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1. Associations of a Breast Cancer Polygenic Risk Score With Tumor Characteristics and Survival

Author: Lopes Cardozo, Josephine MN, Andrulis, Irene L, Bojesen, Stig E, Dörk, Thilo, Eccles, Diana M, Fasching, Peter A, Hooning, Maartje J, Keeman, Renske, Nevanlinna, Heli, Rutgers, Emiel JT, Easton, Douglas F, Hall, Per, Pharoah, Paul DP, van 't Veer, Laura J, Schmidt, Marjanka K, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Auer, Paul L, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Blomqvist, Carl, Bolla, Manjeet K, Bonanni, Bernardo, Boyle, Terry, Brenner, Hermann, Brucker, Sara Y, Brüning, Thomas, Burwinkel, Barbara, Buys, Saundra S, Camp, Nicola J, Canzian, Federico, Cardoso, Fatima, Castelao, Jose E, Cessna, Melissa H, Chan, Tsun L, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Colonna, Sarah V, Copson, Ellen, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Dennis, Joe, Devilee, Peter, Drukker, Caroline A, Dunning, Alison M, Dwek, Miriam, Eliassen, A Heather, Engel, Christoph, Evans, D Gareth, Figueroa, Jonine D, Fletcher, Olivia, Flyger, Henrik, Gago-Dominguez, Manuela, García-Closas, Montserrat, García-Sáenz, José A, Genkinger, Jeanine, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Hahnen, Eric, Haiman, Christopher A, Håkansson, Niclas, Hamann, Ute, Hartman, Mikael, Heemskerk-Gerritsen, Bernadette AM, Hein, Alexander, Ho, Weang-Kee, Hoppe, Reiner, Hopper, John L, Houlston, Richard S, Howell, Anthony, Hunter, David J, Ito, Hidemi, Jakubowska, Anna, Jernström, Helena, John, Esther M, Johnson, Nichola, Jones, Michael E, Joseph, Vijai, Kaaks, Rudolf, Kang, Daehee, Kim, Sung-Won, Kitahara, Cari M, Koppert, Linetta B, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, and Koutros, Stella
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Human Genome, Genetics, Cancer, Women's Health, Breast Cancer, Good Health and Well Being, Female, Humans, Breast Neoplasms, Risk Factors, Prognosis, Proportional Hazards Models, Breast, Breast Cancer Association Consortium and MINDACT Collaborators, Clinical Sciences, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: PurposeA polygenic risk score (PRS) consisting of 313 common genetic variants (PRS313) is associated with risk of breast cancer and contralateral breast cancer. This study aimed to evaluate the association of the PRS313 with clinicopathologic characteristics of, and survival following, breast cancer.MethodsWomen with invasive breast cancer were included, 98,397 of European ancestry and 12,920 of Asian ancestry, from the Breast Cancer Association Consortium (BCAC), and 683 women from the European MINDACT trial. Associations between PRS313 and clinicopathologic characteristics, including the 70-gene signature for MINDACT, were evaluated using logistic regression analyses. Associations of PRS313 (continuous, per standard deviation) with overall survival (OS) and breast cancer-specific survival (BCSS) were evaluated with Cox regression, adjusted for clinicopathologic characteristics and treatment.ResultsThe PRS313 was associated with more favorable tumor characteristics. In BCAC, increasing PRS313 was associated with lower grade, hormone receptor-positive status, and smaller tumor size. In MINDACT, PRS313 was associated with a low risk 70-gene signature. In European women from BCAC, higher PRS313 was associated with better OS and BCSS: hazard ratio (HR) 0.96 (95% CI, 0.94 to 0.97) and 0.96 (95% CI, 0.94 to 0.98), but the association disappeared after adjustment for clinicopathologic characteristics (and treatment): OS HR, 1.01 (95% CI, 0.98 to 1.05) and BCSS HR, 1.02 (95% CI, 0.98 to 1.07). The results in MINDACT and Asian women from BCAC were consistent.ConclusionAn increased PRS313 is associated with favorable tumor characteristics, but is not independently associated with prognosis. Thus, PRS313 has no role in the clinical management of primary breast cancer at the time of diagnosis. Nevertheless, breast cancer mortality rates will be higher for women with higher PRS313 as increasing PRS313 is associated with an increased risk of disease. This information is crucial for modeling effective stratified screening programs.
Published: 2023

2. Distinct Reproductive Risk Profiles for Intrinsic-Like Breast Cancer Subtypes: Pooled Analysis of Population-Based Studies

Author: Jung, Audrey Y, Ahearn, Thomas U, Behrens, Sabine, Middha, Pooja, Bolla, Manjeet K, Wang, Qin, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Freeman, Laura E Beane, Becher, Heiko, Brenner, Hermann, Canzian, Federico, Carey, Lisa A, Consortium, CTS, Czene, Kamila, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine D, Fritschi, Lin, Gabrielson, Marike, Giles, Graham G, Guénel, Pascal, Hadjisavvas, Andreas, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Hüsing, Anika, Kaaks, Rudolf, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Lacey, James V, Le Marchand, Loic, Lissowska, Jolanta, Loizidou, Maria A, Mannermaa, Arto, Maurer, Tabea, Murphy, Rachel A, Olshan, Andrew F, Olsson, Håkan, Patel, Alpa V, Perou, Charles M, Rennert, Gad, Shibli, Rana, Shu, Xiao-Ou, Southey, Melissa C, Stone, Jennifer, Tamimi, Rulla M, Teras, Lauren R, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wang, Sophia S, Wolk, Alicja, Wu, Anna H, Yang, Xiaohong R, Zheng, Wei, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Milne, Roger L, Chatterjee, Nilanjan, Schmidt, Marjanka K, García-Closas, Montserrat, and Chang-Claude, Jenny
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Aging, Cancer, Clinical Research, Women's Health, Breast Cancer, 4.1 Discovery and preclinical testing of markers and technologies, Female, Humans, Breast Neoplasms, Receptor, ErbB-2, Receptors, Progesterone, Receptors, Estrogen, Triple Negative Breast Neoplasms, Case-Control Studies, Risk Factors, Biomarkers, Tumor, CTS Consortium, Receptor, erbB-2, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundReproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.MethodsAnalyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided.ResultsCompared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.ConclusionsThis large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.
Published: 2022

3. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, Joe, Tyrer, Jonathan P, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Qin, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Collée, J Margriet, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, and Soucy, Penny
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Prevention, Cancer, Women's Health, Human Genome, Breast Cancer, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, DNA Copy Number Variations, Female, Genome, Human, Genome-Wide Association Study, Germ Cells, Humans, Risk Factors, NBCS Collaborators, CTS Consortium, ABCTB Investigators, kConFab/AOCS Investigators, Biological sciences, Biomedical and clinical sciences
Abstract: Germline copy 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. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value
Published: 2022

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

Author: Baxter, Joseph S, Johnson, Nichola, Tomczyk, Katarzyna, Gillespie, Andrea, Maguire, Sarah, Brough, Rachel, Fachal, Laura, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Becher, Heiko, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Brucker, Sara Y, Cai, Qiuyin, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chan, Tsun L, Chang-Claude, Jenny, Chanock, Stephen J, Chenevix-Trench, Georgia, Choi, Ji-Yeob, Clarke, Christine L, Collaborators, NBCS, Colonna, Sarah, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Daly, Mary B, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Dwek, Miriam, Eccles, Diana M, Ekici, Arif B, Eliassen, A Heather, Engel, Christoph, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Gago-Dominguez, Manuela, Gao, Chi, García-Closas, Montserrat, García-Sáenz, José A, Ghoussaini, Maya, Giles, Graham G, Goldberg, Mark S, González-Neira, Anna, Guénel, Pascal, Gündert, Melanie, Haeberle, Lothar, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hatse, Sigrid, Hauke, Jan, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Hou, Ming-Feng, Investigators, kConFab, Investigators, ABCTB, Ito, Hidemi, Iwasaki, Motoki, Jager, Agnes, Jakubowska, Anna, Janni, Wolfgang, John, Esther M, Joseph, Vijai, Jung, Audrey, Kaaks, Rudolf, Kang, Daehee, Keeman, Renske, Khusnutdinova, Elza, Kim, Sung-Won, Kosma, Veli-Matti, Kraft, Peter, Kristensen, Vessela N, Kubelka-Sabit, Katerina, Kurian, Allison W, Kwong, Ava, and Lacey, James V
Subjects: Human Genome, Genetics, Cancer, Estrogen, Prevention, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, CRISPR-Cas Systems, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 2, Female, Genetic Association Studies, Genetic Variation, Humans, Insulin-Like Growth Factor Binding Protein 5, Molecular Sequence Annotation, Promoter Regions, Genetic, Risk Factors, Sequence Deletion, NBCS Collaborators, kConFab Investigators, ABCTB Investigators, breast cancer risk, functional annotation, risk locus, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
Published: 2021

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

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

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

Author: Colombo, Mara, Lòpez‐Perolio, Irene, Meeks, Huong D, Caleca, Laura, Parsons, Michael T, Li, Hongyan, Vecchi, Giovanna, Tudini, Emma, Foglia, Claudia, Mondini, Patrizia, Manoukian, Siranoush, Behar, Raquel, Garcia, Encarna B Gómez, Meindl, Alfons, Montagna, Marco, Niederacher, Dieter, Schmidt, Ane Y, Varesco, Liliana, Wappenschmidt, Barbara, Bolla, Manjeet K, Dennis, Joe, Michailidou, Kyriaki, Wang, Qin, Aittomäki, Kristiina, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly‐Fadel, Alicia, Benitez, Javier, Boeckx, Bram, Bogdanova, Natalia V, Bojesen, Stig E, Bonanni, Bernardo, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Chang‐Claude, Jenny, Conroy, Don M, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Gabrielson, Marike, García‐Closas, Montserrat, Giles, Graham G, González‐Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hamann, Ute, Hartman, Mikael, Hauke, Jan, Hollestelle, Antoinette, Hopper, John L, Jakubowska, Anna, Jung, Audrey, Kosma, Veli‐Matti, Lambrechts, Diether, Le Marchand, Loid, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Miao, Hui, Milne, Roger L, Neuhausen, Susan L, Nevanlinna, Heli, Olson, Janet E, Peterlongo, Paolo, Peto, Julian, Pylkäs, Katri, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Schneeweiss, Andreas, Schoemaker, Minouk J, See, Mee Hoong, Southey, Melissa C, Swerdlow, Anthony, Teo, Soo H, Toland, Amanda E, Tomlinson, Ian, Truong, Thérèse, Asperen, Christi J, Ouweland, Ans MW den, der Kolk, Lizet E, Winqvist, Robert, Yannoukakos, Drakoulis, Zheng, Wei, Investigators, kConFab AOCS, Dunning, Alison M, and Easton, Douglas F
Subjects: Cancer, Genetics, Clinical Research, Prevention, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, BRCA2 Protein, Base Sequence, Calibration, Cell Line, Exons, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Mitomycin, Models, Genetic, RNA Splicing, RNA, Messenger, kConFab/AOCS Investigators, BRCA2, digital PCR, multifactorial likelihood analysis, quantitative real-time PCR, spliceogenic variants, Clinical Sciences, Genetics & Heredity
Abstract: Although the spliceogenic nature of the BRCA2 c.68-7T > A variant has been demonstrated, its association with cancer risk remains controversial. In this study, we accurately quantified by real-time PCR and digital PCR (dPCR), the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T > A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 × 10-115 . There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24) nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the nonpathogenicity of the BRCA2 c.68-7T > A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants.
Published: 2018

7. BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer

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

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

Author: Muranen, Taru A, Greco, Dario, Blomqvist, Carl, Aittomäki, Kristiina, Khan, Sofia, Hogervorst, Frans, Verhoef, Senno, Pharoah, Paul DP, Dunning, Alison M, Shah, Mitul, Luben, Robert, Bojesen, Stig E, Nordestgaard, Børge G, Schoemaker, Minouk, Swerdlow, Anthony, García-Closas, Montserrat, Figueroa, Jonine, Dörk, Thilo, Bogdanova, Natalia V, Hall, Per, Li, Jingmei, Khusnutdinova, Elza, Bermisheva, Marina, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Investigators, NBCS, Peto, Julian, dos Santos Silva, Isabel, Couch, Fergus J, Olson, Janet E, Hillemans, Peter, Park-Simon, Tjoung-Won, Brauch, Hiltrud, Hamann, Ute, Burwinkel, Barbara, Marme, Frederik, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Cross, Simon S, Sawyer, Elinor J, Tomlinson, Ian, Lambrechts, Diether, Moisse, Matthieu, Lindblom, Annika, Margolin, Sara, Hollestelle, Antoinette, Martens, John WM, Fasching, Peter A, Beckmann, Matthias W, Andrulis, Irene L, Knight, Julia A, Investigators, kConFab AOCS, Anton-Culver, Hoda, Ziogas, Argyrios, Giles, Graham G, Milne, Roger L, Brenner, Hermann, Arndt, Volker, Mannermaa, Arto, Kosma, Veli-Matti, Chang-Claude, Jenny, Rudolph, Anja, Devilee, Peter, Seynaeve, Caroline, Hopper, John L, Southey, Melissa C, John, Esther M, Whittemore, Alice S, Bolla, Manjeet K, Wang, Qin, Michailidou, Kyriaki, Dennis, Joe, Easton, Douglas F, Schmidt, Marjanka K, and Nevanlinna, Heli
Subjects: Cancer, Prevention, Breast Cancer, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Checkpoint Kinase 2, Female, Genes, Modifier, Genetic Predisposition to Disease, Humans, Odds Ratio, Penetrance, Sequence Deletion, breast cancer, Breast Cancer Association Consortium, CHEK2*1100delC, common variants, polygenic risk score, NBCS Investigators, kConFab/AOCS Investigators, Genetics, Clinical Sciences, Genetics & Heredity
Abstract: PurposeCHEK2*1100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK2*1100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).MethodsUsing genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.ResultsThe PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK2*1100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK2*1100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.ConclusionOur results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
Published: 2017

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

Author: Southey, Melissa C, Goldgar, David E, Winqvist, Robert, Pylkäs, Katri, Couch, Fergus, Tischkowitz, Marc, Foulkes, William D, Dennis, Joe, Michailidou, Kyriaki, van Rensburg, Elizabeth J, Heikkinen, Tuomas, Nevanlinna, Heli, Hopper, John L, Dörk, Thilo, Claes, Kathleen BM, Reis-Filho, Jorge, Teo, Zhi Ling, Radice, Paolo, Catucci, Irene, Peterlongo, Paolo, Tsimiklis, Helen, Odefrey, Fabrice A, Dowty, James G, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, Verhoef, Senno, Carpenter, Jane, Clarke, Christine, Scott, Rodney J, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federik, Burwinkel, Barbara, Yang, Rongxi, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Menéndez, Primitiva, Anton-Culver, Hoda, Neuhausen, Susan, Ziogas, Argyrios, Clarke, Christina A, Brenner, Hermann, Arndt, Volker, Stegmaier, Christa, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Spurdle, Amanda B, Investigators, kConFab, Group, Australian Ovarian Cancer Study, Wauters, Els, Smeets, Dominiek, Beuselinck, Benoit, Floris, Giuseppe, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Olson, Janet E, Vachon, Celine, Pankratz, Vernon S, McLean, Catriona, Haiman, Christopher A, Henderson, Brian E, Schumacher, Fredrick, Le Marchand, Loic, Kristensen, Vessela, Alnæs, Grethe Grenaker, and Zheng, Wei
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Rare Diseases, Aging, Cancer, Prevention, Breast Cancer, Urologic Diseases, Women's Health, Ovarian Cancer, 2.1 Biological and endogenous factors, Ataxia Telangiectasia Mutated Proteins, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Fanconi Anemia Complementation Group N Protein, Female, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Mutation, Nuclear Proteins, Ovarian Neoplasms, Prostatic Neoplasms, Risk, Tumor Suppressor Proteins, Australian Ovarian Cancer Study Group, Cancer: breast, Cancer: ovary, Cancer: prostate, cancer predisposition, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundThe rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study.MethodsWe genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant.ResultsFor European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10-5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10-8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants.ConclusionsThis report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.
Published: 2016

