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

Author

Thomas U. Ahearn, Haoyu Zhang, Kyriaki Michailidou, Roger L. Milne, Manjeet K. Bolla, Joe Dennis, Alison M. Dunning, Michael Lush, Qin Wang, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Adinda Baten, Heiko Becher, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Thomas Brüning, Barbara Burwinkel, Saundra S. Buys, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Christine L. Clarke, NBCS Collaborators, J. Margriet Collée, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Miriam Dwek, Diana M. Eccles, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Giuseppe Floris, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Graham G. Giles, Mark S. Goldberg, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Bernadette A. M. Heemskerk-Gerritsen, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, ABCTB Investigators, kConFab/AOCS Investigators, Milena Jakimovska, Anna Jakubowska, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Saila Kauppila, Renske Keeman, Elza Khusnutdinova, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Katerina Kubelka-Sabit, Allison W. Kurian, Kyriacos Kyriacou, Diether Lambrechts, Derrick G. Lee, Annika Lindblom, Martha Linet, Jolanta Lissowska, Ana Llaneza, Wing-Yee Lo, Robert J. MacInnis, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Maria Elena Martinez, Catriona McLean, Alfons Meindl, Usha Menon, Heli Nevanlinna, William G. Newman, Jesse Nodora, Kenneth Offit, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Julian Peto, Guillermo Pita, Dijana Plaseska-Karanfilska, Ross Prentice, Kevin Punie, Katri Pylkäs, Paolo Radice, Gad Rennert, Atocha Romero, Thomas Rüdiger, Emmanouil Saloustros, Sarah Sampson, Dale P. Sandler, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Ben Schöttker, Mark E. Sherman, Xiao-Ou Shu, Snezhana Smichkoska, Melissa C. Southey, John J. Spinelli, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Lauren R. Teras, Mary Beth Terry, Diana Torres, Melissa A. Troester, Celine M. Vachon, Carolien H. M. van Deurzen, Elke M. van Veen, Philippe Wagner, Clarice R. Weinberg, Camilla Wendt, Jelle Wesseling, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Wei Zheng, Fergus J. Couch, Jacques Simard, Peter Kraft, Douglas F. Easton, Paul D. P. Pharoah, Marjanka K. Schmidt, Montserrat García-Closas, and Nilanjan Chatterjee

Subjects
Breast cancer, Etiologic heterogeneity, Genetic predisposition, Common breast cancer susceptibility variants, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate

Published
2022
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2. A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

Author

Elin Barnekow, Johan Hasslow, Wen Liu, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin, and Annika Lindblom

Subjects
GRIA4, haplotype, Cancer och onkologi, TGIF2LX, Organic Chemistry, familial, General Medicine, Catalysis, Computer Science Applications, Inorganic Chemistry, risk loci, breast cancer, Cancer and Oncology, SMARCA2, GWAS, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy
Abstract

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1–25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10−11), 11q22.3 (OR 2.4; p 5.2 × 10−9), 15q11.2 (OR 3.6; p 2.3 × 10−8), 16q24.1 (OR 3; p 3 × 10−8) and Xq21.31 (OR 3.3; p 1.7 × 10−8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.

Published
2023

3. Incorporating progesterone receptor expression into the PREDICT breast prognostic model

Author

Isabelle Grootes, Renske Keeman, Fiona M. Blows, Roger L. Milne, Graham G. Giles, Anthony J. Swerdlow, Peter A. Fasching, Mustapha Abubakar, Irene L. Andrulis, Hoda Anton-Culver, Matthias W. Beckmann, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Ignacio Briceno, Barbara Burwinkel, Nicola J. Camp, Jose E. Castelao, Ji-Yeob Choi, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, Kristina Ernst, D. Gareth Evans, Jonine D. Figueroa, Visnja Fink, Giuseppe Floris, Stephen Fox, Marike Gabrielson, Manuela Gago-Dominguez, José A. García-Sáenz, Anna González-Neira, Lothar Haeberle, Christopher A. Haiman, Per Hall, Ute Hamann, Elaine F. Harkness, Mikael Hartman, Alexander Hein, Maartje J. Hooning, Ming-Feng Hou, Sacha J. Howell, Hidemi Ito, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Jung, Daehee Kang, Vessela N. Kristensen, Ava Kwong, Diether Lambrechts, Jingmei Li, Jan Lubiński, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Nur Aishah Mohd Taib, Anna Marie Mulligan, Heli Nevanlinna, William G. Newman, Kenneth Offit, Ana Osorio, Sue K. Park, Tjoung-Won Park-Simon, Alpa V. Patel, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Gad Rennert, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Andreas Schneeweiss, Fabienne Schochter, Minouk J. Schoemaker, Chen-Yang Shen, Rana Shibli, Peter Sinn, William J. Tapper, Essa Tawfiq, Soo Hwang Teo, Lauren R. Teras, Diana Torres, Celine M. Vachon, Carolien H.M. van Deurzen, Camilla Wendt, Justin A. Williams, Robert Winqvist, Mark Elwood, Marjanka K. Schmidt, Montserrat García-Closas, Paul D.P. Pharoah, Medical Oncology, Pathology, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, University of Helsinki, Helsinki University Hospital Area, Institute for Molecular Medicine Finland, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology

Subjects
Cancer Research, Breast Neoplasms/pathology, Manchester Cancer Research Centre, Receptor, ErbB-2, Receptors, Progesterone/metabolism, ResearchInstitutes_Networks_Beacons/mcrc, ADJUVANT TAMOXIFEN, 3122 Cancers, Receptor, ErbB-2/metabolism, Breast Neoplasms, PREDICT Breast, Prognosis, THERAPY, Progesterone receptor, Breast cancer, breast cancer, ESTROGEN-RECEPTOR, Oncology, SDG 3 - Good Health and Well-being, Humans, Female, CANCER PATIENTS, Receptors, Progesterone, Progesterone
Abstract

