phet) = 1.3 × 10−143], but no evidence of ethnic differences in per allele OR (Phet = 0.43). rs865686 was associated with estrogen receptor–positive (ER+) disease (per G-allele OR, 0.89; 95% CI, 0.86–0.91; P = 3.13 × 10−22) but less strongly, if at all, with ER-negative (ER−) disease (OR, 0.98; 95% CI, 0.94–1.02; P = 0.26; Phet = 1.16 × 10−6), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER+ tumors. Conclusions: This study is the first to show that rs865686 is a susceptibility marker for ER+ breast cancer. Impact: The findings further support the view that genetic susceptibility varies according to tumor subtype. Cancer Epidemiol Biomarkers Prev; 21(10); 1783–. ©2012 AACR.

Published
2016

6. 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
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7. Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

Author

Ian W. Brock, Dan Connley, Timothy L. Mosbruger, Ryan Abo, Nicola J. Camp, Malcolm W.R. Reed, Sushilaben H. Rigas, Rachel E. Factor, Brandt Jones, Marina Parry, George J Burghel, Lisa A. Cannon-Albright, Alex Bigelow, Theresa L. Werner, Rachel Cosby, Wei-Yu Lin, Robert Sargent, Guoying Wang, Stacey Knight, Venkatesh Rajamanickam, Philip S. Bernard, Angela Cox, Kristofer C. Berrett, Jason Gertz, Pei Yi Tai, and Rosalie G. Waller

Subjects
Risk, 0301 basic medicine, Cancer Research, Breast Neoplasms, Locus (genetics), Biology, ENCODE, Polymorphism, Single Nucleotide, Article, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Genetic variation, Humans, Genetic Predisposition to Disease, Enhancer, Genetic association, Genetics, Haplotype, Genetic Variation, 030104 developmental biology, Haplotypes, Oncology, 030220 oncology & carcinogenesis, Female, Imputation (genetics)
Abstract

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916–25. ©2016 AACR.

Published
2016

8. 7q21-rs6964587 and breast cancer risk: an extended case-control study by the Breast Cancer Association Consortium

Author

Argyrios Ziogas, Alfons Meindl, Jonathan Beesley, Jianjun Liu, Georgia Chenevix-Trench, Caroline Seynaeve, Laura Baglietto, Malcolm W.R. Reed, Angela Cox, Kamila Czene, Douglas F. Easton, Arif B. Ekici, Kristiina Aittomäki, Chen-Yang Shen, John L. Hopper, Peter A. Fasching, Lorna Gibson, Núria Malats, Stig E. Bojesen, Astrid K. Irwanto, Tuomas Heikkinen, Peter Devilee, Heli Nevanlinna, Ian W. Brock, Xiaoqing Chen, Jolanta Lissowska, Ruediger Schulz-Wendtland, Henrik Flyger, Montserrat Garcia-Closas, Xianshu Wang, Justo Lorenzo-Bermejo, Jenny Chang-Claude, Zachary S. Fredericksen, Jyh Cherng Yu, Julian Peto, Børge G. Nordestgaard, Sara Margolin, Annika Lindblom, Arto Mannermaa, Letitia D. Smith, Barbara Burwinkel, Matthias W. Beckmann, Beate Pesch, Joerg Heil, José Ignacio Arias, Fergus J. Couch, Rebecca Hein, Dong Young Noh, Olivia Fletcher, Stephen J. Chanock, Ute Hamann, Graeme Elliott, Per Hall, Vesa Kataja, Pei Ei Wu, Keun-Young Yoo, Daehee Kang, Karen A. Pooley, Yon Ko, Carl Blomqvist, Dallas R. English, Mark E. Sherman, Graham G. Giles, Alina Vrieling, Roger L. Milne, Rob A. E. M. Tollenaar, Shan Wang-Gohrke, Gianluca Severi, Alison M. Dunning, Carmel Apicella, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Christie J. van Asperen, Isabel dos Santos Silva, Janet E. Olson, Dieter Flesch-Janys, Bernd Frank, Melissa C. Southey, Paul D.P. Pharoah, Huan Ming Hsu, M. Pilar Zamora, Manjeet K. Humphreys, Medical Oncology, and Hematology

Subjects
Oncology, A Kinase Anchor Proteins, Logistic regression, Medical and Health Sciences, 0302 clinical medicine, Medizinische Fakultät, Risk Factors, Epidemiology, Odds Ratio, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, Single Nucleotide, AOCS Group, Biological Sciences, Control subjects, 3. Good health, 030220 oncology & carcinogenesis, Pair 7, Female, GENICA Network, Chromosomes, Human, Pair 7, Human, Asian Continental Ancestry Group, medicine.medical_specialty, Alleles, Breast Neoplasms, Case-Control Studies, Cytoskeletal Proteins, European Continental Ancestry Group, Genes, Recessive, Genetic Predisposition to Disease, Humans, Logistic Models, Polymorphism, Single Nucleotide, Single-nucleotide polymorphism, Biology, Chromosomes, Article, White People, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Recessive, ddc:610, Polymorphism, Allele, 030304 developmental biology, Case-control study, Odds ratio, medicine.disease, Genes
Abstract

Background: Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case–control studies. Methods: The authors genotyped 14 843 invasive case patients and 19 852 control subjects with white European ancestry and 2595 invasive case patients and 2192 control subjects with Asian ancestry. ORs were estimated by logistic regression, adjusted for study. Heterogeneity in ORs was assessed by fitting interaction terms or by subclassifying case patients and applying polytomous logistic regression. Results: For white European women, the minor T allele of 7q21-rs6964587 was associated with breast cancer risk under a recessive model (OR 1.07, 95% CI 1.00 to 1.13, p=0.04). Results were inconclusive for Asian women. From a combined analysis of 24 154 case patients and 33 376 control subjects of white European ancestry from the present and previous series, the best-fitting model was recessive, with an estimated OR of 1.08 (95% CI 1.03 to 1.13, p=0.001). The OR was greater at younger ages (p trend=0.01). Conclusion: This may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.