10. Fine‐scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer

Author: Shi, Jiajun, Zhang, Yanfeng, Zheng, Wei, Michailidou, Kyriaki, Ghoussaini, Maya, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Lush, Michael, Milne, Roger L, Shu, Xiao‐Ou, Beesley, Jonathan, Kar, Siddhartha, Andrulis, Irene L, Anton‐Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Zhao, Zhiguo, Guo, Xingyi, Benitez, Javier, Beeghly‐Fadiel, Alicia, Blot, William, Bogdanova, Natalia V, Bojesen, Stig E, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang‐Claude, Jenny, Choi, Ji‐Yeob, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dork, Thilo, Fasching, Peter A, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García‐Closas, Montserrat, Giles, Graham G, Grip, Mervi, Guenel, Pascal, Haiman, Christopher A, Hamann, Ute, Hartman, Mikael, Miao, Hui, Hollestelle, Antoinette, Hopper, John L, Hsiung, Chia‐Ni, Investigators, kConFab, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Torres, Diana, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia A, Kosma, Veli‐Matti, Lambrechts, Diether, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Le Marchand, Loic, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Nord, Silje, Børresen‐Dale, Anne‐Lise, Olson, Janet E, Orr, Nick, van den Ouweland, Ans MW, Peterlongo, Paolo, Putti, Thomas Choudary, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shen, Chen‐Yang, Hou, Ming‐Feng, Shrubsole, Matha J, and Southey, Melissa C
Subjects: Genetics, Cancer, Breast Cancer, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 8, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Linkage Disequilibrium, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, White People, breast cancer, genetic susceptibility, 8q24, fine-mapping, single nucleotide polymorphism, Mervi Grip, kConFab Investigators, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.
Published: 2016

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

Author: Guo, Yan, Warren Andersen, Shaneda, Shu, Xiao-Ou, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Garcia-Closas, Montserrat, Milne, Roger L, Schmidt, Marjanka K, Chang-Claude, Jenny, Dunning, Allison, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Bogdanova, Natalia V, Bonanni, Bernardo, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, Jenkins, Mark, John, Esther M, Johnson, Nichola, Jones, Michael E, Kabisch, Maria, Kibriya, Muhammad, Knight, Julia A, Koppert, Linetta B, Kosma, Veli-Matti, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Luben, Robert, Lubinski, Jan, Malone, Kathi E, Mannermaa, Arto, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perez, Jose IA, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Shah, Mitul, Shrubsole, Martha J, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob B, and Verhoef, Senno
Subjects: Humans, Breast Neoplasms, Genetic Predisposition to Disease, Body Mass Index, Models, Statistical, Risk Factors, Menopause, Polymorphism, Single Nucleotide, Middle Aged, European Continental Ancestry Group, Female, Mendelian Randomization Analysis, Models, Statistical, Polymorphism, Single Nucleotide, Genetics, Prevention, Breast Cancer, Nutrition, Clinical Research, Cancer, Aging, Human Genome, 2.1 Biological and endogenous factors, General & Internal Medicine, Medical and Health Sciences
Abstract: BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases = 46,325, controls = 42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR] = 0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32 × 10-10). The associations were similar for both premenopausal (OR = 0.44, 95% CI:0.31-0.62, p = 9.91 × 10-8) and postmenopausal breast cancer (OR = 0.57, 95% CI: 0.46-0.71, p = 1.88 × 10-8). This association was replicated in the data from the DRIVE consortium (OR = 0.72, 95% CI: 0.60-0.84, p = 1.64 × 10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p
Published: 2016

12. Age- and Tumor Subtype–Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers

Author: Schmidt, Marjanka K, Hogervorst, Frans, van Hien, Richard, Cornelissen, Sten, Broeks, Annegien, Adank, Muriel A, Meijers, Hanne, Waisfisz, Quinten, Hollestelle, Antoinette, Schutte, Mieke, van den Ouweland, Ans, Hooning, Maartje, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Antoniou, Antonis C, Arndt, Volker, Bermisheva, Marina, Bogdanova, Natalia V, Bolla, Manjeet K, Brauch, Hiltrud, Brenner, Hermann, Brüning, Thomas, Burwinkel, Barbara, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dunning, Alison M, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Galle, Eva, García-Closas, Montserrat, Giles, Graham G, Haeberle, Lothar, Hall, Per, Hillemanns, Peter, Hopper, John L, Jakubowska, Anna, John, Esther M, Jones, Michael, Khusnutdinova, Elza, Knight, Julia A, Kosma, Veli-Matti, Kristensen, Vessela, Lee, Andrew, Lindblom, Annika, Lubinski, Jan, Mannermaa, Arto, Margolin, Sara, Meindl, Alfons, Milne, Roger L, Muranen, Taru A, Newcomb, Polly A, Offit, Kenneth, Park-Simon, Tjoung-Won, Peto, Julian, Pharoah, Paul DP, Robson, Mark, Rudolph, Anja, Sawyer, Elinor J, Schmutzler, Rita K, Seynaeve, Caroline, Soens, Julie, Southey, Melissa C, Spurdle, Amanda B, Surowy, Harald, Swerdlow, Anthony, Tollenaar, Rob AEM, Tomlinson, Ian, Trentham-Dietz, Amy, Vachon, Celine, Wang, Qin, Whittemore, Alice S, Ziogas, Argyrios, van der Kolk, Lizet, Nevanlinna, Heli, Dörk, Thilo, Bojesen, Stig, and Easton, Douglas F
Subjects: Clinical Research, Genetics, Cancer, Breast Cancer, Aetiology, 2.1 Biological and endogenous factors, Adult, Age Factors, Aged, Aged, 80 and over, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Female, Genetic Predisposition to Disease, Heterozygote, Homozygote, Humans, Middle Aged, Odds Ratio, Receptors, Estrogen, Receptors, Progesterone, Risk Assessment, Sequence Deletion, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeCHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations; however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC.Patients and methodsCHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies.ResultsProportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center-based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69; P = 2.3 × 10(-20)). The OR was higher for estrogen receptor (ER)-positive disease (2.55 [95%CI, 2.10 to 3.10; P = 4.9 × 10(-21)]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88; P = .12]; P interaction = 9.9 × 10(-4)). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom.ConclusionThese CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Published: 2016

13. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Author: Arndt, Volker, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham, Guénel, Pascal, Haiman, Christopher, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje, Hopper, John, Jakubowska, Anna, Jasmine, Farzana, John, Esther, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan, Nevanlinna, Heli, Neven, Patrick, Olson, Janet, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor, Schmutzler, Rita, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa, Swerdlow, Anthony, Toland, Amanda, Tomlinson, Ian, Torres, Diana, Truong, Thérèse, Ursin, Giske, Van Der Luijt, Rob, Verhoef, Senno, Wang-Gohrke, Shan, Whittemore, Alice, Winqvist, Robert, Pilar Zamora, M, Zhao, Hui, Dunning, Alison, Simard, Jacques, Hall, Per, Kraft, Peter, Pharoah, Paul, Hunter, David, Easton, Douglas, and Zheng, Wei
Subjects: Breast cancer, Epidemiology, GWAS, Genetic susceptibility, Type 2 diabetes, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People
Abstract: PURPOSE: Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS: We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS: The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS: We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

14. Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry

Author: Zhao, Zhiguo, Wen, Wanqing, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Zhang, Ben, Long, Jirong, Shu, Xiao-Ou, Schmidt, Marjanka K, Milne, Roger L, García-Closas, Montserrat, Chang-Claude, Jenny, Lindstrom, Sara, Bojesen, Stig E, Ahsan, Habibul, Aittomäki, Kristiina, Andrulis, Irene L, Anton-Culver, Hoda, Arndt, Volker, Beckmann, Matthias W, Beeghly-Fadiel, Alicia, Benitez, Javier, Blomqvist, Carl, Bogdanova, Natalia V, Børresen-Dale, Anne-Lise, Brand, Judith, Brauch, Hiltrud, Brenner, Hermann, Burwinkel, Barbara, Cai, Qiuyin, Casey, Graham, Chenevix-Trench, Georgia, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dumont, Martine, Fasching, Peter A, Figueroa, Jonine, Flesch-Janys, Dieter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gammon, Marilie, Giles, Graham G, Guénel, Pascal, Haiman, Christopher A, Hamann, Ute, Harrington, Patricia, Hartman, Mikael, Hooning, Maartje J, Hopper, John L, Jakubowska, Anna, Jasmine, Farzana, John, Esther M, Johnson, Nichola, Kabisch, Maria, Khan, Sofia, Kibriya, Muhammad, Knight, Julia A, Kosma, Veli-Matti, Kriege, Mieke, Kristensen, Vessela, Le Marchand, Loic, Lee, Eunjung, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Luben, Robert, Lubinski, Jan, Malone, Kathleen E, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, McLean, Catriona, Meijers-Heijboer, Hanne, Meindl, Alfons, Miao, Hui, Muir, Kenneth, Neuhausen, Susan L, Nevanlinna, Heli, Neven, Patrick, Olson, Janet E, Perkins, Barbara, Peterlongo, Paolo, Phillips, Kelly-Anne, Pylkäs, Katri, Rudolph, Anja, Santella, Regina, Sawyer, Elinor J, Schmutzler, Rita K, Schoemaker, Minouk, Shah, Mitul, Shrubsole, Martha, Southey, Melissa C, Swerdlow, Anthony J, Toland, Amanda E, and Tomlinson, Ian
Subjects: Genetics, Breast Cancer, Prevention, Diabetes, Aging, Cancer, Clinical Research, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Case-Control Studies, Diabetes Mellitus, Type 2, Ethnicity, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People, Type 2 diabetes, Genetic susceptibility, GWAS, Breast cancer, Epidemiology, Oncology and Carcinogenesis, Public Health and Health Services
Abstract: PurposeType 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.MethodsWe constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies.ResultsThe T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04).ConclusionsWe have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.
Published: 2016

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

Author: Easton, Douglas F, Lesueur, Fabienne, Decker, Brennan, Michailidou, Kyriaki, Li, Jun, Allen, Jamie, Luccarini, Craig, Pooley, Karen A, Shah, Mitul, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Ahmad, Jamil, Thompson, Ella R, Damiola, Francesca, Pertesi, Maroulio, Voegele, Catherine, Mebirouk, Noura, Robinot, Nivonirina, Durand, Geoffroy, Forey, Nathalie, Luben, Robert N, Ahmed, Shahana, Aittomäki, Kristiina, Anton-Culver, Hoda, Arndt, Volker, Australian Ovarian Cancer Study Group, Baynes, Caroline, Beckman, Matthias W, Benitez, Javier, Van Den Berg, David, Blot, William J, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Chang-Claude, Jenny, Chia, Kee Seng, Choi, Ji-Yeob, Conroy, Don M, Cox, Angela, Cross, Simon S, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Eriksson, Mikael, Fasching, Peter A, Figueroa, Jonine, Flyger, Henrik, Fostira, Florentia, García-Closas, Montserrat, Giles, Graham G, Glendon, Gord, González-Neira, Anna, Guénel, Pascal, Haiman, Christopher A, Hall, Per, Hart, Steven N, Hartman, Mikael, Hooning, Maartje J, Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, James, Paul A, John, Esther M, Johnson, Nichola, Jones, Michael, Kabisch, Maria, Kang, Daehee, kConFab Investigators, Kosma, Veli-Matti, Kristensen, Vessela, Lambrechts, Diether, Li, Na, Lifepool Investigators, Lindblom, Annika, Long, Jirong, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Matsuo, Keitaro, Meindl, Alfons, Mitchell, Gillian, Muir, Kenneth, NBCS Investigators, Nevelsteen, Ines, van den Ouweland, Ans, Peterlongo, Paolo, Phuah, Sze Yee, Pylkäs, Katri, Rowley, Simone M, Sangrajrang, Suleeporn, Schmutzler, Rita K, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Surowy, Harald, Swerdlow, Anthony, and Teo, Soo H
Subjects: Australian Ovarian Cancer Study Group, kConFab Investigators, Lifepool Investigators, NBCS Investigators, Humans, Breast Neoplasms, Genetic Predisposition to Disease, RNA Helicases, DNA-Binding Proteins, Risk, Cohort Studies, Mutation, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Fanconi Anemia Complementation Group Proteins, Genetic Association Studies, Cancer: breast, Genetics & Heredity, Biological Sciences, Medical and Health Sciences
Abstract: BACKGROUND:BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS:We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS:The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS:These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.
Published: 2016

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

Author: Dunning, Alison M, Michailidou, Kyriaki, Kuchenbaecker, Karoline B, Thompson, Deborah, French, Juliet D, Beesley, Jonathan, Healey, Catherine S, Kar, Siddhartha, Pooley, Karen A, Lopez-Knowles, Elena, Dicks, Ed, Barrowdale, Daniel, Sinnott-Armstrong, Nicholas A, Sallari, Richard C, Hillman, Kristine M, Kaufmann, Susanne, Sivakumaran, Haran, Moradi Marjaneh, Mahdi, Lee, Jason S, Hills, Margaret, Jarosz, Monika, Drury, Suzie, Canisius, Sander, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Hopper, John L, Southey, Melissa C, Broeks, Annegien, Schmidt, Marjanka K, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Fasching, Peter A, Dos-Santos-Silva, Isabel, Peto, Julian, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, González-Neira, Anna, Perez, Jose IA, Anton-Culver, Hoda, Eunjung, Lee, Arndt, Volker, Brenner, Hermann, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Aittomäki, Kristiina, Blomqvist, Carl, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natasha, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-Chen, Wu, Anna H, Lambrechts, Diether, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Olson, Janet E, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Henderson, Brian E, Goldberg, Mark S, Teo, Soo H, Yip, Cheng Har, Nord, Silje, Borresen-Dale, Anne-Lise, Kristensen, Vessela, Long, Jirong, Zheng, Wei, Pylkäs, Katri, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, Figueroa, Jonine, Sherman, Mark E, Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, van den Ouweland, Ans MW, Humphreys, Keith, Gao, Yu-Tang, and Shu, Xiao-Ou
Subjects: EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Carrier Proteins, Cell Cycle Proteins, Estrogen Receptor alpha, Risk Factors, Gene Expression, Gene Expression Regulation, Neoplastic, Base Sequence, Protein Binding, Phenotype, Polymorphism, Single Nucleotide, Female, Genetic Association Studies, Cancer, Clinical Research, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract: We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression.
Published: 2016

17. Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus.