Background: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).Method: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.Results: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0. 902 for patients with ER-positive tumours (p = 2.3 x 10(-6)) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.Conclusion: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predic-tions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration. (C) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Published
2022

4. A Swedish Genome-Wide Haplotype Association Analysis Identifies a Novel Breast Cancer Susceptibility Locus in 8p21.2 and Characterizes Three Loci on Chromosomes 10, 11 and 16

Author

Elin Barnekow, Wen Liu, Hafdis T. Helgadottir, Kyriaki Michailidou, Joe Dennis, Patrick Bryant, Jessada Thutkawkorapin, Camilla Wendt, Kamila Czene, Per Hall, Sara Margolin, and Annika Lindblom

Subjects
Cancer Research, BNIP3L, FGFR2, TOX3, CASC16, breast cancer, GWAS, haplotype, Cancer och onkologi, Oncology, Cancer and Oncology, Medical Genetics, Medicinsk genetik
Abstract

Background: The heritability of breast cancer is partly explained but much of the genetic contribution remains to be identified. Haplotypes are often used as markers of ethnicity as they are preserved through generations. We have previously demonstrated that haplotype analysis, in addition to standard SNP association studies, could give novel and more detailed information on genetic cancer susceptibility. Methods: In order to examine the association of a SNP or a haplotype to breast cancer risk, we performed a genome wide haplotype association study, using sliding window analysis of window sizes 1-25 and 50 SNPs, in 3200 Swedish breast cancer cases and 5021 controls. Results: We identified a novel breast cancer susceptibility locus in 8p21.1 (OR 2.08; p 3.92 x 10(-8)), confirmed three known loci in 10q26.13, 11q13.3, 16q12.1-2 and further identified novel subloci within these three loci. Altogether 76 risk SNPs, 3302 risk haplotypes of window size 2-25 and 113 risk haplotypes of window size 50 at p < 5 x 10(-8) on chromosomes 8, 10, 11 and 16 were identified. In the known loci haplotype analysis reached an OR of 1.48 in overall breast cancer and in familial cases OR 1.68. Conclusions: Analyzing haplotypes, rather than single variants, could detect novel susceptibility loci even in small study populations but the method requires a fairly homogenous study population. De två första författarna delar förstaförfattarskapet.

Published
2022

5. Prediction and clinical utility of a contralateral breast cancer risk model

Author

William J. Tapper, Montserrat Garcia-Closas, Douglas F. Easton, Alison M. Dunning, Annika Lindblom, Rob A. E. M. Tollenaar, Hester S. A. Oldenburg, Per Hall, Chantal Van Ongeval, Diether Lambrechts, Daniele Giardiello, Agnes Jager, Jonine D. Figueroa, Melissa C. Southey, Qin Wang, Jan Lubinski, Ewout W. Steyerberg, Marjanka K. Schmidt, Manjeet K. Bolla, Anna Jakubowska, Paul D.P. Pharoah, Diana Eccles, Carl Blomqvist, Heli Nevanlinna, Flora E. van Leeuwen, Pieter J. Westenend, Mitul Shah, Iris Kramer, Luigi Mariani, Mehdi Manoochehri, Delal Akdeniz, Peter A. Fasching, Alexandra J. van den Broek, Muriel A. Adank, Saskia Pelders, Maartje J. Hooning, Christopher A. Haiman, Sabine Siesling, Loic Le Marchand, Peter Devilee, Michael Hauptmann, Ute Hamann, Jenny Chang-Claude, Camilla Wendt, Stig E. Bojesen, Lothar Haeberle, Mariël Brinkhuis, Laura J. van't Veer, Renske Keeman, Kamila Czene, Henrik Flyger, John L. Hopper, Audrey Y. Jung, Carolien H.M. van Deurzen, Vincent T.H.B.M. Smit, Health Technology & Services Research, Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Apollo - University of Cambridge Repository, Blomqvist, Carl [0000-0003-3041-1938], Department of Oncology, Clinicum, HUS Comprehensive Cancer Center, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, University of Helsinki, Public Health, Medical Oncology, and Pathology

Subjects
Oncology, medicine.medical_treatment, BRCA mutation carriers, 0302 clinical medicine, Medizinische Fakultät, 3123 Gynaecology and paediatrics, Risk Factors, 030212 general & internal medicine, Family history, 10. No inequality, Netherlands, education.field_of_study, BRCA1 Protein, Area under the curve, Disease Management, Neoplasms, Second Primary, Prognosis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Primary tumor, 3. Good health, Preventive mastectomy, 030220 oncology & carcinogenesis, Area Under Curve, Female, Disease Susceptibility, Mastectomy, Clinical decision-making, Research Article, medicine.medical_specialty, Population, 3122 Cancers, Breast Neoplasms, Risk Assessment, lcsh:RC254-282, 03 medical and health sciences, Germline mutation, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, ddc:610, education, Germ-Line Mutation, Proportional Hazards Models, BRCA2 Protein, business.industry, medicine.disease, Contralateral breast cancer, business, Risk prediction model
Abstract

Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

Published
2019

6. Rare Copy Number Variants (CNVs) and Breast Cancer Risk

Author

Vessela N. Kristensen, Abctb Investigators, Elinor J. Sawyer, Jose Esteban Castelao, Christine L. Clarke, Argyrios Ziogas, Natalia Bogdanova, Pascal Guénel, Lin Fritschi, Marina Bermisheva, Alicja Wolk, Anthony J. Swerdlow, Graham G. Giles, Antoinette Hollestelle, Camilla Wendt, Stig E. Bojesen, Reiner Hoppe, Laure Dossus, Marike Gabrielson, Doug Easton, Dimitrios Mavroudis, Rulla M. Tamimi, Manuela Gago-Dominguez, Roger L. Milne, Kristan J. Aronson, Kyriaki Michailidou, Logan C. Walker, Siranoush Manoukian, Taru A. Muranen, Melissa A. Troester, Celine M. Vachon, Javier Benítez, Alicja Lukomska, Martha S. Linet, Heli Nevanlinna, Marjanka K. Schmidt, Thilo Dörk, Kubelka-Sabit K, Rita K. Schmutzler, Antonenkova Nn, Pharoah Pd, Anna González-Neira, H Brenner, Dijana Plaseska-Karanfilska, Fergus J. Couch, Ian Tomlinson, Thérèse Truong, Sabine Behrens, A. H. Eliassen, Peter A. Fasching, Cox A, P. Kraft, Wei Zheng, Rudolph Kaaks, Tyrer Jp, Renske Keeman, Rachel A. Murphy, Georgia Chenevix-Trench, Dale P. Sandler, Olivia Fletcher, Leila Dorling, Sara Margolin, Thomas U. Ahearn, Agnes Jager, Christopher A. Haiman, Lauren R. Teras, Tjoung-Won Park-Simon, James V. Lacey, Per Hall, Matthias W. Beckmann, Jacques Simard, Michael Jones, Collee Jm, D G Evans, Shibli R, Investigators k, Katri Pylkäs, Xiaohong R. Yang, Esther M. John, Eric Hahnen, D Lambrechts, Peter Devilee, Kamila Czene, Jonine D. Figueroa, Alison M. Dunning, Hoda Anton-Culver, Stella Koutros, Melissa C. Southey, Kosma, Joe Dennis, Yon-Dschun Ko, Mary Beth Terry, Jenny Chang-Claude, Anthony Howell, Beane Freeman Le, Charles M. Perou, Qinghua Wang, Henrik Flyger, Nichola Johnson, John L. Hopper, Paolo Peterlongo, Simon S. Cross, Jack A. Taylor, Audrey Y. Jung, Robert Winqvist, Håkan Olsson, Arndt, Irene L. Andrulis, Nicole L. Larson, Penny Soucy, Anna Jakubowska, Cari M. Kitahara, Janet E. Olson, Emmanouil Saloustros, Elza Khusnutdinova, Manjeet K. Bolla, M Garcia-Closas, Ann Smeets, Mikael Eriksson, Allison W. Kurian, Gadi Rennert, and Arto Mannermaa

Subjects
Genetics, 0303 health sciences, Cancer, Disease, Biology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, 030220 oncology & carcinogenesis, Gene duplication, medicine, Human genome, Copy-number variation, Gene, CHEK2, 030304 developmental biology
Abstract

BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Published
2021

7. The association between weight at birth and breast cancer risk revisited using Mendelian randomisation

Author

Thilo Dörk, Artitaya Lophatananon, Rudolf Kaaks, Dezheng Huo, Manuela Gago-Dominguez, Jenny Chang-Claude, Daniel P C Considine, Irene L. Andrulis, Wei Zheng, Graham G. Giles, Els Van Nieuwenhuysen, Jingmei Li, Sara Margolin, Paolo Radice, Rulla M. Tamimi, D. Gareth Evans, Jacques Simard, Paul D.P. Pharoah, Mikael Hartman, Håkan Olsson, Hermann Brenner, Kenneth Muir, Stephen Burgess, Roger L. Milne, Camilla Wendt, Siddhartha Kar, Kevin Punie, Kar, Siddhartha P [0000-0002-2314-1426], and Apollo - University of Cambridge Repository

Subjects
Oncology, medicine.medical_specialty, Epidemiology, Birth weight, Breast Neoplasms, Single-nucleotide polymorphism, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Internal medicine, medicine, Birth Weight, Humans, 030212 general & internal medicine, Mendelian randomisation, Genetic association, Cancer, business.industry, Odds ratio, Mendelian Randomization Analysis, medicine.disease, Confidence interval, Menopause, Menarche, Female, business, Body mass index
Abstract

Observational studies suggest that higher birth weight (BW) is associated with increased risk of breast cancer in adult life. We conducted a two-sample Mendelian randomisation (MR) study to assess whether this association is causal. Sixty independent single nucleotide polymorphisms (SNPs) known to be associated at P

Published
2019

8. Identifying breast cancer susceptibility genes – a review of the genetic background in familial breast cancer

Author

Sara Margolin and Camilla Wendt

Subjects
Oncology, medicine.medical_specialty, DNA Mutational Analysis, MEDLINE, Breast Neoplasms, Breast cancer susceptibility genes, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Humans, Neoplasm, Genetic Predisposition to Disease, Radiology, Nuclear Medicine and imaging, Risk factor, skin and connective tissue diseases, business.industry, Hematology, General Medicine, medicine.disease, 030220 oncology & carcinogenesis, Female, Familial breast cancer, business, Genetic Background, Genes, Neoplasm, Genome-Wide Association Study
Abstract

Heritage is the most important risk factor for breast cancer. About 15-20% of breast cancer is familial, referring to affected women who have one or more first- or second-degree relatives with the disease. The heritable component in these families is substantial, especially in families with aggregation of breast cancer with low age at onset. Identifying breast cancer susceptibility genes: Since the discovery of the highly penetrant autosomal dominant susceptibility genes BRCA1 and BRCA2 in the 1990s, several more breast cancer genes that confer a moderate to high risk of breast cancer have been identified. Furthermore, during the last decade, advances in genomic technologies have led to large scale genotyping in genome-wide association studies that have identified a considerable amount of common low penetrance loci. In total, the high risk genes, BRCA1, BRCA2, TP53, STK11, CD1 and PTEN account for approximately 20% of the familial risk. Moderate risk variants account for up to 5% of the inherited familial risk. The more than 180 identified low-risk loci explain 18% of the familial risk. Altogether more than half of the genetic background in familial breast cancer remains unclear. Other genes and low risk loci that explain a part the remaining fraction will probably be identified. Clinical aspects and future perspectives: Definitive clinical recommendations can be drawn only for carriers of germline variants in a limited number of high and moderate risk genes for which an association with breast cancer has been established. Future progress in evaluating previously identified breast cancer candidate variants and low risk loci as well as exploring new ones can play an important role in improving individual risk prediction in familial breast cancer.