Published
2011
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9. Associations of common variants at 1p11.2 and 14q24.1 (RAD51L1) with breast cancer risk and heterogeneity by tumor subtype: findings from the Breast Cancer Association Consortium

Author

Peter Hillemanns, Mark E. Robson, Roger L. Milne, Amanda B. Spurdle, Rob A. E. M. Tollenaar, Federik Marme, Michael Bremer, Jan Lubinski, Linda Titus-Ernstoff, Kamila Czene, Stephen J. Chanock, Mervi Grip, Graham G. Giles, Penny Webb, G. Chenevix-Trench, Natalia Bogdanova, John L. Hopper, Frances P. O'Malley, Arto Mannermaa, Mark E. Sherman, Chen-Yang Shen, Suleeporn Sangrajrang, Julian Peto, Irene L. Andrulis, Yuri I. Rogov, Annika Lindblom, Børge G. Nordestgaard, James McKay, Barbara Burwinkel, M. Pilar Zamora, José Ignacio Arias, Beate Pesch, Vijai Joseph, Shamil Hanafievich Gantcev, Fergus J. Couch, Dong Young Noh, Betül T. Yesilyurt, Jenny Chang-Claude, Ute Hamann, Vesa Kataja, Sara Margolin, Thilo Dörk, Katarzyna Jaworska, Yon Ko, Nichola Johnson, Hiltrud Brauch, Matthias W. Beckmann, Heli Nevanlinna, Malcolm W.R. Reed, Melissa C. Southey, Arif B. Ekici, Jolanta Lissowska, Isabel dos Santos Silva, Johann H. Karstens, Robert Winqvist, Shian Ling Ding, Stig E. Bojesen, Ian Tomlinson, Anna Marie Mulligan, Montserrat Garcia-Closas, Volker Harth, Katarzyna Durda, Valerie Gaborieau, Tuomas Heikkinen, Thomas Brüning, Mia M. Gaudet, Monica Barile, Sylvia Rabstein, Christina Justenhoven, Anna Jakubowska, Paul D.P. Pharoah, Jonathan Beesley, Hermann Brenner, Elza Khusnutdinova, Heiko Müller, Jyh Cherng Yu, Adam M. Lee, Paolo Peterlongo, Clare Turnbull, Doug Easton, Radka Platte, Keun-Young Yoo, J. Margriet Collée, Paolo Radice, Laura Baglietto, Sei Hyun Ahn, Paul Brennan, Olivia Fletcher, Fleur Hammet, Ans M.W. van den Ouweland, Catriona Maclean, Carl Blomqvist, Sheila Seal, Peter Schürmann, Natalia Antonenkova, Katri Pylkäs, Angela Cox, Kenneth Offit, Huan Ming Hsu, Arja Jukkola-Vuorinen, Maartje J. Hooning, Peter A. Fasching, Alison M. Dunning, Nick Orr, Volker Arndt, Javier Benitez, Diether Lambrechts, Robert B. Diasio, Manjeet K. Humphreys, Ian W. Brock, Marjanka K. Schmidt, Per Hall, Hoda Anton-Culver, Anthony J. Swerdlow, Jonine D. Figueroa, Julia A. Knight, Ylermi Soini, Alan Ashworth, Veli-Matti Kosma, Anna deFazio, Reiner Strick, Darya Prokofieva, Shan Wang-Gohrke, Polly A. Newcomb, Dorota M. Gertig, Henrik Flyger, David D.L. Bowtell, Laura J. van't Veer, John W.M. Martens, Carmel Apicella, Anthony Renwick, Andreas Schneeweiss, Michael J. Kerin, Christian Baisch, Xianshu Wang, Kathleen Egan, Argyrios Ziogas, A. Green, Marina Bermisheva, Christof Sohn, Stéphanie Peeters, Daehee Kang, Rebecca Hein, Nazneen Rahman, Annegien Broeks, Georgia Chenevix-Trench, Elinor J. Sawyer, Louise A. Brinton, Michael Jones, Xiaoqing Chen, Kristiina Aittomäki, Esther M. John, Siranoush Manoukian, Hand Peter Fischer, Amy Trentham-Dietz, Simon S. Cross, Marie Rose Chrisiaens, Gianluca Severi, Medical Oncology, and Clinical Genetics

Subjects
Oncology, Receptor, ErbB-2, 6q25.1, Estrogen receptor, Genome-wide association study, Alleles, Breast Neoplasms, Case-Control Studies, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 14, Confidence Intervals, DNA-Binding Proteins, Female, Genetic Heterogeneity, Genetic Predisposition to Disease, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, Risk Factors, Genome-Wide Association Study, Molecular Biology, Genetics, Genetics (clinical), brca1, 0302 clinical medicine, ErbB-2, Receptors, glucose, mutation carriers, Progesterone, 0303 health sciences, Association Studies Articles, General Medicine, Single Nucleotide, 3. Good health, 030220 oncology & carcinogenesis, Pair 1, metaanalysis, Human, Receptor, medicine.medical_specialty, Single-nucleotide polymorphism, Biology, Chromosomes, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, SNP, Polymorphism, 030304 developmental biology, Genetic heterogeneity, Pair 14, Case-control study, Odds ratio, confer susceptibility, medicine.disease, Estrogen, susceptibility loci, Immunology, genome-wide association, polymorphisms
Abstract

A genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) at 1p11.2 and 14q24.1 (RAD51L1) as breast cancer susceptibility loci. The initial GWAS suggested stronger effects for both loci for estrogen receptor (ER)-positive tumors. Using data from the Breast Cancer Association Consortium (BCAC), we sought to determine whether risks differ by ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), grade, node status, tumor size, and ductal or lobular morphology. We genotyped rs11249433 at 1p.11.2, and two highly correlated SNPs rs999737 and rs10483813 (r(2) = 0.98) at 14q24.1 (RAD51L1), for up to 46 036 invasive breast cancer cases and 46 930 controls from 39 studies. Analyses by tumor characteristics focused on subjects reporting to be white women of European ancestry and were based on 25 458 cases, of which 87% had ER data. The SNP at 1p11.2 showed significantly stronger associations with ER-positive tumors [per-allele odds ratio (OR) for ER-positive tumors was 1.13, 95% CI = 1.10-1.16 and, for ER-negative tumors, OR was 1.03, 95% CI = 0.98-1.07, case-only P-heterogeneity = 7.6 x 10 25]. The association with ER-positive tumors was stronger for tumors of lower grade (case-only P = 6.7 x 10 23) and lobular histology (case-only P = 0.01). SNPs at 14q24.1 were associated with risk for most tumor subtypes evaluated, including triple-negative breast cancers, which has not been described previously. Our results underscore the need for large pooling efforts with tumor pathology data to help refine risk estimates for SNP associations with susceptibility to different subtypes of breast cancer.