Author: Horne, Hisani N, Chung, Charles C, Zhang, Han, Yu, Kai, Prokunina-Olsson, Ludmila, Michailidou, Kyriaki, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Hopper, John L, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Anton-Culver, Hoda, Neuhausen, Susan L, Brenner, Hermann, Arndt, Volker, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Hamann, Ute, Nevanlinna, Heli, Khan, Sofia, Matsuo, Keitaro, Iwata, Hiroji, Dörk, Thilo, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Chenevix-Trench, Georgia, kConFab/AOCS Investigators, Wu, Anna H, Ven den Berg, David, Smeets, Ann, Zhao, Hui, Chang-Claude, Jenny, Rudolph, Anja, Radice, Paolo, Barile, Monica, Couch, Fergus J, Vachon, Celine, Giles, Graham G, Milne, Roger L, Haiman, Christopher A, Marchand, Loic Le, Goldberg, Mark S, Teo, Soo H, Taib, Nur AM, Kristensen, Vessela, Borresen-Dale, Anne-Lise, Zheng, Wei, Shrubsole, Martha, Winqvist, Robert, Jukkola-Vuorinen, Arja, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Seynaeve, Caroline, García-Closas, Montserrat, Czene, Kamila, Darabi, Hatef, Hollestelle, Antoinette, Martens, John WM, Li, Jingmei, Lu, Wei, Shu, Xiao-Ou, Cox, Angela, Cross, Simon S, Blot, William, Cai, Qiuyin, Shah, Mitul, Luccarini, Craig, Baynes, Caroline, Harrington, Patricia, Kang, Daehee, Choi, Ji-Yeob, Hartman, Mikael, Chia, Kee Seng, Kabisch, Maria, Torres, Diana, Jakubowska, Anna, and Lubinski, Jan
Subjects: kConFab/AOCS Investigators, Chromosomes, Human, Pair 1, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Population Surveillance, Risk Assessment, Case-Control Studies, Chromosome Mapping, Computational Biology, Gene Frequency, Genotype, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Quantitative Trait Loci, Female, Genetic Association Studies, Neoplasm Grading, General Science & Technology
Abstract: The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.
Published: 2016

18. Fine-scale mapping of the 4q24 locus identifies two independent loci associated with breast cancer risk.

Author: Arndt, Volker, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Blot, William, Bogdanova, Natalia, Bojesen, Stig, Brauch, Hiltrud, Brenner, Hermann, Brinton, Louise, Broeks, Annegien, Brüning, Thomas, Burwinkel, Barbara, Cai, Hui, Canisius, Sander, Chang-Claude, Jenny, Choi, Ji-Yeob, Couch, Fergus, Cox, Angela, Cross, Simon, Czene, Kamila, Darabi, Hatef, Devilee, Peter, Droit, Arnaud, Dörk, Thilo, Fasching, Peter, Fletcher, Olivia, Flyger, Henrik, Fostira, Florentia, Gaborieau, Valerie, García-Closas, Montserrat, Giles, Graham, Grip, Mervi, Guénel, Pascal, Haiman, Christopher, Hamann, Ute, Hartman, Mikael, Hollestelle, Antoinette, Hopper, John, Hsiung, Chia-Ni, Ito, Hidemi, Jakubowska, Anna, Johnson, Nichola, Kabisch, Maria, Kang, Daehee, Khan, Sofia, Knight, Julia, Kosma, Veli-Matti, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lophatananon, Artitaya, Lubinski, Jan, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Marme, Frederik, Matsuo, Keitaro, McLean, Catriona, Meindl, Alfons, Muir, Kenneth, Neuhausen, Susan, Nevanlinna, Heli, Nord, Silje, Olson, Janet, Orr, Nick, Peterlongo, Paolo, Putti, Thomas, Rudolph, Anja, Sangrajrang, Suleeporn, Sawyer, Elinor, Schmidt, Marjanka, Schmutzler, Rita, Shen, Chen-Yang, Shi, Jiajun, Shrubsole, Martha, Southey, Melissa, Swerdlow, Anthony, Teo, Soo, Thienpont, Bernard, Toland, Amanda, Tollenaar, Robert, Tomlinson, Ian, Truong, Thérèse, Tseng, Chiu-Chen, van den Ouweland, Ans, Wen, Wanqing, Winqvist, Robert, Wu, Anna, Yip, Cheng, Zamora, M, Zheng, Ying, Hall, Per, Pharoah, Paul, Simard, Jacques, Chenevix-Trench, Georgia, Dunning, Alison, Easton, Douglas, and Zheng, Wei
Subjects: Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 4, Female, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Logistic Models, Polymorphism, Single Nucleotide, Risk Factors
Abstract: BACKGROUND: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. METHODS: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. RESULTS: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10(-4); OR, 1.04; 95% confidence interval (CI), 1.02-1.07] and rs77928427 (P = 1.86 × 10(-4); OR, 1.04; 95% CI, 1.02-1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r(2) ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor-binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. CONCLUSION: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. IMPACT: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk.
Published: 2015

19. Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression

Author: Darabi, Hatef, McCue, Karen, Beesley, Jonathan, Michailidou, Kyriaki, Nord, Silje, Kar, Siddhartha, Humphreys, Keith, Thompson, Deborah, Ghoussaini, Maya, Bolla, Manjeet K, Dennis, Joe, Wang, Qin, Canisius, Sander, Scott, Christopher G, Apicella, Carmel, Hopper, John L, Southey, Melissa C, Stone, Jennifer, Broeks, Annegien, Schmidt, Marjanka K, Scott, Rodney J, Lophatananon, Artitaya, Muir, Kenneth, Beckmann, Matthias W, Ekici, Arif B, Fasching, Peter A, Heusinger, Katharina, dos-Santos-Silva, Isabel, Peto, Julian, Tomlinson, Ian, Sawyer, Elinor J, Burwinkel, Barbara, Marme, Frederik, Guénel, Pascal, Truong, Thérèse, Bojesen, Stig E, Flyger, Henrik, Benitez, Javier, González-Neira, Anna, Anton-Culver, Hoda, Neuhausen, Susan L, Arndt, Volker, Brenner, Hermann, Engel, Christoph, Meindl, Alfons, Schmutzler, Rita K, Cancer, German Consortium of Hereditary Breast and Ovarian, Arnold, Norbert, Brauch, Hiltrud, Hamann, Ute, Chang-Claude, Jenny, Khan, Sofia, Nevanlinna, Heli, Ito, Hidemi, Matsuo, Keitaro, Bogdanova, Natalia V, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Investigators, kConFab AOCS, Kosma, Veli-Matti, Mannermaa, Arto, Tseng, Chiu-chen, Wu, Anna H, Floris, Giuseppe, Lambrechts, Diether, Rudolph, Anja, Peterlongo, Paolo, Radice, Paolo, Couch, Fergus J, Vachon, Celine, Giles, Graham G, McLean, Catriona, Milne, Roger L, Dugué, Pierre-Antoine, Haiman, Christopher A, Maskarinec, Gertraud, Woolcott, Christy, Henderson, Brian E, Goldberg, Mark S, Simard, Jacques, Teo, Soo H, Mariapun, Shivaani, Helland, Åslaug, Haakensen, Vilde, Zheng, Wei, Beeghly-Fadiel, Alicia, Tamimi, Rulla, Jukkola-Vuorinen, Arja, Winqvist, Robert, Andrulis, Irene L, Knight, Julia A, Devilee, Peter, Tollenaar, Robert AEM, Figueroa, Jonine, García-Closas, Montserrat, Czene, Kamila, Hooning, Maartje J, Tilanus-Linthorst, Madeleine, and Li, Jingmei
Subjects: Human Genome, Aging, Cancer, Clinical Research, Breast Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Age Factors, Asian People, Autophagy-Related Proteins, Body Mass Index, Breast Neoplasms, Chromosome Mapping, Chromosomes, Human, Pair 10, DNA-Binding Proteins, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genome-Wide Association Study, Genotype, Humans, Luciferases, Odds Ratio, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Regression Analysis, Trans-Activators, Transcription Factors, White People, German Consortium of Hereditary Breast and Ovarian Cancer, kConFab/AOCS Investigators, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.
Published: 2015

20. Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2.

Author: Orr, Nick, Dudbridge, Frank, Dryden, Nicola, Maguire, Sarah, Novo, Daniela, Perrakis, Eleni, Johnson, Nichola, Ghoussaini, Maya, Hopper, John, Southey, Melissa, Apicella, Carmel, Stone, Jennifer, Schmidt, Marjanka, Broeks, Annegien, Vant Veer, Laura, Hogervorst, Frans, Fasching, Peter, Haeberle, Lothar, Ekici, Arif, Beckmann, Matthias, Gibson, Lorna, Aitken, Zoe, Warren, Helen, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Chistof, Guénel, Pascal, Truong, Thérèse, Cordina-Duverger, Emilie, Sanchez, Marie, Bojesen, Stig, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Benitez, Javier, Zamora, Maria, Arias Perez, Jose, Menéndez, Primitiva, Neuhausen, Susan, Brenner, Hermann, Dieffenbach, Aida, Arndt, Volker, Stegmaier, Christa, Hamann, Ute, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, Ko, Yon-Dschun, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Bogdanova, Natalia, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana, Chenevix-Trench, Georgia, Beesley, Jonathan, Lambrechts, Diether, Moisse, Matthieu, Floris, Guiseppe, Beuselinck, Benoit, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Peissel, Bernard, Pensotti, Valeria, Couch, Fergus, Olson, Janet, Slettedahl, Seth, Vachon, Celine, Giles, Graham, Milne, Roger, McLean, Catriona, Haiman, Christopher, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark, Labrèche, France, Dumont, Martine, Kristensen, Vessela, Alnæs, Grethe, Nord, Silje, Borresen-Dale, Anne-Lise, Zheng, Wei, and Deming-Halverson, Sandra
Subjects: Adult, Aged, Asian People, Breast Neoplasms, Chromosome Mapping, Chromosomes, Human, Pair 9, Enhancer Elements, Genetic, Estrogen Receptor alpha, Female, GATA3 Transcription Factor, Genetic Association Studies, Genetic Loci, Genetic Predisposition to Disease, Hepatocyte Nuclear Factor 3-alpha, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors, Middle Aged, Polymorphism, Single Nucleotide, Risk, White People
Abstract: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.
Published: 2015

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

Author: Rudolph, Anja, Milne, Roger L, Truong, Thérèse, Knight, Julia A, Seibold, Petra, Flesch‐Janys, Dieter, Behrens, Sabine, Eilber, Ursula, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Dunning, Alison M, Shah, Mitul, Munday, Hannah R, Darabi, Hatef, Eriksson, Mikael, Brand, Judith S, Olson, Janet, Vachon, Celine M, Hallberg, Emily, Castelao, J Esteban, Carracedo, Angel, Torres, Maria, Li, Jingmei, Humphreys, Keith, Cordina‐Duverger, Emilie, Menegaux, Florence, Flyger, Henrik, Nordestgaard, Børge G, Nielsen, Sune F, Yesilyurt, Betul T, Floris, Giuseppe, Leunen, Karin, Engelhardt, Ellen G, Broeks, Annegien, Rutgers, Emiel J, Glendon, Gord, Mulligan, Anna Marie, Cross, Simon, Reed, Malcolm, Gonzalez‐Neira, Anna, Perez, José Ignacio Arias, Provenzano, Elena, Apicella, Carmel, Southey, Melissa C, Spurdle, Amanda, Investigators, kConFab, Group, AOCS, Häberle, Lothar, Beckmann, Matthias W, Ekici, Arif B, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, McLean, Catriona, Baglietto, Laura, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Brüning, Thomas, Hamann, Ute, Ko, Yon‐Dschun, Orr, Nick, Schoemaker, Minouk, Ashworth, Alan, Kosma, Veli‐Matti, Kataja, Vesa, Hartikainen, Jaana M, Mannermaa, Arto, Swerdlow, Anthony, GENICA‐Network, Giles, Graham G, Brenner, Hermann, Fasching, Peter A, Chenevix‐Trench, Georgia, Hopper, John, Benítez, Javier, Cox, Angela, Andrulis, Irene L, Lambrechts, Diether, Gago‐Dominguez, Manuela, Couch, Fergus, Czene, Kamila, Bojesen, Stig E, Easton, Doug F, Schmidt, Marjanka K, Guénel, Pascal, Hall, Per, Pharoah, Paul DP, Garcia‐Closas, Montserrat, and Chang‐Claude, Jenny
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Breast Cancer, Aging, Prevention, Genetics, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Humans, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors, gene-environment interaction, breast cancer, risk factor, genetic susceptibility, kConFab Investigators, AOCS Group, GENICA-Network, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: A large genotyping project within the Breast Cancer Association Consortium (BCAC) recently identified 41 associations between single nucleotide polymorphisms (SNPs) and overall breast cancer (BC) risk. We investigated whether the effects of these 41 SNPs, as well as six SNPs associated with estrogen receptor (ER) negative BC risk are modified by 13 environmental risk factors for BC. Data from 22 studies participating in BCAC were pooled, comprising up to 26,633 cases and 30,119 controls. Interactions between SNPs and environmental factors were evaluated using an empirical Bayes-type shrinkage estimator. Six SNPs showed interactions with associated p-values (pint )
Published: 2015

22. Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Author: Glubb, Dylan M, Maranian, Mel J, Michailidou, Kyriaki, Pooley, Karen A, Meyer, Kerstin B, Kar, Siddhartha, Carlebur, Saskia, O’Reilly, Martin, Betts, Joshua A, Hillman, Kristine M, Kaufmann, Susanne, Beesley, Jonathan, Canisius, Sander, Hopper, John L, Southey, Melissa C, Tsimiklis, Helen, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Hogervorst, Frans B, van der Schoot, C Ellen, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Ruebner, Matthias, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Pharoah, Paul DP, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Yang, Rongxi, Surowy, Harald, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Sanchez, Marie, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, González-Neira, Anna, Benitez, Javier, Zamora, M Pilar, Perez, Jose Ignacio Arias, Anton-Culver, Hoda, Neuhausen, Susan L, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Brauch, Hiltrud, Ko, Yon-Dschun, Brüning, Thomas, Network, The GENICA, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Tanaka, Hideo, Dörk, Thilo, Bogdanova, Natalia V, Helbig, Sonja, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Investigators, kConFab, Wu, Anna H, Tseng, Chiu-chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Zhao, Hui, Weltens, Caroline, van Limbergen, Erik, Chang-Claude, Jenny, Flesch-Janys, Dieter, Rudolph, Anja, Seibold, Petra, and Radice, Paolo
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Human Genome, Prevention, Breast Cancer, Cancer, Estrogen, 2.1 Biological and endogenous factors, Aetiology, Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 5, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, MAP Kinase Kinase Kinase 1, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Racial Groups, Risk Factors, GENICA Network, kConFab Investigators, Norwegian Breast Cancer Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract: Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.
Published: 2015

23. Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk.

Author: Lin, Wei-Yu, Camp, Nicola J, Ghoussaini, Maya, Beesley, Jonathan, Michailidou, Kyriaki, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Stone, Jennifer, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Th Rutgers, Emiel J, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Haeberle, Lothar, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos-Santos-Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Bolla, Manjeet K, Wang, Qin, Dennis, Joe, Sawyer, Elinor J, Cheng, Timothy, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marmé, Frederik, Surowy, Harald M, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Menegaux, Florence, Mulot, Claire, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Benitez, Javier, Zamora, M Pilar, Arias Perez, Jose Ignacio, Menéndez, Primitiva, González-Neira, Anna, Pita, Guillermo, Alonso, M Rosario, Alvarez, Nuria, Herrero, Daniel, Anton-Culver, Hoda, Brenner, Hermann, Dieffenbach, Aida Karina, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita K, Müller-Myhsok, Bertram, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Tessier, Daniel C, Vincent, Daniel, Bacot, Francois, Nevanlinna, Heli, Aittomäki, Kristiina, Blomqvist, Carl, Khan, Sofia, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Horio, Akiyo, Bogdanova, Natalia V, Antonenkova, Natalia N, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Neven, Patrick, Wauters, Els, Wildiers, Hans, Lambrechts, Diether, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, and Flesch-Janys, Dieter
Subjects: GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Breast and Ovarian Cancer Susceptibility (BOCS) Study, Chromosomes, Human, Pair 2, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Proteins, Case-Control Studies, Polymorphism, Single Nucleotide, European Continental Ancestry Group, Female, Caspase 8, CASP8 and FADD-Like Apoptosis Regulating Protein, Genome-Wide Association Study, Genotyping Techniques, Chromosomes, Human, Pair 2, Polymorphism, Single Nucleotide, Prevention, Genetics, Human Genome, Breast Cancer, Cancer, Biotechnology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.
Published: 2015

24. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.