Published
2019

9. Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Author

Arif B. Ekici, Mi Kyung Kim, Dong Young Noh, Keun-Young Yoo, Camilla Wendt, Rebecca Mayes, Anna H. Wu, Lauren R. Teras, Stig E. Bojesen, Henrik Flyger, Angela Cox, Melissa C. Southey, Wanqing Wen, Volker Arndt, Chen-Yang Shen, Soo Hwang Teo, Pascal Guénel, Robert Winqvist, Natalia Bogdanova, Hidemi Ito, Chiu-Chen Tseng, Heli Nevanlinna, Simon S. Cross, Yon Ko, Jingmei Li, Mehdi Manoochehri, Peter A. Fasching, Renske Keeman, Keitaro Matsuo, Paul D.P. Pharoah, Nan Song, Alpa V. Patel, Manjeet K. Bolla, Jong Won Lee, Javier Benitez, Anthony J. Swerdlow, Carl Blomqvist, Jaesung Choi, Sei Hyun Ahn, Bernadette A M Heemskerk-Gerritsen, Seokang Chung, Alison M. Dunning, Diether Lambrechts, James V. Lacey, Hermann Brenner, Reiner Hoppe, Wonshik Han, Joe Dennis, Kenneth Muir, Don M. Conroy, Rebecca Roylance, Michael Jones, Thilo Dörk, Pei Ei Wu, Mitul Shah, Arto Mannermaa, Patricia Harrington, Sue K. Park, Vessela N. Kristensen, Bernardo Bonanni, Jaana M. Hartikainen, Rob A. E. M. Tollenaar, Qin Wang, Paolo Radice, Mikael Hartman, Joo Yong Park, Adinda Baten, Irene L. Andrulis, Douglas F. Easton, Sun Ha Jee, Annika Lindblom, Daehee Kang, Ji Yeob Choi, Elinor J. Sawyer, Fergus J. Couch, Ute Hamann, Kyriaki Michailidou, Anna González-Neira, Thérèse Truong, Olivia Fletcher, Per Hall, Artitaya Lophatananon, Nur Aishah Taib, Maria Elena Martinez, Janet E. Olson, Kamila Czene, John L. Hopper, kConFab Investigators, Nichola Johnson, Christopher A. Haiman, Mervi Grip, Marjanka K. Schmidt, Song, Nan [0000-0002-9182-1060], Park, Sue K [0000-0001-5002-9707], Kim, Mi Kyung [0000-0001-5279-4162], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Hall, Per [0000-0002-5640-9126], Matsuo, Keitaro [0000-0003-1761-6314], Ito, Hidemi [0000-0002-8023-4581], Keeman, Renske [0000-0002-5452-9933], Schmidt, Marjanka K [0000-0002-2228-429X], Fasching, Peter A [0000-0003-4885-8471], Brenner, Hermann [0000-0002-6129-1572], Arndt, Volker [0000-0001-9320-8684], Hartikainen, Jaana M [0000-0001-8267-1905], Dörk, Thilo [0000-0002-9458-0282], Bogdanova, Natalia V [0000-0002-9736-4593], Johnson, Nichola [0000-0002-8230-5662], Nevanlinna, Heli [0000-0002-0916-2976], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Bonanni, Bernardo [0000-0003-3589-2128], Apollo - University of Cambridge Repository, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Helsinki University Hospital Area, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Park, Sue K. [0000-0001-5002-9707], Schmidt, Marjanka K. [0000-0002-2228-429X], Fasching, Peter A. [0000-0003-4885-8471], Hartikainen, Jaana M. [0000-0001-8267-1905], Bogdanova, Natalia V. [0000-0002-9736-4593], Heemskerk-Gerritsen, Bernadette A. M. [0000-0002-9724-6693], and Medical Oncology

Subjects
0301 basic medicine, Oncology, Cancer Research, Candidate gene, PREMENOPAUSAL, medicine.medical_treatment, STEROID-RECEPTOR COACTIVATOR-1, Genome-wide association study, 0302 clinical medicine, HEIGHT, estrogen, 2.1 Biological and endogenous factors, RACIAL-DIFFERENCES, EPIDEMIOLOGY, Gene–environment interaction, Aetiology, RC254-282, Cancer, education.field_of_study, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Hormone replacement therapy (menopause), 3. Good health, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, medicine.medical_specialty, ESR1 MUTATIONS, SUSCEPTIBILITY LOCI, Population, Oncology and Carcinogenesis, 3122 Cancers, Single-nucleotide polymorphism, Biology, Article, 03 medical and health sciences, Breast cancer, breast cancer, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, medicine, Genetics, ddc:610, education, POLYMORPHISMS, Science & Technology, METABOLISM PATHWAY GENES, Prevention, HORMONE REPLACEMENT THERAPY, Human Genome, medicine.disease, gene-environment interaction, Minor allele frequency, 030104 developmental biology
Abstract

Simple Summary Breast cancer is the most common cancer in females worldwide. To date, many gene-environment interaction (GxE) studies have been conducted to better understand how genetic factors combine with environmental factors to influence risk. However, previous studies have not found or found only a few interactions by using SNPs which were discovered from genome-wide association studies and have been conducted, for the most part, within European populations. In this study, we focused on estrogen-related lifestyle factors that have been identified for breast cancer, including several well-established reproductive factors that are mediated by hormonal mechanisms. We aimed to examine whether there are any gene and environmental factor interactions related to estrogen exposure or metabolism using a candidate approach in Korean women. We found two interactions in this study, although they were not replicated in the independent large consortium data. These findings suggest specificity in Koreans for breast cancer risk. In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 x 10(-3)). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 x 10(-4)). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