Published
2011
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10. Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls

Author

Amanda B. Spurdle, Manjeet K. Humphreys, Douglas F. Easton, Marjanka K. Schmidt, F.E. van Leeuwen, Letitia D. Smith, R.A.E.M. Tollenaar, Arto Mannermaa, Daehee Kang, Ian W. Brock, S. E. Bojesen, Jianjun Liu, Alfons Meindl, Melissa C. Southey, José Ignacio Arias, Louise A. Brinton, Jonathan Beesley, Keith Humphreys, Argyrios Ziogas, Jenny Chang-Claude, Laura Baglietto, I dos Santos Silva, G. Elliott, Caroline Seynaeve, Paul D.P. Pharoah, Antonenkova Nn, Peter Devilee, Janet E. Olson, Fergus J. Couch, Georgia Chenevix-Trench, Nicola F. Johnson, MW Reed, Ute Hamann, Vesa Kataja, Roger L. Milne, Nick Orr, Annegien Broeks, Sara Margolin, Dallas R. English, Natalia Bogdanova, Guillermo Pita, L.J. van 't Veer, Matthias W. Beckmann, Carl Blomqvist, M Garcia-Closas, Radka Platte, Keun-Young Yoo, Kristiina Aittomäki, H. Flyger, Dong-Young Noh, Reiner Strick, Iosif V. Zalutsky, Thilo Dörk, Alison M. Dunning, Peter Schürmann, Angela Cox, S. Chanock, Hiltrud Brauch, Melanie Maranian, Peter A. Fasching, Shahana Ahmed, Michael Bremer, Heli Nevanlinna, Tuomas Heikkinen, Kamila Czene, Jolanta Lissowska, Gianluca Severi, Claus R. Bartram, Regina Waltes, John L. Hopper, Zachary S. Fredericksen, Graham G. Giles, Arif B. Ekici, Yon-Dschun Ko, Annika Lindblom, Jonathan J. Morrison, Shan Wang-Gohrke, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Barbara Burwinkel, Javier Benitez, Hoda Anton-Culver, Veli-Matti Kosma, Olivia Fletcher, Xianshu Wang, Per Hall, Alan Ashworth, C. J. van Asperen, Epidemiology and Data Science, EMGO - Quality of care, Hematology, Medical Oncology, and Clinical Genetics

Subjects
Oncology, medicine.medical_specialty, Genotype, Epidemiology, DNA Mutational Analysis, Mutation, Missense, Single-nucleotide polymorphism, Genome-wide association study, Breast Neoplasms, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Biology, Protein Serine-Threonine Kinases, Bioinformatics, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, Internal medicine, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Polymorphism, 030304 developmental biology, 0303 health sciences, Case-Control Studies, DNA-Binding Proteins, Female, Protein-Serine-Threonine Kinases, Tumor Suppressor Proteins, Cancer, Single Nucleotide, medicine.disease, 3. Good health, Minor allele frequency, 030220 oncology & carcinogenesis, Mutation, Breast disease, Missense, genome-wide association ataxia-telangiectasia susceptibility alleles confer susceptibility truncating mutations common variants risk gene spectrum protein
Abstract

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev; 19(9); 2143–51. ©2010 AACR.

Published
2010
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11. Risk of Estrogen Receptor-Positive and -Negative Breast Cancer and Single-Nucleotide Polymorphism 2q35-rs13387042

Author

Gianluca Severi, Hoda Anton-Culver, Veli-Matti Kosma, Peter Hillemanns, Louise A. Brinton, Douglas F. Easton, Georgia Chenevix-Trench, Roger L. Milne, Hui-Chun Wang, Chen-Yang Shen, Christie J. van Asperen, Hiltrud Brauch, M. Pilar Zamora, Rob A. E. M. Tollenaar, Heli Nevanlinna, Kristiina Aittomäki, Olivia Fletcher, Melissa C. Southey, Malcolm W.R. Reed, Jonathan Beesley, Jolanta Lissowska, Isabel dos Santos Silva, Nichola Johnson, Stig E. Bojesen, Per Hall, José Ignacio Arias, Tuomas Heikkinen, Janet E. Olson, Ian W. Brock, Clare Turnbull, Tatjana Nikolaeva, Dong-Young Noh, Yuqing Li, Paul D.P. Pharoah, Michael Bremer, Matthias W. Beckmann, Alison M. Dunning, Kamila Czene, Radka Platte, Keun-Young Yoo, Claus R. Bartram, Letitia D. Smith, John L. Hopper, kConFab Investigators, Natalia Antonenkova, Natalia Bogdanova, Stephen J. Chanock, Graeme Elliott, Vesa Kataja, Christina Justenhoven, Zachary S. Fredericksen, Thilo Dörk, Daehee Kang, Reiner Strick, Iosif V. Zalutsky, Shan Wang-Gohrke, Melanie Maranian, Shahana Ahmed, Peter Schürmann, Angela Cox, Arif B. Ekici, Sou-Tong Chen, Fergus J. Couch, Argyrios Ziogas, Jonathan J. Morrison, Jenny Chang-Claude, Yon-Dschun Ko, Henrik Flyger, Jianjun Liu, Peter A. Fasching, Caroline Seynaeve, Marina Bermisheva, Dallas R. English, Graham G. Giles, Xianshu Wang, Montserrat Garcia-Closas, Jyh-Cherng Yu, Nazneen Rahman, Elza Khusnutdinova, Rita K. Schmutzler, Julian Peto, Børge G. Nordestgaard, Carl Blomqvist, Barbara Burwinkel, Anthony Renwick, Manjeet K. Humphreys, Amanda B. Spurdle, Arto Mannermaa, Susanne Haas, Sarah Hines, Peter Devilee, Alfons Meindl, Laura Baglietto, Javier Benitez, Hematology, Medical Oncology, and Clinical Genetics

Subjects
Cancer Research, Estrogen receptor, Noninfiltrating, Linkage Disequilibrium, 0302 clinical medicine, Gene Frequency, Neoplasms, Ductal, Receptors, Odds Ratio, Breast, Progesterone, 0303 health sciences, Tumor, Medicine (all), Carcinoma, Ductal, Breast, Confounding Factors, Epidemiologic, Articles, Single Nucleotide, Middle Aged, Control subjects, Prognosis, 3. Good health, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Female, Breast disease, Receptors, Progesterone, Adult, Asian Continental Ancestry Group, medicine.medical_specialty, Neoplasms, Hormone-Dependent, Genotype, Intraductal, European Continental Ancestry Group, Single-nucleotide polymorphism, Breast Neoplasms, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Breast cancer, European origin, Asian People, SDG 3 - Good Health and Well-being, Predictive Value of Tests, Internal medicine, medicine, Biomarkers, Tumor, Confidence Intervals, Humans, Genetic Predisposition to Disease, Hormone-Dependent, Polymorphism, 030304 developmental biology, Aged, business.industry, Carcinoma, Odds ratio, medicine.disease, Carcinoma, Intraductal, Noninfiltrating, Case-Control Studies, Confounding Factors (Epidemiology), Estrogen, Endocrinology, Multicenter study, business, Humanities, Biomarkers
Abstract