Author: Purrington, Kristen, Slettedahl, Seth, Bolla, Manjeet, Michailidou, Kyriaki, Czene, Kamila, Nevanlinna, Heli, Bojesen, Stig, Andrulis, Irene, Cox, Angela, Hall, Per, Carpenter, Jane, Yannoukakos, Drakoulis, Haiman, Christopher, Fasching, Peter, Mannermaa, Arto, Winqvist, Robert, Brenner, Hermann, Lindblom, Annika, Chenevix-Trench, Georgia, Benitez, Javier, Swerdlow, Anthony, Kristensen, Vessela, Guénel, Pascal, Meindl, Alfons, Darabi, Hatef, Eriksson, Mikael, Fagerholm, Rainer, Aittomäki, Kristiina, Blomqvist, Carl, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Wang, Xianshu, Olswold, Curtis, Olson, Janet, Mulligan, Anna, Knight, Julia, Tchatchou, Sandrine, Reed, Malcolm, Cross, Simon, Liu, Jianjun, Li, Jingmei, Humphreys, Keith, Clarke, Christine, Scott, Rodney, Fostira, Florentia, Fountzilas, George, Konstantopoulou, Irene, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Ekici, Arif, Hartmann, Arndt, Beckmann, Matthias, Hartikainen, Jaana, Kosma, Veli-Matti, Kataja, Vesa, Jukkola-Vuorinen, Arja, Pylkäs, Katri, Kauppila, Saila, Dieffenbach, Aida, Stegmaier, Christa, Arndt, Volker, Margolin, Sara, Balleine, Rosemary, Arias Perez, Jose, Pilar Zamora, M, Menéndez, Primitiva, Ashworth, Alan, Jones, Michael, Orr, Nick, Arveux, Patrick, Kerbrat, Pierre, Truong, Thérèse, Bugert, Peter, Toland, Amanda, Ambrosone, Christine, Labrèche, France, Goldberg, Mark, Dumont, Martine, Ziogas, Argyrios, Lee, Eunjung, Dite, Gillian, Apicella, Carmel, Southey, Melissa, Long, Jirong, Shrubsole, Martha, Deming-Halverson, Sandra, Ficarazzi, Filomena, Barile, Monica, Peterlongo, Paolo, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Tollenaar, Robert, Seynaeve, Caroline, Brüning, Thomas, Ko, Yon-Dschun, Van Deurzen, Carolien, Martens, John, and Kriege, Mieke
Subjects: Breast Neoplasms, Carrier Proteins, Case-Control Studies, Female, Genetic Variation, Haplotypes, Humans, Neoplasm Staging, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Risk Factors, Tumor Suppressor Proteins
Abstract: Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39 067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10(-10)) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk (P = 2.1 × 10(-3)). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.
Published: 2014

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

Author: Johnson, Nichola, Dudbridge, Frank, Orr, Nick, Gibson, Lorna, Jones, Michael E, Schoemaker, Minouk J, Folkerd, Elizabeth J, Haynes, Ben P, Hopper, John L, Southey, Melissa C, Dite, Gillian S, Apicella, Carmel, Schmidt, Marjanka K, Broeks, Annegien, Van't Veer, Laura J, Atsma, Femke, Muir, Kenneth, Lophatananon, Artitaya, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Renner, Stefan P, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Therese, Cordina, Emilie, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger, Zamora, M Pilar, Arias Perez, Jose Ignacio, Benitez, Javier, Bernstein, Leslie, Anton-Culver, Hoda, Ziogas, Argyrios, Clarke Dur, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Dieffenbach, Aida Karina, Meindl, Alfons, Heil, Joerg, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Dörk, Thilo, Bogdanova, Natalia V, Antonenkova, Natalia N, Lindblom, Annika, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, Beesley, Jonathan, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Van den Berg, David, Tseng, Chiu-Chen, Lambrechts, Diether, Smeets, Dominiek, Neven, Patrick, Wildiers, Hans, Chang-Claude, Jenny, Rudolph, Anja, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Pensotti, Valeria, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Haiman, Chris, Simard, Jacques, and Goldberg, Mark S
Subjects: GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Humans, Breast Neoplasms, Genetic Predisposition to Disease, Reproductive History, Risk Factors, Age Factors, Age of Onset, Premenopause, Menarche, Genotype, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Cytochrome P-450 CYP3A, Genetic Association Studies, Human Genome, Aging, Clinical Research, Cancer, Genetics, Breast Cancer, Oncology & Carcinogenesis, Oncology and Carcinogenesis
Abstract: IntroductionWe have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.MethodsWe further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics.ResultsWe confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P(trend) = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P(trend) = 0.005) but not cases (P(trend) = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P(het) = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (OR(het) = 0.84, 95% CI 0.75, 0.94; OR(hom) = 0.81, 95% CI 0.51, 1.30; P(trend) = 0.002) but not for those who had their menarche age ≤11 years (OR(het) = 1.06, 95% CI 0.95, 1.19, OR(hom) = 1.07, 95% CI 0.67, 1.72; P(trend) = 0.29).ConclusionsTo our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
Published: 2014

26. Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer.

Author: Purrington, Kristen, Slager, Susan, Eccles, Diana, Yannoukakos, Drakoulis, Fasching, Peter, Miron, Penelope, Carpenter, Jane, Chang-Claude, Jenny, Martin, Nicholas, Montgomery, Grant, Kristensen, Vessela, Goodfellow, Paul, Tapper, William, Rafiq, Sajjad, Gerty, Susan, Durcan, Lorraine, Konstantopoulou, Irene, Fostira, Florentia, Vratimos, Athanassios, Apostolou, Paraskevi, Konstanta, Irene, Kotoula, Vassiliki, Lakis, Sotiris, Dimopoulos, Meletios, Skarlos, Dimosthenis, Pectasides, Dimitrios, Fountzilas, George, Beckmann, Matthias, Hein, Alexander, Ruebner, Matthias, Ekici, Arif, Hartmann, Arndt, Schulz-Wendtland, Ruediger, Renner, Stefan, Janni, Wolfgang, Rack, Brigitte, Scholz, Christoph, Neugebauer, Julia, Andergassen, Ulrich, Lux, Michael, Haeberle, Lothar, Clarke, Christine, Pathmanathan, Nirmala, Rudolph, Anja, Flesch-Janys, Dieter, Nickels, Stefan, Olson, Janet, Ingle, James, Olswold, Curtis, Slettedahl, Seth, Eckel-Passow, Jeanette, Anderson, S, Visscher, Daniel, Cafourek, Victoria, Sicotte, Hugues, Prodduturi, Naresh, Weiderpass, Elisabete, Bernstein, Leslie, Ivanovich, Jennifer, Giles, Graham, Baglietto, Laura, Southey, Melissa, Kosma, Veli-Matti, Fischer, Hans-Peter, Reed, Malcom, Cross, Simon, Deming-Halverson, Sandra, Shrubsole, Martha, Cai, Qiuyin, Shu, Xiao-Ou, Daly, Mary, Weaver, Joellen, Ross, Eric, Klemp, Jennifer, Sharma, Priyanka, Torres, Diana, Rüdiger, Thomas, Wölfing, Heidrun, Ulmer, Hans-Ulrich, Försti, Asta, Khoury, Thaer, Kumar, Shicha, Pilarski, Robert, Shapiro, Charles, Greco, Dario, Heikkilä, Päivi, Aittomäki, Kristiina, Blomqvist, Carl, Irwanto, Astrid, Liu, Jianjun, Pankratz, Vernon, Wang, Xianshu, Severi, Gianluca, Mannermaa, Arto, Easton, Douglas, Hall, Per, Brauch, Hiltrud, Cox, Angela, Zheng, Wei, and Godwin, Andrew
Subjects: Adult, Aged, Aged, 80 and over, Case-Control Studies, Chromosomes, Human, Pair 19, Estrogen Receptor alpha, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Triple Negative Breast Neoplasms, Young Adult
Abstract: Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Published: 2014

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

Author: Sawyer, Elinor, Roylance, Rebecca, Petridis, Christos, Brook, Mark, Nowinski, Salpie, Papouli, Efterpi, Fletcher, Olivia, Pinder, Sarah, Hanby, Andrew, Kohut, Kelly, Gorman, Patricia, Caneppele, Michele, Peto, Julian, Dos Santos Silva, Isabel, Johnson, Nichola, Swann, Ruth, Dwek, Miriam, Perkins, Katherine-Anne, Gillett, Cheryl, Houlston, Richard, Ross, Gillian, De Ieso, Paolo, Southey, Melissa, Hopper, John, Provenzano, Elena, Apicella, Carmel, Wesseling, Jelle, Cornelissen, Sten, Keeman, Renske, Fasching, Peter, Jud, Sebastian, Ekici, Arif, Beckmann, Matthias, Kerin, Michael, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Therese, Laurent-Puig, Pierre, Kerbrat, Pierre, Bojesen, Stig, Nordestgaard, Børge, Nielsen, Sune, Flyger, Henrik, Milne, Roger, Perez, Jose, Menéndez, Primitiva, Benitez, Javier, Brenner, Hermann, Dieffenbach, Aida, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Lichtner, Peter, Schmutzler, Rita, Lochmann, Magdalena, Brauch, Hiltrud, Fischer, Hans-Peter, Ko, Yon-Dschun, Nevanlinna, Heli, Muranen, Taru, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Dörk, Thilo, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana, Chenevix-Trench, Georgia, Lambrechts, Diether, Weltens, Caroline, Van Limbergen, Erik, Hatse, Sigrid, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Bonanni, Bernardo, Volorio, Sara, Giles, Graham, Severi, Gianluca, Baglietto, Laura, McLean, Catriona, Haiman, Christopher, Henderson, Brian, Schumacher, Fredrick, Le Marchand, Loic, Simard, Jacques, Goldberg, Mark, Labrèche, France, Dumont, Martine, Kristensen, Vessela, and Winqvist, Robert
Subjects: Breast Neoplasms, Carcinoma in Situ, Carcinoma, Lobular, Case-Control Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Middle Aged, Polymorphism, Single Nucleotide
Abstract: Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P
Published: 2014

28. Identification of New Genetic Susceptibility Loci for Breast Cancer Through Consideration of Gene‐Environment Interactions

Author: Schoeps, Anja, Rudolph, Anja, Seibold, Petra, Dunning, Alison M, Milne, Roger L, Bojesen, Stig E, Swerdlow, Anthony, Andrulis, Irene, Brenner, Hermann, Behrens, Sabine, Orr, Nicholas, Jones, Michael, Ashworth, Alan, Li, Jingmei, Cramp, Helen, Connley, Dan, Czene, Kamila, Darabi, Hatef, Chanock, Stephen J, Lissowska, Jolanta, Figueroa, Jonine D, Knight, Julia, Glendon, Gord, Mulligan, Anna M, Dumont, Martine, Severi, Gianluca, Baglietto, Laura, Olson, Janet, Vachon, Celine, Purrington, Kristen, Moisse, Matthieu, Neven, Patrick, Wildiers, Hans, Spurdle, Amanda, Kosma, Veli‐Matti, Kataja, Vesa, Hartikainen, Jaana M, Hamann, Ute, Ko, Yon‐Dschun, Dieffenbach, Aida K, Arndt, Volker, Stegmaier, Christa, Malats, Núria, Perez, José I Arias, Benítez, Javier, Flyger, Henrik, Nordestgaard, Børge G, Truong, Thérèse, Cordina‐Duverger, Emilie, Menegaux, Florence, dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Häberle, Lothar, Beckmann, Matthias W, Ekici, Arif B, Braaf, Linde, Atsma, Femke, Broek, Alexandra J den, Makalic, Enes, Schmidt, Daniel F, Southey, Melissa C, Cox, Angela, Simard, Jacques, Giles, Graham G, Lambrechts, Diether, Mannermaa, Arto, Brauch, Hiltrud, Guénel, Pascal, Peto, Julian, Fasching, Peter A, Hopper, John, Flesch‐Janys, Dieter, Couch, Fergus, Chenevix‐Trench, Georgia, Pharoah, Paul DP, Garcia‐Closas, Montserrat, Schmidt, Marjanka K, Hall, Per, Easton, Douglas F, and Chang‐Claude, Jenny
Subjects: Biological Sciences, Genetics, Epidemiology, Health Services and Systems, Health Sciences, Genetic Testing, Human Genome, Prevention, Breast Cancer, Aging, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Body Height, Body Mass Index, Breast Neoplasms, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 6, Female, Gene-Environment Interaction, Genetic Loci, Genetic Predisposition to Disease, Humans, Linkage Disequilibrium, Menarche, Middle Aged, Parity, Polymorphism, Single Nucleotide, Postmenopause, White People, breast cancer risk, gene-environment interaction, polymorphisms, body mass index, case-control study, Public Health and Health Services
Abstract: Genes that alter disease risk only in combination with certain environmental exposures may not be detected in genetic association analysis. By using methods accounting for gene-environment (G × E) interaction, we aimed to identify novel genetic loci associated with breast cancer risk. Up to 34,475 cases and 34,786 controls of European ancestry from up to 23 studies in the Breast Cancer Association Consortium were included. Overall, 71,527 single nucleotide polymorphisms (SNPs), enriched for association with breast cancer, were tested for interaction with 10 environmental risk factors using three recently proposed hybrid methods and a joint test of association and interaction. Analyses were adjusted for age, study, population stratification, and confounding factors as applicable. Three SNPs in two independent loci showed statistically significant association: SNPs rs10483028 and rs2242714 in perfect linkage disequilibrium on chromosome 21 and rs12197388 in ARID1B on chromosome 6. While rs12197388 was identified using the joint test with parity and with age at menarche (P-values = 3 × 10(-07)), the variants on chromosome 21 q22.12, which showed interaction with adult body mass index (BMI) in 8,891 postmenopausal women, were identified by all methods applied. SNP rs10483028 was associated with breast cancer in women with a BMI below 25 kg/m(2) (OR = 1.26, 95% CI 1.15-1.38) but not in women with a BMI of 30 kg/m(2) or higher (OR = 0.89, 95% CI 0.72-1.11, P for interaction = 3.2 × 10(-05)). Our findings confirm comparable power of the recent methods for detecting G × E interaction and the utility of using G × E interaction analyses to identify new susceptibility loci.
Published: 2014

29. Fine-scale mapping of the FGFR2 breast cancer risk locus: putative functional variants differentially bind FOXA1 and E2F1.