Published
2021

10. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author

Pascal Guénel, John J. Spinelli, Hoda Anton-Culver, Veli-Matti Kosma, Beth Y. Karlan, Antonis C. Antoniou, Brian D. Carter, Drakoulis Yannoukakos, Orland Diez, Montserrat Garcia-Closas, Uffe Birk Jensen, Susan M. Gapstur, Christine L. Clarke, Florentia Fostira, Trinidad Caldés, Wei Zheng, Diana Eccles, Don M. Conroy, Kristan J. Aronson, Sara Margolin, Thomas U. Ahearn, Hedy S. Rennert, Evgeny N. Imyanitov, Rulla M. Tamimi, Mary Beth Terry, Jenny Chang-Claude, Per Hall, Daniel R. Barnes, Alex Teulé, D. Gareth Evans, Åke Borg, Frans B. L. Hogervorst, Yon-Dschun Ko, Celine M. Vachon, Graham G. Giles, Simona Agata, Gad Rennert, Yuan Chun Ding, J. Margriet Collée, Alison M. Dunning, Regina M. Santella, Banu Arun, William J. Tapper, Melissa C. Southey, Finn Cilius Nielsen, Michael T. Parsons, Marjanka K. Schmidt, Alfons Meindl, Vassilios Georgoulias, Simon A. Gayther, Debra Frost, Noura Mebirouk, Hebon Investigators, Austin Miller, Sue K. Park, Anthony J Swerdlow, Emmanouil Saloustros, Isabel dos-Santos-Silva, Laura Ottini, Jack A. Taylor, Siranoush Manoukian, Maria A. Caligo, Douglas F. Easton, Christoph Engel, Antoinette Hollestelle, Ana Vega, Muriel A. Adank, Mia M. Gaudet, Heko Becher, Lothar Haeberle, Priyanka Sharma, Katherine L. Nathanson, Mads Thomassen, Miriam Dwek, Manuela Gago-Dominguez, Hiltrud Brauch, Kamila Czene, Peter A. Fasching, Peter J. Hulick, David E. Goldgar, Lesley McGuffog, Anna Jakubowska, Paul D.P. Pharoah, Adrià López-Fernández, Bruce Poppe, Volker Arndt, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Jennifer Stone, Wendy K. Chung, Joseph Vijai, Qin Wang, Penny Soucy, Miquel Angel Pujana, Diether Lambrechts, Vanesa García-Barberán, Andrea Gehrig, Anna González-Neira, Thérèse Truong, Jenny Lester, Wei He, Dale P. Sandler, Rita K. Schmutzler, Julian Peto, A. Heather Eliassen, Paolo Radice, Yael Laitman, Johanna Rantala, Kelly-Anne Phillips, Amanda E. Toland, Bernardo Bonanni, Muhammad Usman Rashid, Heli Nevanlinna, John L. Hopper, Kevin Punie, kConFab Investigators, Thilo Dörk, Judy Garber, Alison H. Trainer, Irene L. Andrulis, Jeffrey N. Weitzel, Michael Jones, Caroline Baynes, David J. Hunter, Mark S. Goldberg, Kristiina Aittomäki, Barbara Burwinkel, Jonathan Beesley, Maria Rossing, Norbert Arnold, Kathleen Claes, Renske Keeman, Esther M. John, John W.M. Martens, Katie M. O'Brien, Paolo Peterlongo, Mark H. Greene, Tracy A. O'Mara, Saundra S. Buys, Craig Luccarini, Atocha Romero, Paul A. James, Siddhartha Yadav, Zoe Steinsnyder, Diana Torres, Rudolf Kaaks, Camilla Wendt, Fabienne Lesueur, Ana Osorio, Olufunmilayo I. Olopade, Christopher A. Haiman, Agnes Jager, Tricia Lindstrom, Peter Devilee, Kristin K. Zorn, Loic Le Marchand, Darling J. Horcasitas, Michael Lush, Mark E. Robson, Jennifer T. Loud, Roger L. Milne, Lin Fritschi, Johanna I. Kiiski, Eric Hahnen, Jacques Simard, Annelie Augustinsson, Stig E. Bojesen, Kenneth Offit, Nadine Andrieu, Xiaohong R. Yang, Pooja Middha Kapoor, Joe Dennis, Beth N. Peshkin, Nadege Presneau, Darcy L. Thull, Fergus J. Couch, Gunnar Schmidt, Ute Hamann, Susan M. Domchek, Henrik Flyger, Mary B. Daly, Håkan Olsson, Clarice R. Weinberg, Niclas Håkansson, Elza Khusnutdinova, Inge Søkilde Pedersen, Manjeet K. Bolla, Steven N. Hart, Carl Blomqvist, Janet E. Olson, Maren T. Scheuner, Barbara Wappenschmidt, Marc Tischkowitz, Dominique Stoppa-Lyonnet, Nadine Tung, Stephen J. Chanock, Leslie Bernstein, Mikael Eriksson, José A. García-Sáenz, Jonathan Tyrer, Jose E. Castelao, Peter Kraft, Goska Leslie, Arto Mannermaa, Christopher G. Scott, Jacopo Azzollini, Eitan Friedman, Allison W. Kurian, Katarzyna Białkowska, Argyrios Ziogas, Hermann Brenner, Andrew K. Godwin, Patricia Harrington, Juliette Coignard, Daniele Campa, Susan L. Neuhausen, Marco Montagna, Marina Bermisheva, Alicja Wolk, Eric C. Polley, Abctb Investigators, and Daniel Barrowdale

Subjects
Adult, Genotype, media_common.quotation_subject, Science, Quantitative Trait Loci, General Physics and Astronomy, Breast Neoplasms, 02 engineering and technology, Brca1 brca2, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Linkage Disequilibrium, 03 medical and health sciences, Breast cancer, Cancer epidemiology, Humans, Genetic Predisposition to Disease, Author Correction, Cancer genetics, Alleles, 030304 developmental biology, media_common, BRCA2 Protein, 0303 health sciences, Multidisciplinary, BRCA1 Protein, Published Erratum, General Chemistry, Art, Middle Aged, 021001 nanoscience & nanotechnology, 3. Good health, Risk factors, Mutation, Female, 0210 nano-technology, Humanities, Genome-Wide Association Study
Abstract

