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1. Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

Author: Lakeman, Inge MM, Rodríguez-Girondo, Mar DM, Lee, Andrew, Celosse, Nandi, Braspenning, Merel E, Van Engelen, Klaartje, Van De Beek, Irma, Van Der Hout, Annemiek H, Gómez García, Encarna B, Mensenkamp, Arjen R, Ausems, Margreet GEM, Hooning, Maartje J, Adank, Muriel A, Hollestelle, Antoinette, Schmidt, Marjanka K, Van Asperen, Christi J, Devilee, Peter, Human genetics, Cancer Center Amsterdam, Medical Oncology, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Lakeman, Inge MM [0000-0002-2990-7154], Lee, Andrew [0000-0003-0677-0252], Mensenkamp, Arjen R [0000-0003-3805-877X], Devilee, Peter [0000-0002-8023-2009], and Apollo - University of Cambridge Repository
Subjects: Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Polymorphism, Genetic, MODELS, LOCI, WOMEN, Breast Neoplasms, VARIANTS, Medical Oncology, Risk Assessment, PANEL, SDG 3 - Good Health and Well-being, Genetic, Risk Factors, Genetics, Humans, Female, Genetic Predisposition to Disease, Polymorphism, Cancer genetics, Genetics (clinical), Retrospective Studies
Abstract: Peer reviewed: True, Acknowledgements: We would like to thank Mary Velthuizen (University Medical Center Utrecht), J Margriet Collée (Erasmus Medical Center Rotterdam), Wendy Prager-van den Smissen (Erasmus Medical Center Rotterdam), Daoud Ait Moha (The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital), Jan C Oosterwijk (University Medical Center Groningen), Janet R Vos (Radboud University Medical Center), Jeroen FJ Laros (Leiden University Medical Center) and Adri JM Krol (Leiden University Medical Center) for collecting and converting the pedigree files of the included families., BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.
Published: 2023

2. Prospective validation of the BOADICEA multifactorial breast cancer risk prediction model in a large prospective cohort study

Author: Xin Yang, Mikael Eriksson, Kamila Czene, Andrew Lee, Goska Leslie, Michael Lush, Jean Wang, Joe Dennis, Leila Dorling, Sara Carvalho, Nasim Mavaddat, Jacques Simard, Marjanka K Schmidt, Douglas F Easton, Per Hall, Antonis C Antoniou, Yang, Xin [0000-0003-0037-3790], Lee, Andrew [0000-0003-0677-0252], Antoniou, Antonis C [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: genetic counseling, public health, Genes, BRCA2, Genetics, Humans, Female, Breast Neoplasms, Genetic Predisposition to Disease, Prospective Studies, Middle Aged, women's health, Risk Assessment, Genetics (clinical)
Abstract: Peer reviewed: True, Acknowledgements: We would like to thank all the participants, clinicians and other healthcare professionals who have contributed to the KARMA cohort., Funder: CHU de Quebec, Funder: NIHR Cambridge Biomedical Research Centre, Funder: Quebec Breast Cancer Foundation, Funder: Ontario Research Fund, Funder: the Märit and Hans Rausing’s Initiative Against Breast Cancer, BACKGROUND: The multifactorial Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) breast cancer risk prediction model has been recently extended to consider all established breast cancer risk factors. We assessed the clinical validity of the model in a large independent prospective cohort. METHODS: We validated BOADICEA (V.6) in the Swedish KARolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) cohort including 66 415 women of European ancestry (median age 54 years, IQR 45-63; 816 incident breast cancers) without previous cancer diagnosis. We calculated 5-year risks on the basis of questionnaire-based risk factors, pedigree-structured first-degree family history, mammographic density (BI-RADS), a validated breast cancer polygenic risk score (PRS) based on 313-SNPs, and pathogenic variant status in 8 breast cancer susceptibility genes: BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D and BARD1. Calibration was assessed by comparing observed and expected risks in deciles of predicted risk and the calibration slope. The discriminatory ability was assessed using the area under the curve (AUC). RESULTS: Among the individual model components, the PRS contributed most to breast cancer risk stratification. BOADICEA was well calibrated in predicting the risks for low-risk and high-risk women when all, or subsets of risk factors are included in the risk prediction. Discrimination was maximised when all risk factors are considered (AUC=0.70, 95% CI: 0.66 to 0.73; expected-to-observed ratio=0.88, 95% CI: 0.75 to 1.04; calibration slope=0.97, 95% CI: 0.95 to 0.99). The full multifactorial model classified 3.6% women as high risk (5-year risk ≥3%) and 11.1% as very low risk (5-year risk
Published: 2022
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3. Incorporating alternative Polygenic Risk Scores into the BOADICEA breast cancer risk prediction model