Author: Meyer, Kerstin B, O'Reilly, Martin, Michailidou, Kyriaki, Carlebur, Saskia, Edwards, Stacey L, French, Juliet D, Prathalingham, Radhika, Dennis, Joe, Bolla, Manjeet K, Wang, Qin, de Santiago, Ines, Hopper, John L, Tsimiklis, Helen, Apicella, Carmel, Southey, Melissa C, Schmidt, Marjanka K, Broeks, Annegien, Van 't Veer, Laura J, Hogervorst, Frans B, Muir, Kenneth, Lophatananon, Artitaya, Stewart-Brown, Sarah, Siriwanarangsan, Pornthep, Fasching, Peter A, Lux, Michael P, Ekici, Arif B, Beckmann, Matthias W, Peto, Julian, Dos Santos Silva, Isabel, Fletcher, Olivia, Johnson, Nichola, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael J, Miller, Nicola, Marme, Federick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Menegaux, Florence, Bojesen, Stig E, Nordestgaard, Børge G, Nielsen, Sune F, Flyger, Henrik, Milne, Roger L, Zamora, M Pilar, Arias, Jose I, Benitez, Javier, Neuhausen, Susan, Anton-Culver, Hoda, Ziogas, Argyrios, Dur, Christina C, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Meindl, Alfons, Schmutzler, Rita K, Engel, Christoph, Ditsch, Nina, Brauch, Hiltrud, Brüning, Thomas, Ko, Yon-Dschun, GENICA Network, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Matsuo, Keitaro, Ito, Hidemi, Iwata, Hiroji, Yatabe, Yasushi, Dörk, Thilo, Helbig, Sonja, Bogdanova, Natalia V, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana M, Chenevix-Trench, Georgia, kConFab Investigators, Australian Ovarian Cancer Study Group, Wu, Anna H, Tseng, Chiu-Chen, Van Den Berg, David, Stram, Daniel O, Lambrechts, Diether, Thienpont, Bernard, Christiaens, Marie-Rose, Smeets, Ann, Chang-Claude, Jenny, Rudolph, Anja, Seibold, Petra, Flesch-Janys, Dieter, and Radice, Paolo
Subjects: GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Cell Line, Tumor, Humans, Breast Neoplasms, Case-Control Studies, Chromatin Immunoprecipitation, Chromosome Mapping, Gene Expression Regulation, Neoplastic, RNA Interference, Binding Sites, Protein Binding, Haplotypes, Alleles, Female, E2F1 Transcription Factor, Receptor, Fibroblast Growth Factor, Type 2, Hepatocyte Nuclear Factor 3-alpha, Promoter Regions, Genetic, Genetic Loci, Position-Specific Scoring Matrices, Genetic Association Studies, Asian People, White People, Black People, Cancer, Human Genome, Breast Cancer, Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: The 10q26 locus in the second intron of FGFR2 is the locus most strongly associated with estrogen-receptor-positive breast cancer in genome-wide association studies. We conducted fine-scale mapping in case-control studies genotyped with a custom chip (iCOGS), comprising 41 studies (n = 89,050) of European ancestry, 9 Asian ancestry studies (n = 13,983), and 2 African ancestry studies (n = 2,028) from the Breast Cancer Association Consortium. We identified three statistically independent risk signals within the locus. Within risk signals 1 and 3, genetic analysis identified five and two variants, respectively, highly correlated with the most strongly associated SNPs. By using a combination of genetic fine mapping, data on DNase hypersensitivity, and electrophoretic mobility shift assays to study protein-DNA binding, we identified rs35054928, rs2981578, and rs45631563 as putative functional SNPs. Chromatin immunoprecipitation showed that FOXA1 preferentially bound to the risk-associated allele (C) of rs2981578 and was able to recruit ERα to this site in an allele-specific manner, whereas E2F1 preferentially bound the risk variant of rs35054928. The risk alleles were preferentially found in open chromatin and bound by Ser5 phosphorylated RNA polymerase II, suggesting that the risk alleles are associated with changes in transcription. Chromatin conformation capture demonstrated that the risk region was able to interact with the promoter of FGFR2, the likely target gene of this risk region. A role for FOXA1 in mediating breast cancer susceptibility at this locus is consistent with the finding that the FGFR2 risk locus primarily predisposes to estrogen-receptor-positive disease.
Published: 2013

30. A genome-wide association study to identify genetic susceptibility loci that modify ductal and lobular postmenopausal breast cancer risk associated with menopausal hormone therapy use: a two-stage design with replication

Author: Hein, Rebecca, Flesch-Janys, Dieter, Dahmen, Norbert, Beckmann, Lars, Lindström, Sara, Schoof, Nils, Czene, Kamila, Mittelstraß, Kirstin, Illig, Thomas, Seibold, Petra, Behrens, Sabine, Humphreys, Keith, Li, Jingmei, Liu, Jianjun, Olson, Janet E, Wang, Xianshu, Hankinson, Susan E, Truong, Thérèse, Menegaux, Florence, dos Santos Silva, Isabel, Johnson, Nichola, The GENICA Network, Chen, Shou-Tung, Yu, Jyh-Cherng, Ziogas, Argyrios, Kataja, Vesa, Kosma, Veli-Matti, Mannermaa, Arto, Anton-Culver, Hoda, Shen, Chen-Yang, Brauch, Hiltrud, Peto, Julian, Guénel, Pascal, Kraft, Peter, Couch, Fergus J, Easton, Douglas F, Hall, Per, and Chang-Claude, Jenny
Subjects: Cancer, Aging, Prevention, Breast Cancer, Genetics, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Case-Control Studies, Chromosomes, Human, Estrogen Replacement Therapy, Estrogens, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Postmenopause, Progestins, Risk Factors, Sequence Analysis, DNA, Postmenopausal breast cancer risk, Menopausal hormone therapy, Polymorphisms, Gene-environment interaction, Genome-wide association study, Case-only study, GENICA Network, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: Menopausal hormone therapy (MHT) is associated with an elevated risk of breast cancer in postmenopausal women. To identify genetic loci that modify breast cancer risk related to MHT use in postmenopausal women, we conducted a two-stage genome-wide association study (GWAS) with replication. In stage I, we performed a case-only GWAS in 731 invasive breast cancer cases from the German case-control study Mammary Carcinoma Risk Factor Investigation (MARIE). The 1,200 single nucleotide polymorphisms (SNPs) showing the lowest P values for interaction with current MHT use (within 6 months prior to breast cancer diagnosis), were carried forward to stage II, involving pooled case-control analyses including additional MARIE subjects (1,375 cases, 1,974 controls) as well as 795 cases and 764 controls of a Swedish case-control study. A joint P value was calculated for a combined analysis of stages I and II. Replication of the most significant interaction of the combined stage I and II was performed using 5,795 cases and 5,390 controls from nine studies of the Breast Cancer Association Consortium (BCAC). The combined stage I and II yielded five SNPs on chromosomes 2, 7, and 18 with joint P values
Published: 2013

31. CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer.

Author: Weischer, Maren, Nordestgaard, Børge G, Pharoah, Paul, Bolla, Manjeet K, Nevanlinna, Heli, Van't Veer, Laura J, Garcia-Closas, Montserrat, Hopper, John L, Hall, Per, Andrulis, Irene L, Devilee, Peter, Fasching, Peter A, Anton-Culver, Hoda, Lambrechts, Diether, Hooning, Maartje, Cox, Angela, Giles, Graham G, Burwinkel, Barbara, Lindblom, Annika, Couch, Fergus J, Mannermaa, Arto, Grenaker Alnæs, Grethe, John, Esther M, Dörk, Thilo, Flyger, Henrik, Dunning, Alison M, Wang, Qin, Muranen, Taru A, van Hien, Richard, Figueroa, Jonine, Southey, Melissa C, Czene, Kamila, Knight, Julia A, Tollenaar, Rob AEM, Beckmann, Matthias W, Ziogas, Argyrios, Christiaens, Marie-Rose, Collée, Johanna Margriet, Reed, Malcolm WR, Severi, Gianluca, Marme, Frederik, Margolin, Sara, Olson, Janet E, Kosma, Veli-Matti, Kristensen, Vessela N, Miron, Alexander, Bogdanova, Natalia, Shah, Mitul, Blomqvist, Carl, Broeks, Annegien, Sherman, Mark, Phillips, Kelly-Anne, Li, Jingmei, Liu, Jianjun, Glendon, Gord, Seynaeve, Caroline, Ekici, Arif B, Leunen, Karin, Kriege, Mieke, Cross, Simon S, Baglietto, Laura, Sohn, Christof, Wang, Xianshu, Kataja, Vesa, Børresen-Dale, Anne-Lise, Meyer, Andreas, Easton, Douglas F, Schmidt, Marjanka K, and Bojesen, Stig E
Subjects: Humans, Breast Neoplasms, Neoplasms, Second Primary, Genetic Predisposition to Disease, Prognosis, Case-Control Studies, Prospective Studies, Genotype, Heterozygote, Germ-Line Mutation, Middle Aged, Female, Checkpoint Kinase 2, Protein Serine-Threonine Kinases, Breast Cancer, Clinical Research, Cancer, Prevention, Genetics, Estrogen, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract: PurposeWe tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer.Patients and methodsFrom 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies.ResultsCHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only.ConclusionAmong women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer.
Published: 2012

32. 9q31.2-rs865686 as a Susceptibility Locus for Estrogen Receptor-Positive Breast Cancer: Evidence from the Breast Cancer Association Consortium

Author: Warren, Helen, Dudbridge, Frank, Fletcher, Olivia, Orr, Nick, Johnson, Nichola, Hopper, John L, Apicella, Carmel, Southey, Melissa C, Mahmoodi, Maryam, Schmidt, Marjanka K, Broeks, Annegien, Cornelissen, Sten, Braaf, Linda M, Muir, Kenneth R, Lophatananon, Artitaya, Chaiwerawattana, Arkom, Wiangnon, Surapon, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Schulz-Wendtland, Ruediger, Sawyer, Elinor J, Tomlinson, Ian, Kerin, Michael, Burwinkel, Barbara, Marme, Frederik, Schneeweiss, Andreas, Sohn, Christof, Guénel, Pascal, Truong, Thérèse, Laurent-Puig, Pierre, Mulot, Claire, Bojesen, Stig E, Nielsen, Sune F, Flyger, Henrik, Nordestgaard, Børge G, Milne, Roger L, Benítez, Javier, Arias-Pérez, José-Ignacio, Zamora, M Pilar, Anton-Culver, Hoda, Ziogas, Argyrios, Bernstein, Leslie, Dur, Christina Clarke, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Langheinz, Anne, Meindl, Alfons, Golatta, Michael, Bartram, Claus R, Schmutzler, Rita K, Brauch, Hiltrud, Justenhoven, Christina, Brüning, Thomas, Network, for The GENICA, Chang-Claude, Jenny, Wang-Gohrke, Shan, Eilber, Ursula, Dörk, Thilo, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Nevanlinna, Heli, Muranen, Taru A, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Antonenkova, Natalia, Rogov, Yuriy, Bermisheva, Marina, Prokofyeva, Darya, Zinnatullina, Guzel, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Hartikainen, Jaana M, Kataja, Vesa, Chenevix-Trench, Georgia, Beesley, Jonathan, Chen, Xiaoqing, Investigators, for kConFab, Group, Australian Ovarian Cancer Study, Lambrechts, Diether, Smeets, Ann, Paridaens, Robert, Weltens, Caroline, Flesch-Janys, Dieter, Buck, Katharina, Behrens, Sabine, Peterlongo, Paolo, Bernard, Loris, Manoukian, Siranoush, Radice, Paolo, Couch, Fergus J, Vachon, Celine, Wang, Xianshu, and Olson, Janet
Subjects: Health Services and Systems, Biomedical and Clinical Sciences, Health Sciences, Oncology and Carcinogenesis, Genetics, Human Genome, Aging, Breast Cancer, Clinical Research, Cancer, 2.1 Biological and endogenous factors, Aetiology, Aged, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 9, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Middle Aged, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Medical and Health Sciences, Epidemiology, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundOur recent genome-wide association study identified a novel breast cancer susceptibility locus at 9q31.2 (rs865686).MethodsTo 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).ResultsThis replication study provides additional strong evidence of an inverse association between rs865686 and breast cancer risk [study-adjusted per G-allele OR, 0.90; 95% confidence interval (CI), 0.88; 0.91, P = 2.01 × 10(-29)] among women of European ancestry. There were ethnic differences in the estimated minor (G)-allele frequency among controls [0.09, 0.30, and 0.38 among, respectively, Asians, Eastern Europeans, and other Europeans; P for heterogeneity (P(het)) = 1.3 × 10(-143)], but no evidence of ethnic differences in per allele OR (P(het) = 0.43). rs865686 was associated with estrogen receptor-positive (ER(+)) disease (per G-allele OR, 0.89; 95% CI, 0.86-0.91; P = 3.13 × 10(-22)) but less strongly, if at all, with ER-negative (ER(-)) disease (OR, 0.98; 95% CI, 0.94-1.02; P = 0.26; P(het) = 1.16 × 10(-6)), with no evidence of independent heterogeneity by progesterone receptor or HER2 status. The strength of the breast cancer association decreased with increasing age at diagnosis, with case-only analysis showing a trend in the number of copies of the G allele with increasing age at diagnosis (P for linear trend = 0.0095), but only among women with ER(+) tumors.ConclusionsThis study is the first to show that rs865686 is a susceptibility marker for ER(+) breast cancer.ImpactThe findings further support the view that genetic susceptibility varies according to tumor subtype.
Published: 2012

33. PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2

Author: Wishart, GC, Bajdik, CD, Dicks, E, Provenzano, E, Schmidt, MK, Sherman, M, Greenberg, DC, Green, AR, Gelmon, KA, Kosma, V-M, Olson, JE, Beckmann, MW, Winqvist, R, Cross, SS, Severi, G, Huntsman, D, Pylkäs, K, Ellis, I, Nielsen, TO, Giles, G, Blomqvist, C, Fasching, PA, Couch, FJ, Rakha, E, Foulkes, WD, Blows, FM, Bégin, LR, van't Veer, LJ, Southey, M, Nevanlinna, H, Mannermaa, A, Cox, A, Cheang, M, Baglietto, L, Caldas, C, Garcia-Closas, M, and Pharoah, PDP
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Clinical Research, Cancer, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Adult, Aged, Breast Neoplasms, Cohort Studies, Female, Humans, Middle Aged, Models, Statistical, Prognosis, Proportional Hazards Models, Receptor, ErbB-2, Reproducibility of Results, Young Adult, breast cancer, HER2, prognostic model, Receptor, erbB-2, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.
Published: 2012

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

Author: Hein, Rebecca, Maranian, Melanie, Hopper, John, Kapuscinski, Miroslaw, Southey, Melissa, Park, Daniel, Schmidt, Marjanka, Broeks, Annegien, Hogervorst, Frans, Bueno-de-Mesquita, H, Muir, Kenneth, Lophatananon, Artitaya, Rattanamongkongul, Suthee, Puttawibul, Puttisak, Fasching, Peter, Hein, Alexander, Ekici, Arif, Beckmann, Matthias, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Sawyer, Elinor, Tomlinson, Ian, Kerin, Michael, Miller, Nicola, Marmee, Frederick, Schneeweiss, Andreas, Sohn, Christof, Burwinkel, Barbara, Guénel, Pascal, Cordina-Duverger, Emilie, Menegaux, Florence, Truong, Thérèse, Bojesen, Stig, Nordestgaard, Børge, Flyger, Henrik, Milne, Roger, Perez, Jose, Zamora, M, Benítez, Javier, Bernstein, Leslie, Clarke, Christina, Brenner, Hermann, Müller, Heiko, Arndt, Volker, Stegmaier, Christa, Rahman, Nazneen, Seal, Sheila, Turnbull, Clare, Renwick, Anthony, Meindl, Alfons, Schott, Sarah, Bartram, Claus, Schmutzler, Rita, Brauch, Hiltrud, Hamann, Ute, Ko, Yon-Dschun, Wang-Gohrke, Shan, Dörk, Thilo, Schürmann, Peter, Karstens, Johann, Hillemanns, Peter, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Bogdanova, Natalia, Zalutsky, Iosif, Antonenkova, Natalia, Bermisheva, Marina, Prokovieva, Darya, Farahtdinova, Albina, Khusnutdinova, Elza, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Hartikainen, Jaana, Chen, Xiaoqing, Beesley, Jonathan, Lambrechts, Diether, Zhao, Hui, Neven, Patrick, Wildiers, Hans, Nickels, Stefan, Flesch-Janys, Dieter, Radice, Paolo, Peterlongo, Paolo, Manoukian, Siranoush, Barile, Monica, Couch, Fergus, Olson, Janet, Wang, Xianshu, Fredericksen, Zachary, Giles, Graham, Baglietto, Laura, McLean, Catriona, and Severi, Gianluca
Subjects: Asia, Breast Neoplasms, Chromosomes, Human, Pair 6, Europe, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Haplotypes, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Receptors, Estrogen, Risk Factors
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER-) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26-1.48), p = 7.6 × 10(-14) in Asians and 1.09 (95% CI 1.07-1.11), p = 6.8 × 10(-18) in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19-1.41), p = 1.2 × 10(-9) in Asians and 1.12 (95% CI 1.08-1.17), p = 3.8 × 10(-9) in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER- than ER+ tumours in Europeans [OR (ER-) = 1.20 (95% CI 1.15-1.25), p = 1.8 × 10(-17) versus OR (ER+) = 1.07 (95% CI 1.04-1.1), p = 1.3 × 10(-7), p(heterogeneity) = 5.1 × 10(-6)]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER- tumours.
Published: 2012