Background: A recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)–positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium. Methods: 2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided. Results: We found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 x 10–19). The odds ratio was lower than that previously reported (P = .02) and did not vary by age or ethnicity (all P .2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10–15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P = .0003) and both progesterone receptor (PR)–positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 x 10–14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P = .00002). Conclusion: The rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women. Roger L. Milne, Javier Benitez, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittomaki, Carl Blomqvist, Jose Ignacio Arias, M. Pilar Zamora, Barbara Burwinkel, Claus R. Bartram, Alfons Meindl, Rita K. Schmutzler, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W. R. Reed, Melissa C. Southey, Letitia Smith, Amanda B. Spurdle, John L. Hopper, Fergus J. Couch, Janet E. Olson, Xianshu Wang, Zachary Fredericksen, Peter Schurmann, Michael Bremer, Peter Hillemanns, Thilo Dork, Peter Devilee, Christie J. van Asperen, Rob A. E. M. Tollenaar, Caroline Seynaeve, Per Hall, Kamila Czene, Jianjun Liu, Yuqing Li, Shahana Ahmed, Alison M. Dunning, Melanie Maranian, Paul D. P. Pharoah, Georgia Chenevix-Trench, Jonathan Beesley, kConFab Investigators,, AOCS Group, Natalia V. Bogdanova, Natalia N. Antonenkova, Iosif V. Zalutsky, Hoda Anton-Culver, Argyrios Ziogas, Hiltrud Brauch, Christina Justenhoven, Yon-Dschun Ko, Susanne Haas, Peter A. Fasching, Reiner Strick, Arif B. Ekici, Matthias W. Beckmann, Graham G. Giles, Gianluca Severi, Laura Baglietto, Dallas R. English, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Clare Turnbull, Sarah Hines, Anthony Renwick, Nazneen Rahman, Borge G. Nordestgaard, Stig E. Bojesen, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Montserrat Garcia-Closas, Stephen Chanock, Jolanta Lissowska, Louise A. Brinton, Jenny Chang-Claude, Shan Wang-Gohrke, Chen-Yang Shen, Hui-Chun Wang, Jyh-Cherng Yu, Sou-Tong Chen, Marina Bermisheva, Tatjana Nikolaeva, Elza Khusnutdinova, Manjeet K. Humphreys, Jonathan Morrison, Radka Platte, Douglas F. Easton, on behalf of the Breast Cancer Association Consortium

Published
2009

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

Author

Martine Tranchant, Fergus J. Couch, Meeri Otsukka, Sabine Behrens, Jirong Long, Nadia Obi, Kamila Czene, John L. Hopper, Heather Thorne, Robert Pilarski, Anja Rudolph, Simon S. Cross, Volker Harth, Gabrielle Colleran, Hatef Darabi, Thomas Van Brussel, Eunjung Lee, Anne Lotz, E. Krol-Warmerdam, M. Pilar Zamora, Qin Wang, Andy C. H. Lee, Annie Fung, Kara Sargus, Melissa C. Southey, Katja Butterbach, Nuria Álvarez, Francois Bacot, Jeffrey G. Meyer, Ian W. Brock, Jessica Clague De Hart, Pierre Laurent-Puig, Irene L. Andrulis, Pei Chao, Arnaud Droit, Per Hall, Daniel C. Tessier, Paolo Radice, Frederic Robidoux, Don M. Conroy, Irja Erkkilä, Daniel Vincent, Antoinette Hollestelle, Christopher A. Hilker, Alicia Beeghly-Fadiel, Muhabbet Celik, Peggy Reynolds, Caroline Baynes, Sophia S. Wang, Katri Pylkäs, Kang In Nee, Robert Winqvist, Henrik Flyger, Annette Heemskerk, Sara Margolin, Hui Cai, Julie M. Cunningham, Prat Boonyawongviroj, Bernardo Bonanni, Anthony J. Swerdlow, Dan Connley, Huiyan Ma, Valerie Gaborieau, David O. Nelson, Keitaro Matsuo, Sylvie La Boissière, Pornthep Siriwanarungsan, Hidemi Ito, Ursula Eilber, Matthias W. Beckmann, Sylvia Rabstein, Natalia Bogdanova, Anna Jakubowska, Yves Raoul, Robert A.E.M. Tollenaar, Frans B. L. Hogervorst, Hannah L Park, Pierre Kerbrat, Ying Zheng, Paul D.P. Pharoah, Wanqing Wen, Judith Heinz, Annika Lindblom, Christa Stegmaier, Manjeet K. Bolla, Loris Bernard, Anna H. Wu, Alison M. Dunning, Hermann Brenner, A. Green, Thilo Dörk, Chia-Ni Hsiung, Dennis Deapen, Michael G. Schrauder, Gilian Peuteman, S.E. Higham, Sabapathy P. Balasubramanian, Irene Feroce, Christina Justenhoven, Angela Jones, William J. Blot, Nichola Johnson, Petra Seibold, D. Bowtell, Jiajun Shi, Wei Zheng, U Hamann, Pascal Guenel, P. Webb, Soo Hwang Teo, Daniela Zaffaroni, J. Blom, Rita K. Schmutzler, Douglas F. Easton, Yani Lu, Witold Zatonski, Phuah Sze Yee, Susan L. Neuhausen, Kenneth Muir, Sofia Khan, Daehee Kang, Silke Landrith, Helena Kemiläinen, Maggie Angelakos, Rich Pinder, Javier Benitez, Til Olchers, Senno Verhoef, Fred Schumacher, Martha J. Shrubsole, Teresa Selander, Teh Yew Ching, Christof Sohn, Patrick Arveux, Dorota M. Gertig, Saila Kauppila, Mervi Grip, Florentia Fostira, Jenny Chang-Claude, Michael Stagner, Kathleen Corthouts, Ellen Van Der Schoot, H Nevanlinna, Peter Bugert, Christian Baisch, Eija Myöhänen, Sonja Wolf, Hoda Anton-Culver, Nicola Miller, Cheng Har Yip, Neonila Szeszenia-Dabrowska, Nicholas K. Hayward, Dieter Flesch-Janys, Barbara Burwinkel, J. Molenaar, Eileen Williams, Marjanka K. Schmidt, Yon Ko, Anja Nieuwlaat, Chen-Yang Shen, Veli-Matti Kosma, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Artitaya Lophatananon, Mikael Hartman, Jonathan Beesley, Bernard Peissel, Paolo Peterlongo, Ji Yeob Choi, Craig Luccarini, Rosalind A. Eeles, Niall M. McInerney, Bernard Thienpont, Xiao-Ou Shu, Léa Héguy, Maya Ghoussaini, Sander Canisius, Wing-Yee Lo, Suleeporn Sangrajrang, Nur Aishah Taib, June Yashiki, Kirsimari Aaltonen, Louise A. Brinton, Elinor J. Sawyer, Alina Vrieling, Angela Cox, Frederik Marmé, Matthias Rübner, Graham G. Giles, Sonja Oeser, Hans Christiansen, Andrew Rowan, Ed Dicks, Andeas Schneeweiß, Catriona McLean, Antonis C. Antoniou, B. Pesch, Eveline Niedermayr, Volker Arndt, Janet E. Olson, Dominiek Smeets, Jingmei Li, Georgia Chenevix-Trench, Claire Mulot, Siranoush Manoukian, Hans Fischer, Ellen Crepin, Arto Mannermaa, Ali Amin Al Olama, Helen Cramp, Ans M.W. van den Ouweland, Olivia Fletcher, Sharon A. Windebank, Peter Hillemanns, Nayana Weerasooriya, James V. Lacey, Leslie Bernstein, Romuald Le Scodan, Giulietta Scuvera, P. Parsons, Thomas C. Putti, Elaine Ryder-Mills, Sara Benlloch, Beata Peplonska, Stig E. Bojesen, Kimberley Chua, Stefan Nickels, Nick Orr, Roger L. Milne, Tuomas Heikkinen, Christopher A. Haiman, Natalia Antonenkova, Volker Hermann, Maria Kabisch, Kenneth Offit, Julia A. Knight, Angela Maniscalco, Arja Jukkola-Vuorinen, Hartwig Ziegler, Chenjie Zeng, Jacques Simard, Pamela L. Horn-Ross, Daphne S.C. Lee, Xingyi Guo, Jan Lubinski, Michael J. Kerin, Loic Le Marchand, Sune F. Nielsen, Peter Devilee, A. De Fazio, Qiuyin Cai, Annie Turgeon, Yoon Sook-Yee, Silje Nord, Petra Bos, Hiltrud Brauch, Kyriaki Michailidou, Shivaani Mariapun, Kari Mononen, Alfons Meindl, Peter B. Kang, Siddhartha Kar, Alessandra Rossi, G. Chenevix-Trench, Diether Lambrechts, Karl von Smitten, Zsofia Kote-Jarai, Emiel J. Th. Rutgers, Chiu-Chen Tseng, Peter A. Fasching, Lesley McGuffog, Annegien Broekss, Johann H. Karstens, Montserrat Garcia-Closas, Thomas Brüning, David C. Whiteman, Judi Maskiell, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, and Obstetrics & Gynecology