Author: Mavaddat, Nasim, Ficorella, Lorenzo, Carver, Tim, Lee, Andrew, Cunningham, Alex P, Lush, Michael, Dennis, Joe, Tischkowitz, Marc, Downes, Kate, Hu, Donglei, Hahnen, Eric, Schmutzler, Rita K, Stockley, Tracy L, Downs, Gregory S, Zhang, Tong, Chiarelli, Anna M, Bojesen, Stig E, Liu, Cong, Chung, Wendy K, Pardo, Monica, Feliubadaló, Lidia, Balmaña, Judith, Simard, Jacques, Antoniou, Antonis C, Easton, Douglas F, Mavaddat, Nasim [0000-0003-0307-055X], Ficorella, Lorenzo [0000-0002-0577-1571], Carver, Tim [0000-0003-1508-3091], Lee, Andrew [0000-0003-0677-0252], Cunningham, Alex P [0000-0002-3737-9611], Lush, Michael [0000-0001-5945-3440], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Downes, Kate [0000-0003-0366-1579], Hu, Donglei [0000-0002-0351-001X], Hahnen, Eric [0000-0002-1152-8367], Schmutzler, Rita K [0000-0001-8160-4348], Stockley, Tracy L [0000-0002-4476-9722], Downs, Gregory S [0000-0002-5622-9010], Zhang, Tong [0000-0001-7108-0974], Chiarelli, Anna M [0000-0002-7382-513X], Bojesen, Stig E [0000-0002-4061-4133], Liu, Cong [0000-0001-6024-3037], Chung, Wendy K [0000-0003-3438-5685], Pardo, Monica [0000-0003-2015-9564], Feliubadaló, Lidia [0000-0002-1736-0112], Balmaña, Judith [0000-0002-0762-6415], Simard, Jacques [0000-0001-6906-3390], Antoniou, Antonis C [0000-0001-9223-3116], Easton, Douglas F [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Institut Català de la Salut, [Mavaddat N, Ficorella L, Carver T, Lee A, Cunningham AP, Lush M] Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. [Pardo M] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Balmaña J] Hereditary Cancer Genetics Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: neoplasias::neoplasias por localización::neoplasias de la mama [ENFERMEDADES], Epidemiology, Otros calificadores::Otros calificadores::/genética [Otros calificadores], Neoplasms::Neoplasms by Site::Breast Neoplasms [DISEASES], Genetic Phenomena::Genotype::Genetic Predisposition to Disease [PHENOMENA AND PROCESSES], Breast Neoplasms, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Risk Assessment, Polymorphism, Single Nucleotide, Mama - Càncer - Factors de risc, Oncology, Risk Factors, Mama - Càncer - Diàtesi, Other subheadings::Other subheadings::/genetics [Other subheadings], Mama - Càncer - Aspectes genètics, Humans, Female, Genetic Predisposition to Disease, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], fenómenos genéticos::genotipo::predisposición genética a la enfermedad [FENÓMENOS Y PROCESOS], Retrospective Studies
Abstract: Polygenic risk; Prediction; Breast cancer Riesgo poligénico; Predicción; Cáncer de mama Risc poligènic; Predicció; Càncer de mama Background: The multifactorial risk prediction model BOADICEA enables identification of women at higher or lower risk of developing breast cancer. BOADICEA models genetic susceptibility in terms of the effects of rare variants in breast cancer susceptibility genes and a polygenic component, decomposed into an unmeasured and a measured component - the polygenic risk score (PRS). The current version was developed using a 313 SNP PRS. Here, we evaluated approaches to incorporating this PRS and alternative PRS in BOADICEA. Methods: The mean, SD, and proportion of the overall polygenic component explained by the PRS (α2) need to be estimated. α was estimated using logistic regression, where the age-specific log-OR is constrained to be a function of the age-dependent polygenic relative risk in BOADICEA; and using a retrospective likelihood (RL) approach that models, in addition, the unmeasured polygenic component. Results: Parameters were computed for 11 PRS, including 6 variations of the 313 SNP PRS used in clinical trials and implementation studies. The logistic regression approach underestimates α⁠, as compared with the RL estimates. The RL α estimates were very close to those obtained by assuming proportionality to the OR per 1 SD, with the constant of proportionality estimated using the 313 SNP PRS. Small variations in the SNPs included in the PRS can lead to large differences in the mean. Conclusions: BOADICEA can be readily adapted to different PRS in a manner that maintains consistency of the model. This work has been supported by grants from Cancer Research UK (PPRPGM-Nov20\100002); the European Union's Horizon 2020 Research and Innovation Programme under grant agreement numbers 633784 (B-CAST) and 634935 (BRIDGES); the PERSPECTIVE I&I project which is funded by the Government of Canada through Genome Canada (#13529) and the Canadian Institutes of Health Research (#155865), the Ministère de l’Économie et de l'Innovation du Québec through Genome Québec, the Quebec Breast Cancer Foundation, the CHU de Quebec Foundation and the Ontario Research Fund; and by the NIHR Cambridge Biomedical Research Centre (BRC-1215–20014). BCAC is funded by the European Union's Horizon 2020 Research and Innovation Programme (grant numbers 634935 and 633784 for BRIDGES and B-CAST respectively), and the PERSPECTIVE I&I project. Additional funding for BCAC is provided via the Confluence project which is funded with intramural funds from the NCI Intramural Research Program, NIH. Genotyping of the OncoArray was funded by the NIH Grant U19 CA148065, and Cancer Research UK Grant C1287/A16563 and the PERSPECTIVE project supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (grant GPH-129344) and, the Ministère de l’Économie, Science et Innovation du Québec through Genome Québec and the PSRSIIRI-701 grant, and the Quebec Breast Cancer Foundation. MT was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215–20014) and Cancer Research UK C22770/A31523 (International Alliance for Cancer Early Detection programme). The PRISMA study has been funded by Instituto de Salud Carlos III through the project " PI19/01195″ (Co-funded by European Regional Development Fund "A way to make Europe") and it received the institutional support of CERCA Program (Generalitat de Catalunya). The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Published: 2022