35. Breast cancer risk and 6q22.33: combined results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2.

Author: Kirchhoff, Tomas, Gaudet, Mia M, Antoniou, Antonis C, McGuffog, Lesley, Humphreys, Manjeet K, Dunning, Alison M, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Ahn, Sei-Hyun, Dork, Thilo, Schürmann, Peter, Karstens, Johann H, Hillemanns, Peter, Couch, Fergus J, Olson, Janet, Vachon, Celine, Wang, Xianshu, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Burwinkel, Barbara, Meindl, Alfons, Brauch, Hiltrud, Hamann, Ute, Ko, Yon-Dschun, GENICA Network, Broeks, Annegien, Schmidt, Marjanka K, Van 't Veer, Laura J, Braaf, Linde M, Johnson, Nichola, Fletcher, Olivia, Gibson, Lorna, Peto, Julian, Turnbull, Clare, Seal, Sheila, Renwick, Anthony, Rahman, Nazneen, Wu, Pei-Ei, Yu, Jyh-Cherng, Hsiung, Chia-Ni, Shen, Chen-Yang, Southey, Melissa C, Hopper, John L, Hammet, Fleur, Van Dorpe, Thijs, Dieudonne, Anne-Sophie, Hatse, Sigrid, Lambrechts, Diether, Andrulis, Irene L, Bogdanova, Natalia, Antonenkova, Natalia, Rogov, Juri I, Prokofieva, Daria, Bermisheva, Marina, Khusnutdinova, Elza, van Asperen, Christi J, Tollenaar, Robert AEM, Hooning, Maartje J, Devilee, Peter, Margolin, Sara, Lindblom, Annika, Milne, Roger L, Arias, José Ignacio, Zamora, M Pilar, Benítez, Javier, Severi, Gianluca, Baglietto, Laura, Giles, Graham G, kConFab, AOCS Study Group, Spurdle, Amanda B, Beesley, Jonathan, Chen, Xiaoqing, Holland, Helene, Healey, Sue, Wang-Gohrke, Shan, Chang-Claude, Jenny, Mannermaa, Arto, Kosma, Veli-Matti, Kauppinen, Jaana, Kataja, Vesa, Agnarsson, Bjarni A, Caligo, Maria A, Godwin, Andrew K, Nevanlinna, Heli, Heikkinen, Tuomas, Fredericksen, Zachary, Lindor, Noralane, Nathanson, Katherine L, Domchek, Susan M, SWE-BRCA, Loman, Niklas, Karlsson, Per, and Stenmark Askmalm, Marie
Subjects: GENICA Network, kConFab, AOCS Study Group, SWE-BRCA, HEBON, EMBRACE, BCAC/CIMBA, Chromosomes, Human, Pair 6, Humans, Breast Neoplasms, Genetic Predisposition to Disease, BRCA1 Protein, BRCA2 Protein, Receptors, Estrogen, Confidence Intervals, Proportional Hazards Models, Odds Ratio, Risk Factors, Heterozygote, Polymorphism, Single Nucleotide, Alleles, Middle Aged, Female, Genetic Association Studies, Chromosomes, Human, Pair 6, Polymorphism, Single Nucleotide, Receptors, Estrogen, General Science & Technology
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I(2) = 49.3%; p =
Published: 2012

36. Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk

Author: Stevens, KN, Garcia-Closas, M, Fredericksen, Z, Kosel, M, Pankratz, VS, Hopper, JL, Dite, GS, Apicella, C, Southey, MC, Schmidt, MK, Broeks, A, Van ‘t Veer, LJ, Tollenaar, RAEM, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Johnson, N, Peto, J, dos Santos Silva, I, Gibson, L, Sawyer, E, Tomlinson, I, Kerin, MJ, Chanock, S, Lissowska, J, Hunter, DJ, Hoover, RN, Thomas, GD, Milne, RL, Pérez, JI Arias, González-Neira, A, Benítez, J, Burwinkel, B, Meindl, A, Schmutzler, RK, Bartrar, CR, Hamann, U, Ko, YD, Brüning, T, Chang-Claude, J, Hein, R, Wang-Gohrke, S, Dörk, T, Schürmann, P, Bremer, M, Hillemanns, P, Bogdanova, N, Zalutsky, JV, Rogov, YI, Antonenkova, N, Lindblom, A, Margolin, S, Mannermaa, A, Kataja, V, Kosma, V-M, Hartikainen, J, Chenevix-Trench, G, Chen, X, Peterlongo, P, Bonanni, B, Bernard, L, Manoukian, S, Wang, X, Cerhan, J, Vachon, CM, Olson, J, Giles, GG, Baglietto, L, McLean, CA, Severi, G, John, EM, Miron, A, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Andrulis, I, Knight, JA, Glendon, G, Mulligan, AM, Cox, A, Brock, IW, Elliott, G, Cross, SS, Pharoah, PP, Dunning, AM, Pooley, KA, Humphreys, MK, Wang, J, Kang, D, Yoo, K-Y, Noh, D-Y, Sangrajrang, S, Gabrieau, V, Brennan, P, McKay, J, Anton-Culver, H, Ziogas, A, and Couch, FJ
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Genetics, Cancer, Breast Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Case-Control Studies, Class I Phosphatidylinositol 3-Kinases, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Phosphatidylinositol 3-Kinases, genetic susceptibility, neoplasms, association study, GENICA Network, kConFab Investigators, Australian Ovarian Cancer Study Group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundSomatic 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.MethodsA 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).ResultsRs1607237 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 × 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).ConclusionCommon germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
Published: 2011

37. 7q21-rs6964587 and breast cancer risk: an extended case–control study by the Breast Cancer Association Consortium

Author: Milne, Roger L, Lorenzo-Bermejo, Justo, Burwinkel, Barbara, Malats, Núria, Arias, Jose Ignacio, Zamora, M Pilar, Benítez, Javier, Humphreys, Manjeet K, García-Closas, Montserrat, Chanock, Stephen J, Lissowska, Jolanta, Sherman, Mark E, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Anton-Culver, Hoda, Ziogas, Argyrios, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Irwanto, Astrid K, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Margolin, Sara, Lindblom, Annika, Fasching, Peter A, Schulz-Wendtland, Ruediger, Ekici, Arif B, Beckmann, Matthias W, Wang-Gohrke, Shan, Shen, Chen-Yang, Yu, Jyh-Cherng, Hsu, Huan-Ming, Wu, Pei-Ei, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Beesley, Jonathan, Chen, Xiaoqing, Investigators, kConFab, Group, AOCS, Fletcher, Olivia, Gibson, Lorna, dos Santos Silva, Isabel, Peto, Julian, Frank, Bernd, Heil, Joerg, Meindl, Alfons, Chang-Claude, Jenny, Hein, Rebecca, Vrieling, Alina, Flesch-Janys, Dieter, Southey, Melissa C, Smith, Letitia, Apicella, Carmel, Hopper, John L, Dunning, Alison M, Pooley, Karen A, Pharoah, Paul DP, Hamann, Ute, Pesch, Beate, Ko, Yon-Dschun, Network, The GENICA, Easton, Douglas F, and Chenevix-Trench, Georgia
Subjects: Biological Sciences, Biomedical and Clinical Sciences, Genetics, Oncology and Carcinogenesis, Breast Cancer, Clinical Research, Cancer, Aetiology, 2.1 Biological and endogenous factors, A Kinase Anchor Proteins, Alleles, Asian People, Breast Neoplasms, Case-Control Studies, Chromosomes, Human, Pair 7, Cytoskeletal Proteins, Female, Genes, Recessive, Genetic Predisposition to Disease, Humans, Logistic Models, Odds Ratio, Polymorphism, Single Nucleotide, Risk Factors, White People, AOCS Group, GENICA Network, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract: BackgroundUsing 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.MethodsThe 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.ResultsFor 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).ConclusionThis may be the first common susceptibility allele for breast cancer to be identified with a recessive mode of inheritance.
Published: 2011

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

Author: Azzato, Elizabeth M, Tyrer, Jonathan, Fasching, Peter A, Beckmann, Matthias W, Ekici, Arif B, Schulz-Wendtland, Rüdiger, Bojesen, Stig E, Nordestgaard, Børge G, Flyger, Henrik, Milne, Roger L, Arias, José Ignacio, Menéndez, Primitiva, Benítez, Javier, Chang-Claude, Jenny, Hein, Rebecca, Wang-Gohrke, Shan, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Kataja, Vesa, Beesley, Jonathan, Chen, Xiaoqing, Chenevix-Trench, Georgia, Couch, Fergus J, Olson, Janet E, Fredericksen, Zachary S, Wang, Xianshu, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, Southey, Melissa C, Devilee, Peter, Tollenaar, Rob AEM, Seynaeve, Caroline, García-Closas, Montserrat, Lissowska, Jolanta, Sherman, Mark E, Bolton, Kelly L, Hall, Per, Czene, Kamila, Cox, Angela, Brock, Ian W, Elliott, Graeme C, Reed, Malcolm WR, Greenberg, David, Anton-Culver, Hoda, Ziogas, Argyrios, Humphreys, Manjeet, Easton, Douglas F, Caporaso, Neil E, and Pharoah, Paul DP
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Prevention, Genetics, Breast Cancer, Human Genome, Cancer, Adult, Aged, Alleles, Biomarkers, Tumor, Breast Neoplasms, Chromosomes, Human, Pair 15, Female, Genotype, Germ-Line Mutation, Humans, Membrane Transport Proteins, Middle Aged, Polymorphism, Single Nucleotide, Proportional Hazards Models, Receptors, Estrogen, Research Design, Risk Assessment, Risk Factors, Survival Analysis, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundTraditional 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.MethodsWe 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.ResultsIn 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)).ConclusionThe 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

39. Risk of Estrogen Receptor–Positive and –Negative Breast Cancer and Single–Nucleotide Polymorphism 2q35-rs13387042

Author: Milne, Roger L, Benítez, Javier, Nevanlinna, Heli, Heikkinen, Tuomas, Aittomäki, Kristiina, Blomqvist, Carl, Arias, José Ignacio, Zamora, M Pilar, Burwinkel, Barbara, Bartram, Claus R, Meindl, Alfons, Schmutzler, Rita K, Cox, Angela, Brock, Ian, Elliott, Graeme, Reed, Malcolm WR, Southey, Melissa C, Smith, Letitia, Spurdle, Amanda B, Hopper, John L, Couch, Fergus J, Olson, Janet E, Wang, Xianshu, Fredericksen, Zachary, Schürmann, Peter, Bremer, Michael, Hillemanns, Peter, Dörk, Thilo, Devilee, Peter, van Asperen, Christie J, Tollenaar, Rob AEM, Seynaeve, Caroline, Hall, Per, Czene, Kamila, Liu, Jianjun, Li, Yuqing, Ahmed, Shahana, Dunning, Alison M, Maranian, Melanie, Pharoah, Paul DP, Chenevix-Trench, Georgia, Beesley, Jonathan, Investigators, kConFab, Group, AOCS, Bogdanova, Natalia V, Antonenkova, Natalia N, Zalutsky, Iosif V, Anton-Culver, Hoda, Ziogas, Argyrios, Brauch, Hiltrud, Justenhoven, Christina, Ko, Yon-Dschun, Haas, Susanne, Fasching, Peter A, Strick, Reiner, Ekici, Arif B, Beckmann, Matthias W, Giles, Graham G, Severi, Gianluca, Baglietto, Laura, English, Dallas R, Fletcher, Olivia, Johnson, Nichola, dos Santos Silva, Isabel, Peto, Julian, Turnbull, Clare, Hines, Sarah, Renwick, Anthony, Rahman, Nazneen, Nordestgaard, Børge G, Bojesen, Stig E, Flyger, Henrik, Kang, Daehee, Yoo, Keun-Young, Noh, Dong-Young, Mannermaa, Arto, Kataja, Vesa, Kosma, Veli-Matti, García-Closas, Montserrat, Chanock, Stephen, Lissowska, Jolanta, Brinton, Louise A, Chang-Claude, Jenny, Wang-Gohrke, Shan, Shen, Chen-Yang, Wang, Hui-Chun, Yu, Jyh-Cherng, Chen, Sou-Tong, Bermisheva, Marina, Nikolaeva, Tatjana, Khusnutdinova, Elza, Humphreys, Manjeet K, Morrison, Jonathan, Platte, Radka, Easton, Douglas F, and Consortium, on behalf of the Breast Cancer Association
Subjects: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Estrogen, Cancer, Women's Health, Genetics, 2.1 Biological and endogenous factors, Adult, Aged, Asian People, Biomarkers, Tumor, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Intraductal, Noninfiltrating, Case-Control Studies, Confidence Intervals, Confounding Factors, Epidemiologic, Female, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Middle Aged, Neoplasms, Hormone-Dependent, Odds Ratio, Polymorphism, Single Nucleotide, Receptors, Estrogen, Receptors, Progesterone, White People, kConFab Investigators, AOCS Group, Breast Cancer Association Consortium, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract: BackgroundA 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.Methods2q35-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.ResultsWe 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; P(trend) = 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 > or = .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).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.
Published: 2009

40. Association of ESR1 gene tagging SNPs with breast cancer risk

Author: Dunning, Alison M, Healey, Catherine S, Baynes, Caroline, Maia, Ana-Teresa, Scollen, Serena, Vega, Ana, Rodríguez, Raquel, Barbosa-Morais, Nuno L, Ponder, Bruce AJ, Low, Yen-Ling, Bingham, Sheila, Haiman, Christopher A, Le Marchand, Loic, Broeks, Annegien, Schmidt, Marjanka K, Hopper, John, Southey, Melissa, Beckmann, Matthias W, Fasching, Peter A, Peto, Julian, Johnson, Nichola, Bojesen, Stig E, Nordestgaard, Børge, Milne, Roger L, Benitez, Javier, Hamann, Ute, Ko, Yon, Schmutzler, Rita K, Burwinkel, Barbara, Schürmann, Peter, Dörk, Thilo, Heikkinen, Tuomas, Nevanlinna, Heli, Lindblom, Annika, Margolin, Sara, Mannermaa, Arto, Kosma, Veli-Matti, Chen, Xiaoqing, Spurdle, Amanda, Change-Claude, Jenny, Flesch-Janys, Dieter, Couch, Fergus J, Olson, Janet E, Severi, Gianluca, Baglietto, Laura, Børresen-Dale, Anne-Lise, Kristensen, Vessela, Hunter, David J, Hankinson, Susan E, Devilee, Peter, Vreeswijk, Maaike, Lissowska, Jolanta, Brinton, Louise, Liu, Jianjun, Hall, Per, Kang, Daehee, Yoo, Keun-Young, Shen, Chen-Yang, Yu, Jyh-Cherng, Anton-Culver, Hoda, Ziogoas, Argyrios, Sigurdson, Alice, Struewing, Jeff, Easton, Douglas F, Garcia-Closas, Montserrat, Humphreys, Manjeet K, Morrison, Jonathan, Pharoah, Paul DP, Pooley, Karen A, and Chenevix-Trench, Georgia
Subjects: Genetics, Cancer, Breast Cancer, Prevention, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Breast Neoplasms, Estrogen Receptor alpha, Female, Genetic Predisposition to Disease, Haplotypes, Humans, Neoplasm Staging, Polymorphism, Single Nucleotide, RNA, Neoplasm, SEARCH, EPIC, MEC, ABCS, ABCFS, BBCC, BBCS, CGPS, CNIO-BCS, GENICA, GC-HBOC, HABCS, HEBCS, KARBAC, KBCS, kConFab and the AOCS Management Group, MARIE, for MCBCS, MCCS, NBCS, NHS, ORIGO, PBCS, SASBAC, SEBCS, TWBCS, UCIBCS, USRTS, BCAC, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract: We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55,000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms.
Published: 2009