Subjects
Genetic Markers, Linkage disequilibrium, Epidemiology, Locus (genetics), Genome-wide association study, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Article, Breast cancer, SDG 3 - Good Health and Well-being, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Gene, Genetics, Molecular epidemiology, Case-control study, Chromosome Mapping, medicine.disease, Logistic Models, Oncology, Genetic marker, Genetic Loci, Case-Control Studies, Female, Chromosomes, Human, Pair 4, Genome-Wide Association Study
Abstract

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk. Cancer Epidemiol Biomarkers Prev; 24(11); 1680–91. ©2015 AACR.

Published
2015

14. FGF receptor genes and breast cancer susceptibility: Results from the Breast Cancer Association Consortium

Author

Arif B. Ekici, Betül T. Yesilyurt, Wei-Yen Lim, Xiao-Ou Shu, Xianshu Wang, Heli Nevanlinna, Katarzyna Jaworska-Bieniek, José Ignacio Arias-Perez, Jenny Chang-Claude, Miao Hui, Hiroji Iwata, Giuseppe Floris, Diether Lambrechts, Graham G. Giles, Leticia Tais Moreno, Chen-Yang Shen, Suleeporn Sangrajrang, Paolo Peterlongo, Malcolm W.R. Reed, Jesús Herranz, F Marmé, Melissa C. Southey, James McKay, H. Flyer, Sook Ryun Park, Dong-Young Noh, Jolanta Lissowska, Jan Lubinski, Alison M. Dunning, Robert Winqvist, Kerstin B. Meyer, Keitaro Matsuo, Stig E. Bojesen, Pascal Guénel, Kavitta Sivanandan, Vesa Kataja, Peter Devilee, Qiuyin Cai, Anna Jakubowska, Paul D.P. Pharoah, Roger L. Milne, Fergus J. Couch, Kenneth Muir, Hidemi Ito, Katarzyna Durda, Georgia Chenevix-Trench, Frederique Mariette, Taru A. Muranen, Qin Wang, Pornthep Siriwanarangsan, Sara Margolin, Manjeet K. Bolla, Daniel F. Schmidt, Celine M. Vachon, Carl Blomqvist, M Garcia-Closas, Claire Mulot, Paolo Radice, Fredrick R. Schumacher, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Mitul Shah, Matthias W. Beckmann, J. M. Collee, Wei Zheng, Philip Iau, Marta Mendiola, Christopher A. Haiman, Mikael Hartman, Hiltrud Brauch, Chiu-Chen Tseng, Dieter Flesch-Janys, F. Labrèche, Javier Benitez, Laura Baglietto, N. Kondo, Michael J. Kerin, Mikael Eriksson, Nicola Miller, Janet E. Olson, Jirong Long, Kristiina Aittomäki, Mark S. Goldberg, Daniel O. Stram, Wan Ting Tay, Artitaya Lophatananon, S. Tchatchou, Guillermo Pita, Loic Le Marchand, Katri Pylkäs, Natalia Bogdanova, Arja Jukkola-Vuorinen, Wei Lu, L.J. van 't Veer, Peter A. Fasching, P. Zamora, Anja Rudolph, Stefan P. Renner, Karin Leunen, Angela Cox, Drakoulis Yannoukakos, Arto Mannermaa, Ian W. Brock, William J. Blot, Nick Orr, Yu Tang Gao, Kristen S. Purrington, Jacques Simard, Maartje J. Hooning, Anthony J. Swerdlow, Siranoush Manoukian, Irene L. Andrulis, David Hardisson, Nichola Johnson, Martine Dumont, Primitiva Menendez-Rodriguez, R.A.E.M. Tollenaar, Veli-Matti Kosma, Gianluca Severi, Aida Karina Dieffenbach, Volker Arndt, Silvia Pineda, Annika Lindblom, D. J. Van Den Berg, Stephen J. Chanock, Cheng Har Yip, Hermann Brenner, Chia-Ni Hsiung, MaryPat Jones, Thomas Brüning, Enes Makalic, Hatef Darabi, Mervi Grip, I dos Santos Silva, J. C. Yu, Sandra Deming-Halverson, Mieke Kriege, Soo Hwang Teo, Gordon Glendon, Julian Peto, Kamila Czene, Annegien Broeks, C. Stegmaier, Børge G. Nordestgaard, Barbara Burwinkel, María R Alonso, John L. Hopper, Joe Dennis, Jun Li, Thilo Dörk, Efraim H. Rosenberg, Divyansh Agarwal, Bing Zhang, Caroline Seynaeve, Jaana M. Hartikainen, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, María José Sánchez, Anna H. Wu, Douglas F. Easton, Olivia Fletcher, M-F. Hou, B. E. Henderson, Daehee Kang, Jung Yun Choi, Keith Humphreys, Kyriaki Michailidou, Sarah Stewart-Brown, Per Hall, Elinor J. Sawyer, Marjanka K. Schmidt, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Martha J. Shrubsole, Clinical Genetics, Cardiothoracic Surgery, Medical Oncology, Surgery, and Erasmus MC other