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

Author: Andy C. H. Lee, Penny Coulson, Minouk J. Schoemaker, Antonis C. Antoniou, Mark N. Brook, Nilanjan Chatterjee, Charlotta V. Mulder, Anthony J. Swerdlow, Amber N. Hurson, Montserrat Garcia-Closas, Michael Jones, Parichoy Pal Choudhury, Apollo - University of Cambridge Repository, Lee, Andrew [0000-0003-0677-0252], and Antoniou, Antonis [0000-0001-9223-3116]
Subjects: Adult, Multifactorial Inheritance, Population, Short Report, Breast Neoplasms, Population based, Absolute risk, Risk Assessment, lcsh:RC254-282, White People, Decile, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Risk Factors, Medicine, Humans, Genetic Predisposition to Disease, education, Prospective cohort study, 030304 developmental biology, Aged, Estimation, 0303 health sciences, education.field_of_study, Tyrer-Cuzick, business.industry, Model validation, Absolute risk reduction, Middle Aged, Models, Theoretical, Prospective cohort, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Risk prediction, 3. Good health, 030220 oncology & carcinogenesis, Population Surveillance, IBIS, Polygenic risk score, Female, BOADICEA, business, Algorithms, Demography
Abstract: Background The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and the Tyrer-Cuzick breast cancer risk prediction models are commonly used in clinical practice and have recently been extended to include polygenic risk scores (PRS). In addition, BOADICEA has also been extended to include reproductive and lifestyle factors, which were already part of Tyrer-Cuzick model. We conducted a comparative prospective validation of these models after incorporating the recently developed 313-variant PRS. Methods Calibration and discrimination of 5-year absolute risk was assessed in a nested case-control sample of 1337 women of European ancestry (619 incident breast cancer cases) aged 23–75 years from the Generations Study. Results The extended BOADICEA model with reproductive/lifestyle factors and PRS was well calibrated across risk deciles; expected-to-observed ratio (E/O) at the highest risk decile :0.97 (95 % CI 0.51 − 1.86) for women younger than 50 years and 1.09 (0.66 − 1.80) for women 50 years or older. Adding reproductive/lifestyle factors and PRS to the BOADICEA model improved discrimination modestly in younger women (area under the curve (AUC) 69.7 % vs. 69.1%) and substantially in older women (AUC 64.6 % vs. 56.8%). The Tyrer-Cuzick model with PRS showed evidence of overestimation at the highest risk decile: E/O = 1.54(0.81 − 2.92) for younger and 1.73 (1.03 − 2.90) for older women. Conclusion The extended BOADICEA model identified women in a European-ancestry population at elevated breast cancer risk more accurately than the Tyrer-Cuzick model with PRS. With the increasing availability of PRS, these analyses can inform choice of risk models incorporating PRS for risk stratified breast cancer prevention among women of European ancestry.
Published: 2021

5. Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence

Author: Lee, Andrew, Mavaddat, Nasim, Cunningham, Alex, Carver, Tim, Ficorella, Lorenzo, Archer, Stephanie, Walter, Fiona M, Tischkowitz, Marc, Roberts, Jonathan, Usher-Smith, Juliet, Simard, Jacques, Schmidt, Marjanka K, Devilee, Peter, Zadnik, Vesna, Jürgens, Hannes, Mouret-Fourme, Emmanuelle, De Pauw, Antoine, Rookus, Matti, Mooij, Thea M, Pharoah, Paul Pd, Easton, Douglas F, Antoniou, Antonis C, Lee, Andrew [0000-0003-0677-0252], Devilee, Peter [0000-0002-8023-2009], Pharoah, Paul Pd [0000-0001-8494-732X], Antoniou, Antonis C [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Adult, Ovarian Neoplasms, genetic counseling, BRCA1 Protein, Incidence, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases, Breast Neoplasms, Carcinoma, Ovarian Epithelial, DNA-Binding Proteins, Risk Factors, Humans, Female, Genetic Predisposition to Disease
Abstract: BACKGROUND: BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) for breast cancer and the epithelial tubo-ovarian cancer (EOC) models included in the CanRisk tool (www.canrisk.org) provide future cancer risks based on pathogenic variants in cancer-susceptibility genes, polygenic risk scores, breast density, questionnaire-based risk factors and family history. Here, we extend the models to include the effects of pathogenic variants in recently established breast cancer and EOC susceptibility genes, up-to-date age-specific pathology distributions and continuous risk factors. METHODS: BOADICEA was extended to further incorporate the associations of pathogenic variants in BARD1, RAD51C and RAD51D with breast cancer risk. The EOC model was extended to include the association of PALB2 pathogenic variants with EOC risk. Age-specific distributions of oestrogen-receptor-negative and triple-negative breast cancer status for pathogenic variant carriers in these genes and CHEK2 and ATM were also incorporated. A novel method to include continuous risk factors was developed, exemplified by including adult height as continuous. RESULTS: BARD1, RAD51C and RAD51D explain 0.31% of the breast cancer polygenic variance. When incorporated into the multifactorial model, 34%-44% of these carriers would be reclassified to the near-population and 15%-22% to the high-risk categories based on the UK National Institute for Health and Care Excellence guidelines. Under the EOC multifactorial model, 62%, 35% and 3% of PALB2 carriers have lifetime EOC risks of 10%, respectively. Including height as continuous, increased the breast cancer relative risk variance from 0.002 to 0.010. CONCLUSIONS: These extensions will allow for better personalised risks for BARD1, RAD51C, RAD51D and PALB2 pathogenic variant carriers and more informed choices on screening, prevention, risk factor modification or other risk-reducing options.
Published: 2022
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6. Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors

Author: Stephanie Archer, Simon A. Gayther, Jatinder Kalsi, Usha Menon, Faiza Gaba, Andy C. H. Lee, Tim Carver, Fiona M Walter, Paul D.P. Pharoah, Antonis C. Antoniou, Marc Tischkowitz, Ian Jacobs, Ranjit Manchanda, Douglas F. Easton, Xin Yang, Jonathan Tyrer, Aleksandra Gentry-Maharaj, Goska Leslie, Andy Ryan, Susan J. Ramus, Alex P Cunningham, Nasim Mavaddat, Lee, Andrew [0000-0003-0677-0252], Yang, Xin [0000-0003-0037-3790], Tyrer, Jonathan [0000-0003-3724-4757], Mavaddat, Nasim [0000-0003-0307-055X], Cunningham, Alex [0000-0002-3737-9611], Archer, Stephanie [0000-0003-1349-7178], Manchanda, Ranjit [0000-0003-3381-5057], Ramus, Susan J [0000-0003-0005-7798], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, and Antoniou, Antonis C [0000-0001-9223-3116]
Subjects: Oncology, medicine.medical_specialty, Percentile, Multifactorial Inheritance, Tubo-ovarian, endocrine system diseases, Genetic counseling, Population, Breast Neoplasms, Carcinoma, Ovarian Epithelial, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Internal medicine, Epidemiology, Medicine, Humans, Genetic Predisposition to Disease, genetics, Family history, education, Adverse effect, Cancer genetics, Genetics (clinical), 030304 developmental biology, Ovarian Neoplasms, clinical decision-making, 0303 health sciences, education.field_of_study, genetic counseling, business.industry, public health, Cancer, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Female, business, early diagnosis
Abstract: Funder: Department of Health; FundRef: http://dx.doi.org/10.13039/501100000276, Funder: Ontario Research Fund, Funder: CHU de Quebec Foundation, Funder: Fondation du cancer du sein du Qu��bec; FundRef: http://dx.doi.org/10.13039/100016328, Funder: The Eve Appeal, Background: Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. Methods: We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. Results: Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%��10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. Conclusion: This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).
Published: 2021
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7. Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models

Author: Roger L. Milne, Andy C. H. Lee, Melissa C. Southey, Robert J. MacInnis, Tu Nguyen-Dumont, Graham G. Giles, Ingrid Winship, John L. Hopper, Mary Beth Terry, Sherly X. Li, Dallas R. English, Antonis C. Antoniou, Li, Sherly X [0000-0002-7840-4051], Nguyen-Dumont, Tú [0000-0002-6217-0182], English, Dallas R [0000-0001-7828-8188], Antoniou, Antonis C [0000-0001-9223-3116], MacInnis, Robert J [0000-0002-1627-5047], Apollo - University of Cambridge Repository, Antoniou, Antonis [0000-0001-9223-3116], Lee, Andrew [0000-0003-0677-0252], Li, Sherly X. [0000-0002-7840-4051], English, Dallas R. [0000-0001-7828-8188], Antoniou, Antonis C. [0000-0001-9223-3116], and MacInnis, Robert J. [0000-0002-1627-5047]
Subjects: Ibis, Cancer Research, biology, business.industry, Cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biology.organism_classification, medicine.disease, calibration, Prospective evaluation, Confidence interval, Article, Clinical research, Breast cancer, breast cancer, Oncology, risk model, Medicine, Family history, business, RC254-282, Demography, Cohort study, discrimination
Abstract: Prospective validation of risk models is needed to assess their clinical utility, particularly over the longer term. We evaluated the performance of six commonly used breast cancer risk models (IBIS, BOADICEA, BRCAPRO, BRCAPRO-BCRAT, BCRAT, and iCARE-lit). 15-year risk scores were estimated using lifestyle factors and family history measures from 7608 women in the Melbourne Collaborative Cohort Study who were aged 50-65 years and unaffected at commencement of follow-up two (conducted in 2003-2007), of whom 351 subsequently developed breast cancer. Risk discrimination was assessed using the C-statistic and calibration using the expected/observed number of incident cases across the spectrum of risk by age group (50-54, 55-59, 60-65 years) and family history of breast cancer. C-statistics were higher for BOADICEA (0.59, 95% confidence interval (CI) 0.56-0.62) and IBIS (0.57, 95% CI 0.54-0.61) than the other models (p-difference �� 0.04). No model except BOADICEA calibrated well across the spectrum of 15-year risk (p-value < 0.03). The performance of BOADICEA and IBIS was similar across age groups and for women with or without a family history. For middle-aged Australian women, BOADICEA and IBIS had the highest discriminatory accuracy of the six risk models, but apart from BOADICEA, no model was well-calibrated across the risk spectrum., This work was primarily supported by grant 1129136 from the Australian National Health and Medical Research Council (NHMRC) (https://www.nhmrc.gov.au/). MCCS cohort recruitment was funded by Cancer Council Victoria (https://www.cancervic.org.au/) and VicHealth (https://www.vichealth.vic.gov.au/). The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383, and ongoing follow-up and data management has been funded by Cancer Council Victoria since 1995. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.TN-D is a recipient of a Career Development Fellowship from the National Breast Cancer Foundation (Australia). JLH and MCS are Senior Principal and Senior Research Fellows of the National Health and Medical Research Council (Australia), respectively. ACA and AJL are supported by grants from Cancer Research UK (C12292/A20861 and PPRPGM19 Nov20\100002).
Published: 2021