Author(s): Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A; Dennis, Joe; Tyrer, Jonathan P; Barnes, Daniel R; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K; Adank, Muriel A; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Arun, Banu K; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campa, Daniele; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen BM; Clarke, Christine L; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J Margriet; Conroy, Don M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M; Dork, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A; Gaudet, Mia M; Gayther, Simon A; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E | Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Published
2021
Full Text
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11. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

Author

Kamila Czene, John L. Hopper, Audrey Y. Jung, William J. Tapper, Sabine Siesling, Camilla Wendt, Daniele Giardiello, Stig E. Bojesen, Michael Hauptmann, Maartje J. Hooning, Pieter J. Westenend, Alison M. Dunning, Diana Eccles, Peter Devilee, Linetta B. Koppert, Delal Akdeniz, Henrik Flyger, Chantal Van Ongeval, Luigi Mariani, Mitul Shah, Saskia Pelders, Muriel A. Adank, Agnes Jager, Jan Lubinski, Melissa C. Southey, Manjeet K. Bolla, Flora E. van Leeuwen, Carl Blomqvist, Anna Jakubowska, Paul D.P. Pharoah, Jenny Chang-Claude, Douglas F. Easton, Laura J. van't Veer, Renske Keeman, Qin Wang, Alexandra J. van den Broek, Hester S. A. Oldenburg, Carolien H.M. van Deurzen, Lothar Haeberle, Per Hall, Rob A. E. M. Tollenaar, Mariël Brinkhuis, Jonine D. Figueroa, Ute Hamann, J. Blom, Montserrat Garcia-Closas, Mehdi Manoochehri, Peter A. Fasching, Diether Lambrechts, Ewout W. Steyerberg, Iris Kramer, Marjanka K. Schmidt, Vincent T.H.B.M. Smit, Christopher A. Haiman, Loic Le Marchand, Annika Lindblom, Heli Nevanlinna, Public Health, and Medical Oncology

Subjects
0301 basic medicine, Cancer Research, IMPACT, Receptor, ErbB-2, Contralateral breast cancer, Cohort Studies, 0302 clinical medicine, Clinical decision making, Risk Factors, Validation, MUTATION, Mastectomy, CALIBRATION, education.field_of_study, Neoplasms, Second Primary, Prognosis, Risk prediction, 3. Good health, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, Clinical decision-making, Adult, medicine.medical_specialty, MODELS, Population, Breast Neoplasms, Risk Assessment, Article, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Humans, In patient, education, Science & Technology, business.industry, External validation, International Agencies, medicine.disease, Confidence interval, 030104 developmental biology, business, Follow-Up Studies
Abstract

BACKGROUND: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). METHODS: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. RESULTS: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. CONCLUSIONS: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making. ispartof: BREAST CANCER RESEARCH AND TREATMENT vol:181 issue:2 pages:423-434 ispartof: location:Netherlands status: published