Subjects
Cancer Research, Fibroblast Growth Factor, Genome-wide association study, disease subtypes, Bioinformatics, susceptibility, Genotype, single-nucleotide polymorphisms, common variants, risk, Research Support, Non-U.S. Gov't, identifies 2, Single Nucleotide, 3. Good health, Multicenter Study, ovarian-cancer, Type 5, Oncology, loci, alleles, Female, Type 4, Type 3, Type 2, Receptor, Type 1, SNP, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, RC0254, Case-Control Studies, Genetic Variation, Genome-Wide Association Study, Humans, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Fibroblast Growth Factor, Type 2, Receptor, Fibroblast Growth Factor, Type 3, Receptor, Fibroblast Growth Factor, Type 4, Receptor, Fibroblast Growth Factor, Type 5, Genetic Predisposition to Disease, Breast cancer, breast cancer, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, medicine, Journal Article, Polymorphism, QH426, Genetic association, brca2 mutations, Case-control study, Genetics and Genomics, Odds ratio, medicine.disease, confer susceptibility, FGF receptors, genome-wide association, Ovarian cancer, Research Support, U.S. Gov't, Non-P.H.S
Abstract

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.\ud \ud Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.\ud \ud Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2.\ud \ud Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK.

Published
2014
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15. A large-scale assessment of two-way SNP interactions in breast cancer susceptibility using 46 450 cases and 42 461 controls from the breast cancer association consortium

Author

Qin Wang, Anna González-Neira, Betül T. Yesilyurt, Paolo Radice, Jenny Chang-Claude, Malcolm W.R. Reed, Graham G. Giles, Robert A.E.M. Tollenaar, Gianluca Severi, Gillian S. Dite, Fredrick R. Schumacher, J. Margriet Collée, Pascal Guénel, Fergus J. Couch, Núria Malats, Dieter Flesch-Janys, Ute Hamann, Michael J. Kerin, Asta Försti, Guillermo Pita, Christina A. Clarke, Heli Nevanlinna, Anja Rudolph, Jolanta Lissowska, Javier Benitez, Pilar Zamora, Brian E. Henderson, Elinor J. Sawyer, Arto Mannermaa, Hiltrud Brauch, Jesús Herranz, Henrik Flyger, Aida Karina Dieffenbach, Karin Leunen, Xianshu Wang, Angela Cox, Celine M. Vachon, Arif B. Ekici, Maartje J. Hooning, Antoinette Hollestelle, Volker Arndt, Hatef Darabi, Penny Soucy, Minouk J. Schoemaker, Thilo Dörk, Hoda Anton-Culver, Melissa C. Southey, Stig E. Bojesen, Yon-Dschun Ko, Natalia Bogdanova, Veli-Matti Kosma, Robert Winqvist, Argyrios Ziogas, Jingmei Li, Carmel Apicella, M. Rosario Alonso, Douglas F. Easton, Arja Jukkola-Vuorinen, Paolo Mariani, Hermann Brenner, Peter A. Fasching, Drakoulis Yannoukakos, Paolo Peterlongo, Annegien Broeks, Federik Marme, Caroline Seynaeve, Taru A. Muranen, Anna Jakubowska, Paul D.P. Pharoah, Joe Dennis, Vesa Kataja, Kamila Czene, Alison M. Dunning, Mikael Eriksson, Vessela N. Kristensen, Ian Tomlinson, Thérèse Truong, Jonathan Tyrer, Thomas Rüdiger, Montserrat Garcia-Closas, Manjeet K. Bolla, Amanda E. Toland, Thomas Brüning, John L. Hopper, kConFab Investigators, Carl Blomqvist, Lothar Häberle, Hans Ulrich Ulmer, Anna Marie Mulligan, Jan Lubinski, Diether Lambrechts, Ian W. Brock, Emiel J. Th. Rutgers, Anthony J. Swerdlow, Grethe I. Grenaker Alnæs, Stephen J. Chanock, Katarzyna Durda, Olivia Fletcher, Mervi Grip, Per Hall, Claire Mulot, Keith Humphreys, Jonine D. Figueroa, Julia A. Knight, Petra Seibold, Alan Ashworth, Laura Baglietto, Katarzyna Jaworska-Bieniek, José Ignacio Arias-Perez, Sara Margolin, Mitul Shah, Matthias W. Beckmann, Bernard Peissel, Kyriaki Michailidou, Peter Devilee, Anne Lise Børresen-Dale, Julian Peto, Georgia Chenevix-Trench, Børge G. Nordestgaard, Barbara Burwinkel, Kristiina Aittomäki, Nicola Miller, Isabel dos Santos Silva, Agnes Jager, Janet E. Olson, Roger L. Milne, Kristen S. Purrington, Jacques Simard, Irene L. Andrulis, Nick Orr, Martine Dumont, Annika Lindblom, Nichola Johnson, Marjanka K. Schmidt, Susan L. Neuhausen, Marie Sanchez, Christopher A. Haiman, Loic Le Marchand, Katri Pylkäs, Giuseppe Floris, Christa Stegmaier, Senno Verhoef, Jaana M. Hartikainen, Gord Glendon, Cancer Center Amsterdam, Oncogenomics, Clinical Genetics, and Medical Oncology