41. The debatable presence of PIWI‐interacting RNAs in invasive breast cancer

Author: Arto Mannermaa, Maria Tengström, Jaana M. Hartikainen, Sami Heikkinen, Emmi Kärkkäinen, and Veli-Matti Kosma
Subjects: 0301 basic medicine, Cancer Research, medicine.medical_treatment, Estrogen receptor, Piwi-interacting RNA, Antineoplastic Agents, Breast Neoplasms, Biology, Disease-Free Survival, 03 medical and health sciences, transcriptomics, 0302 clinical medicine, Breast cancer, breast cancer, medicine, Biomarkers, Tumor, Humans, Radiology, Nuclear Medicine and imaging, Breast, RNA, Small Interfering, prognostic factor, RC254-282, Original Research, next generation sequencing, Predictive marker, Radiotherapy, Sequence Analysis, RNA, Cancer, Clinical Cancer Research, biomarkers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Prognosis, Up-Regulation, Radiation therapy, Tamoxifen, 030104 developmental biology, Treatment Outcome, Oncology, Receptors, Estrogen, 030220 oncology & carcinogenesis, Cancer research, non‐coding RNAs, Cancer biomarkers, Female, Neoplasm Grading, medicine.drug
Abstract: Numerous factors influence breast cancer (BC) prognosis, thus complicating the prediction of outcome. By identifying biomarkers that would distinguish the cases with poorer response to therapy already at the time of diagnosis, the rate of survival could be improved. Lately, Piwi‐interacting RNAs (piRNAs) have been introduced as potential cancer biomarkers, however, due to the recently raised challenges in piRNA annotations, further evaluation of piRNAs’ involvement in cancer is required. We performed small RNA sequencing in 227 fresh‐frozen breast tissue samples from the Eastern Finnish Kuopio Breast Cancer Project material to study the presence of piRNAs in BC and their associations with the clinicopathological features and outcome of BC patients. We observed the presence of three small RNAs annotated as piRNA database entries (DQ596932, DQ570994, and DQ571955) in our samples. The actual species of these RNAs however remain uncertain. All three small RNAs were upregulated in grade III tumors and DQ596932 additionally in estrogen receptor negative tumors. Furthermore, patients with estrogen receptor positive BC and higher DQ571955 had shorter relapse‐free survival and poorer BC‐specific survival, thus indicating DQ571955 as a candidate predictive marker for radiotherapy response in estrogen receptor positive BC. DQ596932 showed possible prognostic value in BC, whereas DQ570994 was identified as a candidate predictive marker for tamoxifen and chemotherapy response. These three small RNAs appear as candidate biomarkers for BC, which could after further investigation provide novel approaches for the treatment of therapy resistant BC. Overall, our results indicate that the prevalence of piRNAs in cancer is most likely not as comprehensive as has been previously thought., We have observed three small RNAs associating with clinical characteristics and patient outcome in breast cancer. The actual species of these RNAs needs further clarification but these results indicate that the dysregulation of piRNAs in cancer is most likely not as general a phenomenon as has been previously thought.
Published: 2021

42. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Author: Dorling, L., Carvalho, S., Allen, J., Gonzalez-Neira, A., Luccarini, C., Wahlstrom, C., Pooley, K.A., Parsons, M.T., Fortuno, C., Wang, Q., Bolla, M.K., Dennis, J., Keeman, R., Alonso, M.R., Alvarez, N., Herraez, B., Fernandez, V., Nunez-Torres, R., Osorio, A., Valcich, J., Li, M., Torngren, T., Harrington, P.A., Baynes, C., Conroy, D.M., Decker, B., Fachal, L., Mavaddat, N., Ahearn, T., Aittomaki, K., Antonenkova, N.N., Arnold, N., Arveux, P., Ausems, M.G.E.M., Auvinen, P., Becher, H., Beckmann, M.W., Behrens, S., Bermisheva, M., Bialkowska, K., Blomqvist, C., Bogdanova, N.V., Bogdanova-Markov, N., Bojesen, S.E., Bonanni, B., Borresen-Dale, A.L., Brauch, H., Bremer, M., Briceno, I., Bruning, T., Burwinkel, B., Cameron, D.A., Camp, N.J., Campbell, A., Carracedo, A., Castelao, J.E., Cessna, M.H., Chanock, S.J., Christiansen, H., Collee, J.M., Cordina-Duverger, E., Cornelissen, S., Czene, K., Dork, T., Ekici, A.B., Engel, C., Eriksson, M., Fasching, P.A., Figueroa, J., Flyger, H., Forsti, A., Gabrielson, M., Gago-Dominguez, M., Georgoulias, V., Gil, F., Giles, G.G., Glendon, G., Garcia, E.B.G., Alnaes, G.I.G., Guenel, P., Hadjisavvas, A., Haeberle, L., Hahnen, E., Hall, P., Hamann, U., Harkness, E.F., Hartikainen, J.M., Hartman, M., He, W., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Ho, W.K., Hooning, M.J., Howell, A., Humphreys, K., Idris, F., Jakubowska, A., Jung, A., Kapoor, P.M., Kerin, M.J., Khusnutdinova, E., Kim, S.W., Ko, Y.D., Kosma, V.M., Kristensen, V.N., Kyriacou, K., Lakeman, I.M.M., Lee, J.W., Lee, M.H., Li, J.M., Lindblom, A., W.Y. lo, Loizidou, M.A., Lophatananon, A., Lubinski, J., MacInnis, R.J., Madsen, M.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Maurer, T., Mavroudis, D., McLean, C., Meindl, A., Mensenkamp, A.R., Michailidou, K., Miller, N., Taib, N.A.M., Muir, K., Mulligan, A.M., Nevanlinna, H., Newman, W.G., Nordestgaard, B.G., Ng, P.S., Oosterwijk, J.C., Park, S.K., Park-Simon, T.W., Perez, J.I.A., Peterlongo, P., Porteous, D.J., Prajzendanc, K., Prokofyeva, D., Radice, P., Rashid, M.U., Rhenius, V., Rookus, M.A., Rudiger, T., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Schneeweiss, A., Schurmann, P., Shah, M., Sohn, C., Southey, M.C., Surowy, H., Suvanto, M., Thanasitthichai, S., Tomlinson, I., Torres, D., Truong, T., Tzardi, M., Valova, Y., Asperen, C.J. van, Dam, R.M. van, Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, Wendt, C., Williams, J.A., Yang, X.H.R., Yoon, S.Y., Zamora, M.P., Evans, D.G., Hoya, M. de la, Simard, J., Antoniou, A.C., Borg, A., Andrulis, I.L., Chang-Claude, J., Garcia-Closas, M., Chenevix-Trench, G., Milne, R.L., Pharoah, P.D.P., Schmidt, M.K., Spurdle, A.B., Vreeswijk, M.P.G., Benitez, J., Dunning, A.M., Kvist, A., Teo, S.H., Devilee, P., Easton, D.F., Breast Canc Assoc Consortium, Erasmus MC other, Medical Oncology, Clinical Genetics, Keeman, Renske [0000-0002-5452-9933], Decker, Brennan [0000-0003-4516-7421], Eriksson, Mikael [0000-0001-8135-4270], Martinez, Maria Elena [0000-0002-6728-1834], Surowy, Harald [0000-0002-3595-9188], Pharoah, Paul DP [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), and Klinische Genetica
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, Adolescent, PALB2, Genetic counseling, Genes, BRCA2, Mutation, Missense, Genes, BRCA1, Estrogen receptor, Breast Neoplasms, 030204 cardiovascular system & hematology, OVARIAN-CANCER, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, 030212 general & internal medicine, skin and connective tissue diseases, CHEK2, Aged, Genetic testing, Genetic association, Aged, 80 and over, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], medicine.diagnostic_test, MUTATIONS, business.industry, Age Factors, Genetic Variation, Sequence Analysis, DNA, General Medicine, Odds ratio, Middle Aged, BRCA1, medicine.disease, 3. Good health, Logistic Models, Female, business
Abstract: BACKGROUNDGenetic testing for breast cancer susceptibility is widely used, but for many genes,evidence of an association with breast cancer is weak, underlying risk estimatesare imprecise, and reliable subtype-specific risk estimates are lacking.METHODSWe used a panel of 34 putative susceptibility genes to perform sequencing onsamples from 60,466 women with breast cancer and 53,461 controls. In separateanalyses for protein-truncating variants and rare missense variants in these genes,we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluatedmissense-variant associations according to domain and classification of pathogenicity.RESULTSProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2)were associated with a risk of breast cancer overall with a P value of less than0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D,and TP53) were associated with a risk of breast cancer overall with a P value ofless than 0.05 and a Bayesian false-discovery probability of less than 0.05. Forprotein-truncating variants in 19 of the remaining 25 genes, the upper limit ofthe 95% confidence interval of the odds ratio for breast cancer overall was lessthan 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios werehigher for estrogen receptor (ER)–positive disease than for ER-negative disease;for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, andRAD51D, odds ratios were higher for ER-negative disease than for ER-positivedisease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 wereassociated with a risk of breast cancer overall with a P value of less than 0.001.For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a riskof breast cancer overall, with the risk being similar to that of protein-truncatingvariants.CONCLUSIONSThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimatesof the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)
Published: 2021
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43. Microvessels in Epithelial Ovarian Tumors: High Microvessel Density Is a Significant Feature of Malignant Ovarian Tumors

Author: Maarit Anttila, Leea Keski-Nisula, Veli-Matti Kosma, Minna Sopo, Seppo Ylä-Herttuala, Oona-Tuuli Muukkonen, and Hanna Sallinen
Subjects: Adult, Cancer Research, Pathology, medicine.medical_specialty, Adolescent, Angiogenesis, CD34, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Young Adult, Lymphatic vessel, medicine, Humans, Aged, Lymphatic Vessels, Aged, 80 and over, Ovarian Neoplasms, Neovascularization, Pathologic, business.industry, General Medicine, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Lymphangiogenesis, medicine.anatomical_structure, Lymphatic system, Oncology, cardiovascular system, Female, Lymph, Neoplasm Grading, business, Ovarian cancer, Microvascular Density
Abstract: Background/aim Examine features of blood and lymphatic vessels in ovarian tumors and their significance to prognosis of ovarian cancer. Patients and methods A total of 139 women with epithelial ovarian tumors were included: 86 malignant, 17 borderline and 36 benign. Density, percentage, mean size and number of blood microvessels in tumors were measured by immunohistochemistry with antibodies against CD34 and CD105. Lymphatic vessel density was assayed using the D2-40 antibody against podoplanin. Results Angiogenesis was most profuse in malignant tumors. Small size of lymph vessels predicted 26% shorter 5-year survival of ovarian cancer patients. Further, high percentage of lymphatic vessels in tumors was associated with lymph node metastasis, and high density with cancer recurrence. Lower number of microvessels, as assessed by CD34 staining, predicted shorter progression-free survival. Additionally, the large size of microvessels assessed by CD34 and the high number of vessels assessed by CD105 were related to residual tumor >1 cm at primary surgery and also, large vessel size was associated with stage III, as assessed by CD105 staining. Conclusion CD34 and CD105 define different characteristics of microvessels. Parameters of lymph vessels may predict the prognosis of ovarian cancer.
Published: 2020
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44. High mutation burden of circulating cell‐free DNA in early‐stage breast cancer patients is associated with a poor relapse‐free survival

Author: Reijo Sironen, Veli-Matti Kosma, Jouni Kujala, Jaana M. Hartikainen, Maria Tengström, and Arto Mannermaa
Subjects: Adult, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, recurrence, Genotype, Breast Neoplasms, Context (language use), lcsh:RC254-282, Disease-Free Survival, Circulating Tumor DNA, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, Humans, Medicine, Radiology, Nuclear Medicine and imaging, Stage (cooking), Liquid biopsy, Genotyping, Finland, Aged, Original Research, liquid biopsy, business.industry, Clinical Cancer Research, Cancer, Sequence Analysis, DNA, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Mutation (genetic algorithm), Biomarker (medicine), biomarker, Female, prognosis, business, Cell-Free Nucleic Acids, serum
Abstract: Background High tumor mutation burden is shown to be associated with a poor clinical outcome. As the tumor‐derived fraction of circulating cell‐free DNA (cfDNA) is shown to reflect the genetic spectrum of the tumor, we examined whether the mutation burden of cfDNA could be used to predict the clinical outcomes of early‐stage breast cancer (BC) patients. Methods We selected a set of 79 Finnish early‐stage BC cases with a good prognosis based on traditional prognostic parameters but some of which still developed relapsed disease during follow‐up. cfDNA was isolated from the serum collected at the time of diagnosis, sequenced, and compared to matched primary tumors, clinical parameters, and survival data. Results High cfDNA mutation burden was associated with the poor relapse‐free survival (RFS) (P = .016, HR = 2.23, 95% Cl 1.16‐4.27) when patients were divided into high and low mutation burden according to the median number of somatic variants. A high discordance was observed between the matched tumor and cfDNA samples, thus highlighting the challenges related to the liquid biopsy of early‐stage cancer cases. Despite the low number of detected tumor‐specific variants, the presence of tumor‐specific somatic variants in the cfDNA was associated with the poor RFS (P = .009, HR = 2.31, 95% Cl 1.23‐4.31). Conclusions Our results confirm previously observed challenges about the accuracy of liquid biopsy‐based genotyping of early‐stage cancers and support the parallel sequencing of tumor and cfDNA while also demonstrating how the presence of tumor‐specific somatic variants and the high mutation burden in the cfDNA are both associated with the poor RFS, thus indicating the prognostic potential of liquid biopsy in the context of early‐stage cancers., High mutation burden and the presence of tumor‐specific mutations in circulating cell‐free DNA in early‐stage breast cancer patients were observed to be associated with a poor relapse‐free survival. Our results suggest that the liquid biopsy of early‐stage cancers might provide potential benefits when making primary prognosis despite the challenges that are associated with the liquid biopsy of early‐stage cancers.
Published: 2020

45. Effect of Social Distancing Due to the COVID-19 Pandemic on the Incidence of Viral Respiratory Tract Infections in Children in Finland During Early 2020

Author: Miia Artama, Tarja Heiskanen-Kosma, Lotta Makela, Ilari Kuitunen, Katri Backman, and Marjo Renko
Subjects: Male, Microbiology (medical), Pediatrics, medicine.medical_specialty, Physical Distancing, Population, Comorbidity, History, 21st Century, 03 medical and health sciences, 0302 clinical medicine, Public health surveillance, 030225 pediatrics, Pandemic, Humans, Medicine, Public Health Surveillance, Pediatrics, Perinatology, and Child Health, Registries, 030212 general & internal medicine, Child, education, Pandemics, Respiratory Tract Infections, Finland, education.field_of_study, Respiratory tract infections, business.industry, Incidence, Social distance, Incidence (epidemiology), Age Factors, COVID-19, medicine.disease, Hospitalization, Infectious Diseases, Infectious disease (medical specialty), Child, Preschool, Pediatrics, Perinatology and Child Health, Female, Emergency Service, Hospital, business
Abstract: BACKGROUND: Social distancing measures are used to reduce the spreading of infection. Our aim was to assess the immediate effects of national lockdown orders due to coronavirus disease 2019 (COVID-19) on pediatric emergency room (ER) visits and respiratory tract infections in hospitals and nationwide in Finland. METHODS: This register-based study used hospital patient information systems and the Finnish national infectious disease register. The participants were all patients visiting pediatric ER in 2 Finnish hospitals (Kuopio University Hospital, Mikkeli Central Hospital) covering 1/5th of the Finnish children population, 4 weeks before and 4 weeks after the start of the nationwide lockdown on March 16, 2020. Nationwide weekly numbers of influenza (A + B) and respiratory syncytial virus (RSV) in children were assessed from the infectious disease register from 2015 to 2020. RESULTS: A major decrease in the rate of daily median pediatric ER visits was detected in both hospitals in the study during the nationwide lockdown compared with the study period before the lockdown (Mikkeli, 19 vs. 7, P < 0.001; Kuopio, 9 vs. 2,5, P < 0.001). The influenza season was shorter (8 weeks from peak to no cases), and the weekly rate of new cases decreased faster compared with the previous 4 influenza seasons (previously 15-20 weeks from peak to no cases). A similar decrease was also seen in RSV cases. No pediatric cases of COVID-19 were found in participating hospitals during the study period. CONCLUSION: These results strongly suggest that social distancing and other lockdown strategies are effective to slow down the spreading of common respiratory viral diseases and decreasing the need for hospitalization among children.
Published: 2020
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46. Predicting breast cancer risk using interacting genetic and demographic factors and machine learning