Published
2020

12. A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Author

Harald Surowy, Rulla M. Tamimi, Javier Benitez, Wing-Yee Lo, Celine M. Vachon, Nadege Presneau, John J. Spinelli, Ann Smeets, Hoda Anton-Culver, Veli-Matti Kosma, Christopher A. Haiman, Martha J. Shrubsole, Ross L. Prentice, Diana Eccles, Ursula Eilber, Loic Le Marchand, Katri Pylkäs, Jirong Long, Michael P. Lux, Sara Margolin, Hedy S. Rennert, Tom Maishman, Mary B. Daly, Rita K. Schmutzler, Julian Peto, Sune F. Nielsen, Eric Hahnen, Niclas Håkansson, Børge G. Nordestgaard, Mitul Shah, Matthias W. Beckmann, Anthony J. Swerdlow, Barbara Burwinkel, Rudolf Kaaks, Usha Menon, William J. Tapper, Argyrios Ziogas, Peter Hillemanns, Fares Al-Ejeh, Roger L. Milne, Wolfgang Janni, Pascal Guénel, Mikael Eriksson, Clarice R. Weinberg, Kyriaki Michailidou, Jonathan Beesley, Marike Gabrielson, J. Esteban Castelao, Margriet Collée, Janet E. Olson, Gad Rennert, Per Broberg, Rob A. E. M. Tollenaar, David Cox, Paolo Peterlongo, Helian Feng, Brian D. Carter, Nichola Johnson, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, Kimberly F. Doheny, Paul L. Auer, Hans Wildiers, Jacques Simard, Michael Untch, Per Hall, Martine Dumont, Julie M. Cunningham, Thilo Dörk, Mary Beth Terry, Jenny Chang-Claude, Lang Wu, Irene L. Andrulis, Xiaohong R. Yang, Caroline Baynes, Isabel dos-Santos-Silva, Douglas F. Easton, Wei Shi, Emily Hallberg, Camilla Wendt, Hiltrud Brauch, Diana Torres, Olufunmilayo I. Olopade, David Van Den Berg, Georgia Chenevix-Trench, Alfons Meindl, Stig E. Bojesen, Jonine D. Figueroa, Dale P. Sandler, Vessela N. Kristensen, Christine L. Clarke, Wei Zheng, Manuela Gago-Dominguez, E Rozali, Henrik Flyger, Sheila Seal, Guanmengqian Huang, Marjanka K. Schmidt, Håkan Olsson, Christopher G. Scott, Kamila Czene, Laura Fachal, Rodney J. Scott, Jennifer Stone, Sara Y. Brucker, Qin Wang, David J. Hunter, Maya Ghoussaini, Christoph Engel, Keith Humphreys, Susan M. Gapstur, Daniel C. Tessier, Paolo Radice, John L. Hopper, Audrey Y. Jung, Lucy Xia, Atocha Romero, Chenjie Zeng, Peter A. Fasching, Jan Lubinski, Anna González-Neira, Nazneen Rahman, Robert N. Hoover, Thérèse Truong, Fergus J. Couch, Anna Marie Mulligan, Robert J. MacInnis, Ute Hamann, Hanne Meijers-Heijboer, Brigitte Rack, Simon S. Cross, Federico Canzian, J.-P. Meyer, Sara Lindström, Natalia Bogdanova, Trinidad Caldés, Olivia Fletcher, Peter Kraft, Elinor J. Sawyer, Alexander Gusev, Louise A. Brinton, Diether Lambrechts, Bingshan Li, Kristan J. Aronson, Jane Romm, Anja Rudolph, Peter Devilee, Qiuyin Cai, Arto Mannermaa, Elad Ziv, Alice S. Whittemore, Abigail Thomas, Hermann Brenner, Montserrat Garcia-Closas, Patrick Neven, Kristine Jones, Miriam Dwek, Sibylle Loibl, Heli Nevanlinna, Jolanta Lissowska, Susan L. Neuhausen, Elza Khusnutdinova, Marina Bermisheva, Alicja Wolk, Lin Fritschi, Xingyi Guo, Angela Cox, Michael Jones, Xiaoqing Chen, Esther M. John, Richard Barfield, Volker Arndt, Patricia Harrington, Quinten Waisfisz, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Stacey L. Edwards, Melissa C. Southey, Andreas Schneeweiss, Jack A. Taylor, Robert Winqvist, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Kathrin Thöne, Dieter Flesch-Janys, Mark S. Goldberg, Craig Luccarini, Sten Cornelissen, Jingmei Li, Michael J. Kerin, Myrto Barrdahl, Xiao-Ou Shu, Alison M. Dunning, Manjeet K. Bolla, Carl Blomqvist, Graham G. Giles, Hans Christiansen, A. Heather Eliassen, Valerie Rhenius, Alexander Hein, Belynda Hicks, Ivana Maleva Kostovska, Tongguang Cheng, Yingchang Lu, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, Amsterdam Reproduction & Development (AR&D), Clinical Genetics, Medical Oncology, Guo, Xingyi [0000-0001-5269-1294], Al-Ejeh, Fares [0000-0002-1553-0077], Li, Bingshan [0000-0003-2129-168X], Gusev, Alexander [0000-0002-7980-4620], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Brauch, Hiltrud [0000-0001-7531-2736], Collée, Margriet [0000-0002-9272-9346], Cox, Angela [0000-0002-5138-1099], Cunningham, Julie M [0000-0002-8159-3025], Fachal, Laura [0000-0002-7256-9752], Fletcher, Olivia [0000-0001-9387-7116], Hein, Alexander [0000-0003-2601-3398], Hicks, Belynda [0000-0001-8014-4888], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Khusnutdinova, Elza [0000-0003-2987-3334], Li, Jingmei [0000-0001-8587-7511], Menon, Usha [0000-0003-3708-1732], Nevanlinna, Heli [0000-0002-0916-2976], Nordestgaard, Børge G [0000-0002-1954-7220], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher G [0000-0003-1340-0647], Shrubsole, Martha J [0000-0002-5591-7575], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Pharoah, Paul DP [0000-0001-8494-732X], Milne, Roger L [0000-0001-5764-7268], Easton, Douglas F [0000-0003-2444-3247], Zheng, Wei [0000-0003-1226-070X], Apollo - University of Cambridge Repository, Human Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
0301 basic medicine, Risk, medicine.medical_specialty, Gene Expression, Genome-wide association study, Breast Neoplasms, Biology, Genome-wide association studies, Polymorphism, Single Nucleotide, Article, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Genetic model, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic association, medicine.disease, 3. Good health, 030104 developmental biology, 030220 oncology & carcinogenesis, Case-Control Studies, Expression quantitative trait loci, Medical genetics, Female, Gene expression, Breast Cancer Genetics, Genome-Wide Association Study
Abstract

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P −6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

Published
2019

13. 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

14. PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1

Author

Qin Wang, kConFab, Paolo Radice, Tao Liu, Isabel dos-Santos-Silva, Douglas F. Easton, Joe Dennis, Qi Guo, Michael Lush, Jessada Thutkawkorapin, Diether Lambrechts, Barbara Kremeyer, Fergus J. Couch, Pascal Guénel, Melanie Gündert, Rita K. Schmutzler, William J. Blot, Julian Peto, Christine B. Ambrosone, Wei Zheng, Mikael Eriksson, Ute Hamann, Johanna Rantala, Barbara Burwinkel, Michael J. Kerin, Johanna Lundin, Graham G. Giles, Hiltrud Brauch, Hoda Anton-Culver, Veli-Matti Kosma, Marjanka K. Schmidt, Aocs Investigators, Paula Maguire, Marike Gabrielson, Judith S. Brand, Simone Picelli, Rajeshwari Marikkannu, Quan Du, Irene L. Andrulis, Valerie Rhenius, Kyriaki Michailidou, Susan L. Neuhausen, Vinaykumar Kontham, Alison M. Dunning, Hermann Brenner, Thilo Dörk, Elinor J. Sawyer, Christopher A. Haiman, Anna González-Neira, Thérèse Truong, Peter Devilee, Qiuyin Cai, Susanna von Holst, Peter A. Fasching, Anna Marie Mulligan, Bernardo Bonanni, Javier Benítez, Kamila Czene, Loic Le Marchand, Katri Pylkäs, Henrik Flyger, Jacques Simard, Manjeet K. Bolla, Alfons Meindl, Per Hall, Simon S. Cross, Annika Lindblom, Emily Hallberg, Christos Aravidis, Sara Margolin, Vessela N. Kristensen, Carl Blomqvist, Annegien Broeks, John W.M. Martens, Jonine D. Figueroa, Xiang Jiao, Montserrat Garcia-Closas, Mitul Shah, Matthias W. Beckmann, Thomas Brüning, Guanmengqian Huang, John L. Hopper, Jan Lubinski, Michael Jones, Anthony J. Swerdlow, Roger L. Milne, Patricia Harrington, Caroline Seynaeve, Arto Mannermaa, Liping Luo, Natalia Antonenkova, Tatjana Adamovic, Angela Cox, Maartje J. Hooning, Volker Arndt, Dieter Flesch-Janys, Camilla Wendt, Stig E. Bojesen, Melissa C. Southey, Robert Winqvist, Anna Jakubowska, Paul D.P. Pharoah, Bram Boeckx, Sandra Deming-Halverson, Heli Nevanlinna, Jenny Chang-Claude, School of Medicine / Clinical Medicine, Cardiology, Medical Oncology, Department of Oncology, Clinicum, University of Helsinki, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and HUS Comprehensive Cancer Center