Subjects
Oncology, epistasis, Genome-wide association study, Bioinformatics, 0302 clinical medicine, Medizinische Fakultät, common variants, Genetics (clinical), risk, 0303 health sciences, Association Studies Articles, identifies 2, Family aggregation, General Medicine, Single Nucleotide, 030220 oncology & carcinogenesis, loci, alleles, Female, medicine.medical_specialty, Single-nucleotide polymorphism, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Genetic, Internal medicine, Genetics, medicine, Genetic predisposition, SNP, Humans, Genetic Predisposition to Disease, ddc:610, Allele, Polymorphism, Molecular Biology, erap1, 030304 developmental biology, Case-control study, Epistasis, Genetic, Case-Control Studies, Genome-Wide Association Study, Logistic Models, medicine.disease, confer susceptibility, genome-wide association, genetic susceptibility
Abstract

Part of the substantial unexplained familial aggregation of breast cancer may be due to interactions between common variants, but few studies have had adequate statistical power to detect interactions of realistic magnitude. We aimed to assess all two-way interactions in breast cancer susceptibility between 70 917 single nucleotide polymorphisms (SNPs) selected primarily based on prior evidence of a marginal effect. Thirty-eight international studies contributed data for 46 450 breast cancer cases and 42 461 controls of European origin as part of a multi-consortium project (COGS). First, SNPs were preselected based on evidence (P < 0.01) of a per-allele main effect, and all two-way combinations of those were evaluated by a per-allele (1 d.f.) test for interaction using logistic regression. Second, all 2.5 billion possible two-SNP combinations were evaluated using Boolean operation-based screening and testing, and SNP pairs with the strongest evidence of interaction (P < 10−4) were selected for more careful assessment by logistic regression. Under the first approach, 3277 SNPs were preselected, but an evaluation of all possible two-SNP combinations (1 d.f.) identified no interactions at P < 10−8. Results from the second analytic approach were consistent with those from the first (P > 10−10). In summary, we observed little evidence of two-way SNP interactions in breast cancer susceptibility, despite the large number of SNPs with potential marginal effects considered and the very large sample size. This finding may have important implications for risk prediction, simplifying the modelling required. Further comprehensive, large-scale genome-wide interaction studies may identify novel interacting loci if the inherent logistic and computational challenges can be overcome.

Published
2013

17. A BCL2 promoter polymorphism rs2279115 is not associated with BCL2 protein expression or patient survival in breast cancer patients

Author

Claire J Searle, Simon S. Cross, Ian W. Brock, Sabapathy P. Balasubramanian, Angela Cox, and Malcolm W.R. Reed

Subjects
Oncology, BCL2, medicine.medical_specialty, Multidisciplinary, Tissue microarray, Survival, business.industry, Proportional hazards model, Research, SNP, Single-nucleotide polymorphism, medicine.disease, Bioinformatics, Genotype frequency, Lymphoma, Breast cancer, hemic and lymphatic diseases, Internal medicine, rs2279115, Genotype, medicine, business
Abstract

The B-cell CLL/lymphoma 2 (BCL2) gene family encodes pro- and anti-apoptotic proteins that are critical regulators of programmed cell death. Higher levels of BCL2 expression in breast tumours have been shown to be an independent prognostic factor for improved survival from breast cancer. The promoter single nucleotide polymorphism (SNP) rs2279115 has been associated with both BCL2 expression and patient survival. The aim of this study was to attempt to replicate these observations in a cohort of 1015 UK women with breast cancer, and to compare genotype frequencies in cases and controls. In this study, 1015 breast cancer cases and 1034 control subjects were genotyped for the rs2279115 SNP by 5’ nuclease PCR. Paraffin embedded tumour tissue for 342 case subjects was assembled into tissue microarrays, and the level of expression of BCL2 was established by immunohistochemistry. Kaplan Meier survival curves and Cox Proportional Hazards models were used to examine the effect of genotype on patient survival. The effect of SNP genotype on tumour BCL2 protein levels and breast cancer susceptibility was assessed by logistic regression. In this study higher BCL2 expression was significantly associated with improved survival from breast cancer (p = 0.015), in keeping with previous reports. The SNP rs2279115 was not found to be associated with tumour expression of BCL2, (p = 0.77), and neither was it associated with case/control status (p = 0.25). There was no significant association between the SNP and overall survival (p = 0.75). In conclusion, we found that higher tumour BCL2 expression is associated with improved survival from breast cancer, in keeping with previous studies. However, in contrast to a previous report, the promoter SNP rs2279115 was not associated with BCL2 expression or overall survival from breast cancer.

Published
2012
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18. 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
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19. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author

Celine M. Vachon, Irene L. Andrulis, Peter Schürmann, Arja Jukkola-Vuorinen, Manjeet K. Humphreys, Lorna Gibson, Natalia Bogdanova, Jean Wang, Annika Lindblom, Marjanka K. Schmidt, Annegien Broeks, Ian W. Brock, A. Miron, Janet E. Olson, James McKay, Michael J. Kerin, Gilles Thomas, Anna González-Neira, Ian Tomlinson, Jaana M. Hartikainen, Anna Marie Mulligan, P. A. Fasching, Gillian S. Dite, I dos Santos Silva, Keun-Young Yoo, Rebecca Hein, Michael Bremer, Thilo Dörk, Ji Arias Pérez, C. R. Bartrar, Sara Margolin, Javier Benitez, Jo Knight, Suleeporn Sangrajrang, Alison M. Dunning, Matthias W. Beckmann, Rita K. Schmutzler, Julian Peto, John L. Hopper, Natalia Antonenkova, Angela Cox, Yuri I. Rogov, Barbara Burwinkel, Robert N. Hoover, L.J. van 't Veer, Nicola F. Johnson, Fergus J. Couch, Jenny Chang-Claude, Arto Mannermaa, Ute Hamann, Hoda Anton-Culver, Douglas F. Easton, Jolanta Lissowska, Graeme Elliott, Vesa Kataja, Montserrat Garcia-Closas, Elinor J. Sawyer, Alfons Meindl, Kristen N. Stevens, Peter Hillemanns, Veli-Matti Kosma, R.A.E.M. Tollenaar, Thomas Brüning, Stephen J. Chanock, Zachary S. Fredericksen, Carmel Apicella, Laura Baglietto, Mervi Grip, Roger L. Milne, James R. Cerhan, Karen A. Pooley, Paolo Peterlongo, Matthew L. Kosel, Daehee Kang, Argyrios Ziogas, Arif B. Ekici, Yon-Dschun Ko, Shan Wang-Gohrke, Graham G. Giles, Alexander Hein, Xianshu Wang, Bernardo Bonanni, Gianluca Severi, Loris Bernard, P Pharoah, Dong-Young Noh, Xiaoqing Chen, Esther M. John, Melissa C. Southey, K. Pylkäs, Robert Winqvist, Vernon S. Pankratz, Catriona McLean, Georgia Chenevix-Trench, J. V. Zalutsky, David J. Hunter, Siranoush Manoukian, Simon S. Cross, Gordon Glendon, V. Gabrieau, and Paul Brennan