Author: Behravan, Hamid, Hartikainen, Jaana M., Tengström, Maria, Kosma, Veli–Matti, and Mannermaa, Arto
Subjects: Databases, Factual, lcsh:R, lcsh:Medicine, Breast Neoplasms, Epistasis, Genetic, Polymorphism, Single Nucleotide, Article, Machine Learning, Breast cancer, Risk Factors, Databases, Genetic, Cancer genomics, Humans, Female, Genetic Predisposition to Disease, lcsh:Q, lcsh:Science, Cancer genetics, Algorithms, Demography
Abstract: Breast cancer (BC) is a multifactorial disease and the most common cancer in women worldwide. We describe a machine learning approach to identify a combination of interacting genetic variants (SNPs) and demographic risk factors for BC, especially factors related to both familial history (Group 1) and oestrogen metabolism (Group 2), for predicting BC risk. This approach identifies the best combinations of interacting genetic and demographic risk factors that yield the highest BC risk prediction accuracy. In tests on the Kuopio Breast Cancer Project (KBCP) dataset, our approach achieves a mean average precision (mAP) of 77.78 in predicting BC risk by using interacting genetic and Group 1 features, which is better than the mAPs of 74.19 and 73.65 achieved using only Group 1 features and interacting SNPs, respectively. Similarly, using interacting genetic and Group 2 features yields a mAP of 78.00, which outperforms the system based on only Group 2 features, which has a mAP of 72.57. Furthermore, the gene interaction maps built from genes associated with SNPs that interact with demographic risk factors indicate important BC-related biological entities, such as angiogenesis, apoptosis and oestrogen-related networks. The results also show that demographic risk factors are individually more important than genetic variants in predicting BC risk.
Published: 2020
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47. Serum alpha-mannosidase as an additional barrier to eliciting oligomannose-specific HIV-1-neutralizing antibodies

Author: Quratulain Qureshi, Tess Kirilenko, Naiomi Lu, Paul Kosma, Nino Trattnig, Ralph Pantophlet, and Jean-François Bruxelle
Subjects: Male, Mannosidase, Glycoconjugate, Glycobiology, Human immunodeficiency virus (HIV), Oligosaccharides, lcsh:Medicine, HIV Infections, HIV Antibodies, medicine.disease_cause, Epitopes, Mice, 0302 clinical medicine, lcsh:Science, AIDS Vaccines, chemistry.chemical_classification, 0303 health sciences, Multidisciplinary, biology, env Gene Products, Human Immunodeficiency Virus, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Antibody, Protein Binding, Glycan, Carbohydrates, alpha-Mannosidase, Article, Antibodies, 03 medical and health sciences, Bacterial Proteins, Polysaccharides, medicine, Animals, Humans, B cell, Glycoproteins, 030304 developmental biology, Vaccines, Conjugate, lcsh:R, Antibodies, Neutralizing, Conjugate vaccines, chemistry, Immunization, Immunology, HIV-1, biology.protein, lcsh:Q, Protein Multimerization, Glycoconjugates
Abstract: Oligomannose-type glycans on HIV-1 gp120 form a patch that is targeted by several broadly neutralizing antibodies (bnAbs) and that therefore is of interest to vaccine design. However, attempts to elicit similar oligomannose-specific bnAbs by immunizing with oligomannosidic glycoconjugates have only been modestly successful so far. A common assumption is that eliciting oligomannose-specific bnAbs is hindered by B cell tolerance, resulting from the presented oligomannosides being sensed as self molecules. Here, we present data, along with existing scientific evidence, supporting an additional, or perhaps alternate, explanation: serum mannosidase trimming of the presented oligomannosides in vivo. Mannosidase trimming lessens the likelihood of eliciting antibodies with capacity to bind full-sized oligomannose, which typifies the binding mode of existing bnAbs to the oligomannose patch. The rapidity of the observed trimming suggests the need for immunization strategies and/or synthetic glycosides that readily avoid or resist mannosidase trimming upon immunization and can overcome possible tolerance restrictions.
Published: 2020
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48. Plerixafor-aided Mobilization of Peripheral Blood Hematopoietic Stem Cells to Support Subsequent High-dose Chemotherapy After a Prior Autologous Transplant

Author: Anastasios Grivas, Maria Karakosta, Evangelos Fergadis, Evangelos Lianos, Aikaterini Kosma, Eleftheria Kranidioti, Aggelos Athanasopoulos, George K. Dimitriadis, Abraam Assi, Constantinos Miltiadous, and Christos Kosmas
Subjects: Adult, Male, Oncology, Benzylamines, Cancer Research, medicine.medical_specialty, CD34, Cyclams, Transplantation, Autologous, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Humans, Medicine, Hematopoietic Stem Cell Mobilization, Multiple myeloma, Aged, Peripheral Blood Stem Cell Transplantation, business.industry, Plerixafor, Hematopoietic stem cell, Hematology, Middle Aged, medicine.disease, Non-Hodgkin's lymphoma, Transplantation, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Female, Sarcoma, business, 030215 immunology, medicine.drug
Abstract: Background An appreciable proportion of patients in need of salvage high-dose chemotherapy (HDC) and autologous peripheral blood stem cell (PBSC) transplantation (PBSCT) fail to mobilize adequate numbers of hematopoietic progenitors, and plerixafor is applied for that purpose. Limited data exist on remobilization of PBSCs in patients who have relapsed after prior HDC + PBSCT. Herein, we report on consecutive patients that had undergone successful prior single or tandem HDC for a variety of malignant neoplasms in our institution, and later required re-mobilization of PBSCs in order to support further HDC cycles. Patients and Methods Plerixafor was administered in combination with granulocyte-colony stimulating factor alone, or after mobilizing chemotherapy. Five patients, 2 B-cell non-Hodgkin lymphomas, 1 multiple myeloma, 1 germ-cell tumor, and 1 Ewing sarcoma, having relapsed after prior HDC + PBSCT, were deemed candidates for further cycle(s) of PBSC-supported HDC. Plerixafor was applied in a “just-in-time” strategy after low CD34+ numbers were measured on the first day of anticipated hematopoietic stem cell collection (non-Hodgkin lymphoma, germ-cell tumor, and Ewing sarcoma), or pre-emptively in multiple myeloma. Results Successful collection of adequate PBSCs was achieved in all patients, from 1.8 to 3.8 × 106/kg after a median of 2 (range, 1-3) leukaphereses; 4 of 5 patients underwent subsequent HDC + PBSCT and engrafted after a median of 11 days (range, 9-55 days) and 25 days (range, 17-76 days) for neutrophils and platelets, respectively. Conclusion Plerixafor proved effective to mobilize adequate numbers of PBSCs in individual patients with relapsed malignancies after prior single or tandem HDC + PBSCT. These PBSCs could establish sustained multi-lineage hematopoietic engraftment without any sequelae.
Published: 2020
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49. Area-based breast percentage density estimation in mammograms using weight-adaptive multitask learning

Author: Naga Raju, Gudhe, Hamid, Behravan, Mazen, Sudah, Hidemi, Okuma, Ritva, Vanninen, Veli-Matti, Kosma, and Arto, Mannermaa
Subjects: Image Processing, Computer-Assisted, Humans, Breast Neoplasms, Female, Breast, Neural Networks, Computer, Breast Density, Mammography
Abstract: Breast density, which is a measure of the relative amount of fibroglandular tissue within the breast area, is one of the most important breast cancer risk factors. Accurate segmentation of fibroglandular tissues and breast area is crucial for computing the breast density. Semiautomatic and fully automatic computer-aided design tools have been developed to estimate the percentage of breast density in mammograms. However, the available approaches are usually limited to specific mammogram views and are inadequate for complete delineation of the pectoral muscle. These tools also perform poorly in cases of data variability and often require an experienced radiologist to adjust the segmentation threshold for fibroglandular tissue within the breast area. This study proposes a new deep learning architecture that automatically estimates the area-based breast percentage density from mammograms using a weight-adaptive multitask learning approach. The proposed approach simultaneously segments the breast and dense tissues and further estimates the breast percentage density. We evaluate the performance of the proposed model in both segmentation and density estimation on an independent evaluation set of 7500 craniocaudal and mediolateral oblique-view mammograms from Kuopio University Hospital, Finland. The proposed multitask segmentation approach outperforms and achieves average relative improvements of 2.88% and 9.78% in terms of F-score compared to the multitask U-net and a fully convolutional neural network, respectively. The estimated breast density values using our approach strongly correlate with radiologists' assessments with a Pearson's correlation of [Formula: see text] (95% confidence interval [0.89, 0.91]). We conclude that our approach greatly improves the segmentation accuracy of the breast area and dense tissues; thus, it can play a vital role in accurately computing the breast density. Our density estimation model considerably reduces the time and effort needed to estimate density values from mammograms by radiologists and therefore, decreases inter- and intra-reader variability.
Published: 2022

50. Rare germline copy number variants (CNVs) and breast cancer risk

Author: Dennis, Joe, Tyrer, Jonathan, Walker, Logan C, Michailidou, Kyriaki, Dorling, Leila, Bolla, Manjeet K, Wang, Jean, Ahearn, Thomas U, Andrulis, Irene L, Anton-Culver, Hoda, Antonenkova, Natalia N, Arndt, Volker, Aronson, Kristan J, Freeman, Laura E Beane, Beckmann, Matthias W, Behrens, Sabine, Benitez, Javier, Bermisheva, Marina, Bogdanova, Natalia V, Bojesen, Stig E, Brenner, Hermann, Castelao, Jose E, Chang-Claude, Jenny, Chenevix-Trench, Georgia, Clarke, Christine L, Kristensen, Vessela N, Sahlberg, Kristine K, Børresen-Dale, Anne-Lise, Gram, Inger Torhild, Engebråten, Olav, Naume, Bjørn, Geisler, Jürgen, Alnæs, Grethe I Grenaker, Collée, J Margriet, Lacey, James, Martinez, Elena, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Devilee, Peter, Dörk, Thilo, Dossus, Laure, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Fasching, Peter A, Figueroa, Jonine, Fletcher, Olivia, Flyger, Henrik, Fritschi, Lin, Gabrielson, Marike, Gago-Dominguez, Manuela, García-Closas, Montserrat, Giles, Graham G, González-Neira, Anna, Guénel, Pascal, Hahnen, Eric, Haiman, Christopher A, Hall, Per, Hollestelle, Antoinette, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Clarke, Christine, Carpenter, Jane, Marsh, Deborah, Scott, Rodney, Baxter, Robert, Yip, Desmond, Davis, Alison, Pathmanathan, Nirmala, Simpson, Peter, Graham, Dinny, Sachchithananthan, Mythily, Campbell, Ian, De Fazio, Anna, Fox, Stephen, Kirk, Judy, Lindeman, Geoff, Milne, Roger, Southey, Melissa, Spurdle, Amanda, Thorne, Heather, Jager, Agnes, Jakubowska, Anna, John, Esther M, Johnson, Nichola, Jones, Michael E, Jung, Audrey, Kaaks, Rudolf, Keeman, Renske, Khusnutdinova, Elza, Kitahara, Cari M, Ko, Yon-Dschun, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Kubelka-Sabit, Katerina, Kurian, Allison W, Lacey, James V, Lambrechts, Diether, Larson, Nicole L, Linet, Martha, Ogrodniczak, Alicja, Mannermaa, Arto, Manoukian, Siranoush, Margolin, Sara, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Murphy, Rachel A, Nevanlinna, Heli, Olson, Janet E, Olsson, Håkan, Park-Simon, Tjoung-Won, Perou, Charles M, Peterlongo, Paolo, Plaseska-Karanfilska, Dijana, Pylkäs, Katri, Rennert, Gad, Saloustros, Emmanouil, Sandler, Dale P, Sawyer, Elinor J, Schmidt, Marjanka K, Schmutzler, Rita K, Shibli, Rana, Smeets, Ann, Soucy, Penny, Southey, Melissa C, Swerdlow, Anthony J, Tamimi, Rulla M, Taylor, Jack A, Teras, Lauren R, Terry, Mary Beth, Tomlinson, Ian, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wendt, Camilla, Winqvist, Robert, Wolk, Alicja, Yang, Xiaohong R, Zheng, Wei, Ziogas, Argyrios, Simard, Jacques, Dunning, Alison, Pharoah, Paul, Easton, Douglas, Dennis, Joe [0000-0003-4591-1214], Tyrer, Jonathan [0000-0003-3724-4757], Walker, Logan C [0000-0003-0018-3719], Michailidou, Kyriaki [0000-0001-7065-1237], Wang, Jean [0000-0002-9139-0627], Andrulis, Irene L [0000-0002-4226-6435], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Behrens, Sabine [0000-0002-9714-104X], Kristensen, Vessela N [0000-0001-5012-7438], Dörk, Thilo [0000-0002-9458-0282], Dossus, Laure [0000-0003-2716-5748], Figueroa, Jonine [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Giles, Graham G [0000-0003-4946-9099], Hollestelle, Antoinette [0000-0003-1166-1966], Jakubowska, Anna [0000-0002-5650-0501], Johnson, Nichola [0000-0002-8230-5662], Jones, Michael E [0000-0001-7479-3451], Keeman, Renske [0000-0002-5452-9933], Larson, Nicole L [0000-0002-2129-6934], Milne, Roger L [0000-0001-5764-7268], Nevanlinna, Heli [0000-0002-0916-2976], Olson, Janet E [0000-0003-4944-7789], Peterlongo, Paolo [0000-0001-6951-6855], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Rennert, Gad [0000-0002-8512-068X], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Simard, Jacques [0000-0001-6906-3390], Dunning, Alison [0000-0001-6651-7166], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Wilson, Leila [0000-0003-1214-8080], Clinical Genetics, Medical Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum
Subjects: endocrine system diseases, 45/43, Medicine (miscellaneous), Genome-wide association studies, Basic medicine, Breast cancer, Other medical sciences, Runx2, Risk Factors, Biology (General), skin and connective tissue diseases, 0303 health sciences, 030305 genetics & heredity, article, 3. Good health, Female, General Agricultural and Biological Sciences, Medical Genetics, Mutations, DNA Copy Number Variations, Locus, QH301-705.5, kConFab/AOCS Investigators, ABCTB Investigators, 631/208/205/2138, Breast Neoplasms, Breast Neoplasms/genetics, General Biochemistry, Genetics and Molecular Biology, NBCS Collaborators, Association, Deletion, 03 medical and health sciences, SDG 3 - Good Health and Well-being, mental disorders, Humans, 030304 developmental biology, Medicinsk genetik, Cancer och onkologi, Genome, Human, Health sciences, 631/67/1347, CTS Consortium, Germ Cells, Genes, Clinical medicine, Cancer and Oncology, Case-Control Studies, 3111 Biomedicine, Structural variation, Brca1, Genome-Wide Association Study
Abstract: Germline copy 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. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value, Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.
Published: 2021
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