Subjects
EXPRESSION, 0301 basic medicine, Cellbiologi, 3122 Cancers, DNA-SEQUENCING DATA, Locus (genetics), Single-nucleotide polymorphism, Biology, Genome, FAMILIES, risk haplotype, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, Genetic linkage, Journal Article, medicine, linkage analysis, Allele, Gene, WIDE LINKAGE SCAN, Genetics, Cancer och onkologi, MUTATIONS, familial breast cancer, Haplotype, LOCALIZATION, ASSOCIATION, sequencing, Cell Biology, medicine.disease, GENE, 3. Good health, GENOME, 030104 developmental biology, Oncology, DISCOVERY, Cancer and Oncology, 030220 oncology & carcinogenesis, Priority Research Paper
Abstract

Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD >2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene., published version, peerReviewed

Published
2017

15. Association analysis identifies 65 new breast cancer risk loci

Author

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

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

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

Published
2017

16. Parent of Origin and Prognosis in Familial Breast Cancer in Sweden

Author

Camilla Wendt, Sara Margolin, Annika Lindblom, Anna von Wachenfeldt, and Brita Arver

Subjects
Oncology, Adult, Male, Risk, Cancer Research, medicine.medical_specialty, Mothers, Breast Neoplasms, Kaplan-Meier Estimate, Disease-Free Survival, Cohort Studies, Fathers, Survival data, Breast cancer, Internal medicine, medicine, Humans, In patient, Paternal Inheritance, Aged, Proportional Hazards Models, Aged, 80 and over, Family Health, Sweden, business.industry, Hazard ratio, Significant difference, General Medicine, Middle Aged, medicine.disease, Prognosis, Confidence interval, Female, Familial breast cancer, business
Abstract

BACKGROUND It has been suggested that prognosis in familial breast cancer could be influenced by the parent of origin, with a worse prognosis when inherited paternally. This study aimed to investigate the effect of the parent of origin on prognosis. PATIENTS AND METHODS Index patients were divided into two study groups depending on the parent of origin. Tumour characteristics and survival data for index patients were collected. RESULTS In total, 319 families fulfilled the inclusion criteria. No significant difference in overall or recurrence-free survival between those with maternal and those with paternal inheritance was observed, with hazard ratios (HR) of 0.99 (95% confidence interval (CI)=0.54 to 1.80, p=0.97) and 1.22 (95% CI=0.78 to 1.92, p=0.38), respectively. CONCLUSION We found no evidence for a worse prognosis in patients with paternally inherited breast cancer. However, only large differences in prognosis were excluded and the tendency for worse recurrence-free survival in the group with paternal inheritance therefore merits further study.

Published
2016

17. Tumour spectrum in non-BRCA hereditary breast cancer families in Sweden

Author

Brita Arver, Sara Margolin, Camilla Wendt, Annika Lindblom, and Anna von Wachenfeldt

Subjects
Oncology, medicine.medical_specialty, Genetic counseling, Family history, Population, Context (language use), Bioinformatics, Cancer syndrome, Breast cancer, Endometrial cancer, Internal medicine, Medicine, skin and connective tissue diseases, education, Genetics (clinical), education.field_of_study, business.industry, Research, Cancer, medicine.disease, business, Ovarian cancer
Abstract

Background Approximately 30 % of all breast cancer is at least partly attributed to hereditary factors. Familial breast cancer is often inherited in the context of cancer syndromes. The most commonly mutated genes are BRCA1 and BRCA2 in hereditary breast and ovarian cancer syndrome. The genetic background in families with hereditary breast cancer without predisposing germ line mutations in BRCA1 and BRCA2 (non-BRCA families) is still to a large extent unclear even though progress has been made. The aim of this study was to compare cancer proportions in familial non-BRCA hereditary breast cancer compared to the general population in search of putative new breast cancer syndromes. Methods Pedigrees from 334 non-BRCA hereditary breast cancer families in the county of Stockholm, Sweden, were investigated and the distribution of cancer diagnoses other than breast cancer was compared with the distribution of cancer diagnoses in the general Swedish population in two reference years, 1970 and 2010. A cancer diagnosis was regarded as overrepresented in the non-BRCA families if the confidence interval was above both population reference values. Results We found that endometrial cancer was overrepresented in the non-BRCA families with a 6.36 % proportion (CI 4.67–8.2) compared to the proportion in the general population in the reference years 1970 (3.07 %) and 2010 (2.64 %). Moreover tumours of the ovary, liver, pancreas and prostate were overrepresented. Conclusion In conclusion, we found an overrepresentation of endometrial cancer in our cohort of hereditary non-BRCA families. Our result supports previous inconsistent reports of a putative breast and endometrial cancer syndrome. An association has been suggested in studies of families with several cases of breast cancer in close relatives or bilateral breast cancer. To clarify this issue we suggest further studies on a breast and endometrial cancer syndrome in cohorts with a strong pattern of hereditary breast cancer. Identifying new breast cancer syndromes is of importance to improve genetic counselling for women at risk and a first step towards detection of new susceptibility genes.

Published
2015

18. A breast and endometrial cancer syndrome

Author

Sara Margolin and Camilla Wendt

Subjects
0301 basic medicine, Oncology, medicine.medical_specialty, business.industry, Endometrial cancer, Obstetrics and Gynecology, Cancer, 030105 genetics & heredity, medicine.disease, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, 0302 clinical medicine, Text mining, Breast cancer, 030220 oncology & carcinogenesis, Internal medicine, medicine, business
Published
2016

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