Subjects
Oncology, poor-prognosis, medicine.medical_specialty, Cancer Research, Class I Phosphatidylinositol 3-Kinases, Breast Neoplasms, Biology, Germline, 03 medical and health sciences, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Breast cancer, Polymorphism (computer science), Internal medicine, Neoplasms, medicine, Genetic predisposition, Genetic susceptibility, ovarian, Humans, Genetic Predisposition to Disease, gene, 030304 developmental biology, 0303 health sciences, pten loss, Oncogene, pathway, Case-control study, pik3ca mutations, association, Cancer, Genetic Variation, Genetics and Genomics, Odds ratio, correlate, medicine.disease, 3. Good health, Association study, high-frequency, 030220 oncology & carcinogenesis, Case-Control Studies, Immunology, Female
Abstract

BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR) = 0.97, 95% confidence interval (CI) 0.95-0.99, P = 4.6 x 10(-3)), but did not reach significance in the BCAC replication study alone (OR = 0.98, 95% CI 0.96-1.01, P = 0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer British Journal of Cancer (2011) 105, 1934 - 1939. doi: 10.1038/bjc.2011.448 www.bjcancer.com Published online 27 October 2011 (C) 2011 Cancer Research UK

Published
2011

20. Association Between a Germline OCA2 Polymorphism at Chromosome 15q13.1 and Estrogen Receptor-Negative Breast Cancer Survival

Author

Melissa C. Southey, Paul D.P. Pharoah, Graham G. Giles, Douglas F. Easton, Per Hall, Jonathan Tyrer, Heli Nevanlinna, Henrik Flyger, Kristiina Aittomäki, Caroline Seynaeve, Zachary S. Fredericksen, Jolanta Lissowska, Argyrios Ziogas, Primitiva Menéndez, Børge G. Nordestgaard, Gianluca Severi, Rüdiger Schulz-Wendtland, Angela Cox, Mark E. Sherman, Carl Blomqvist, Vesa Kataja, David Greenberg, Stig E. Bojesen, Tuomas Heikkinen, Javier Benítez, Graeme Elliott, Sara Margolin, Matthias W. Beckmann, Shan Wang-Gohrke, Fergus J. Couch, Roger L. Milne, Rob A. E. M. Tollenaar, Montserrat Garcia-Closas, Arif B. Ekici, Georgia Chenevix-Trench, Arto Mannermaa, Hoda Anton-Culver, Neil E. Caporaso, Veli-Matti Kosma, Kamila Czene, Laura Baglietto, Malcolm W.R. Reed, Xianshu Wang, Kelly L. Bolton, Peter Devilee, Rebecca Hein, José Ignacio Arias, Elizabeth M. Azzato, Janet E. Olson, P. A. Fasching, Manjeet K. Humphreys, Jenny Chang-Claude, Ian W. Brock, Jonathan Beesley, Xiaoqing Chen, and Medical Oncology

Subjects
Oncology, Cancer Research, Genome-wide association study, Bioinformatics, Risk Factors, Receptors, Genotype, education.field_of_study, Tumor, Medicine (all), Single Nucleotide, Articles, Middle Aged, Receptors, Estrogen, Research Design, Female, Human, Adult, medicine.medical_specialty, Population, Breast Neoplasms, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Chromosomes, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Biomarkers, Tumor, medicine, Humans, Polymorphism, Allele, education, Alleles, Germ-Line Mutation, Survival analysis, Aged, Proportional Hazards Models, Chromosomes, Human, Pair 15, Pair 15, Membrane Transport Proteins, Cancer, Survival Analysis, medicine.disease, Estrogen, Biomarkers
Abstract

Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. We evaluated possible associations between overall survival after a breast cancer diagnosis and 10 621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26 978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5' nuclease assay or mass spectrometry and overall survival information for up to 14 096 patients with invasive breast cancer (including 2303 deaths and 70 019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. In the hypothesis-generating dataset, SNP rs4778137 (C > G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 x 10(-5)). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P = .03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 x 10(-4)). The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Published
2010

21. A breast cancer risk haplotype in the caspase-8 gene

Author

Neil Shephard, Sabapathy P. Balasubramanian, Angela Cox, Ian W. Brock, Nicola J. Camp, Bernd Frank, Ryan Abo, Christopher Engel, Sushila H. Rigas, Kristina Allen-Brady, Rita K. Schmutzler, Barbara Burwinkel, Alfons Meindl, Adam Shippen, Claus R. Bartram, Malcolm W.R. Reed, Lisa A. Cannon-Albright, and Wei-Yu Lin

Subjects
Genetics, Cancer Research, Caspase 8, Haplotype, Cancer, Chromosome Mapping, Locus (genetics), Single-nucleotide polymorphism, Breast Neoplasms, Odds ratio, Biology, medicine.disease, Polymorphism, Single Nucleotide, Article, Breast cancer, Oncology, Haplotypes, Case-Control Studies, medicine, Humans, Female, Genetic Predisposition to Disease, Breast disease, Allele
Abstract

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P = 8.0 × 10−5), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12–1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q = 0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer. [Cancer Res 2009;69(7):2724–8]

Published
2009

22. The common PARK8 mutation LRRK2 G2019S is not a risk factor for breast cancer in the absence of Parkinson’s disease

Author

Oliver Bandmann, Heather Mortiboys, Ian W. Brock, and Angela Cox

Subjects
Oncology, medicine.medical_specialty, Parkinson's disease, Neurology, business.industry, medicine.disease, LRRK2, Breast cancer, Internal medicine, Mutation (genetic algorithm), medicine, Cancer research, Neurology (clinical), Risk factor, business, Neuroradiology
Published
2013
Full Text
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24. 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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