8. Should Age-Dependent Absolute Risk Thresholds Be Used for Risk Stratification in Risk-Stratified Breast Cancer Screening?

Author: Jennifer D. Brooks, Douglas F. Easton, Michel Dorval, Bartha Maria Knoppers, Andy C. H. Lee, Tracy Stockley, Hermann Nabi, Jocelyne Chiquette, Antonis C. Antoniou, Andrea Eisen, Nora Pashayan, Jacques Simard, Laurence Eloy, Michael Wolfson, Anna M. Chiarelli, Pashayan, Nora [0000-0003-0843-2468], Antoniou, Antonis C. [0000-0001-9223-3116], Stockley, Tracy L. [0000-0002-4476-9722], Brooks, Jennifer D. [0000-0001-7574-4256], Dorval, Michel [0000-0002-3207-8211], Apollo - University of Cambridge Repository, Antoniou, Antonis [0000-0001-9223-3116], Lee, Andrew [0000-0003-0677-0252], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis C [0000-0001-9223-3116], Stockley, Tracy L [0000-0002-4476-9722], and Brooks, Jennifer D [0000-0001-7574-4256]
Subjects: Medicine (miscellaneous), Age dependent, absolute risk, Article, 03 medical and health sciences, Breast cancer screening, 0302 clinical medicine, Breast cancer, Cancer screening, Medicine, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, business.industry, risk threshold, misclassification, Absolute risk reduction, risk-stratified screening, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, Risk stratification, Lifetime risk, Risk assessment, business, remaining lifetime risk, Demography
Abstract: In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual’s estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age, however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.
Published: 2021

9. Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models

Author: Sherly X. Li, Melissa C. Southey, Tu Nguyen-Dumont, Roger L. Milne, Graham G. Giles, Mary Beth Terry, John L. Hopper, Dallas R. English, Shuai Li, Robert J. MacInnis, Andrew Lee, Xiaochuan Wang, Antonis C. Antoniou, Ingrid Winship, Li, Sherly X [0000-0002-8696-8594], Milne, Roger L [0000-0001-5764-7268], Nguyen-Dumont, Tu [0000-0002-6217-0182], Southey, Melissa C [0000-0002-6313-9005], Lee, Andrew [0000-0003-0677-0252], Li, Shuai [0000-0002-7840-4051], and Apollo - University of Cambridge Repository
Subjects: Adult, Cancer Research, medicine.medical_specialty, Time Factors, Population, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Article, Breast cancer, Predictive Value of Tests, Risk Factors, Internal medicine, Confidence Intervals, medicine, Humans, Genetic Predisposition to Disease, Prospective Studies, Family history, Medical History Taking, Prospective cohort study, education, Life Style, Aged, Family Health, education.field_of_study, Models, Statistical, business.industry, Genetic Variation, Cancer, Middle Aged, medicine.disease, Confidence interval, Clinical research, Oncology, Female, AcademicSubjects/MED00010, business, Algorithms, Cohort study
Abstract: Background The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm and the International Breast Cancer Intervention Study breast cancer risk models are used to provide advice on screening intervals and chemoprevention. We evaluated the performance of these models, which now incorporate polygenic risk scores (PRSs), using a prospective cohort study. Methods We used a case-cohort design, involving women in the Melbourne Collaborative Cohort Study aged 50-75 years when surveyed in 2003-2007, of whom 408 had a first primary breast cancer diagnosed within 10 years (cases), and 2783 were from the subcohort. Ten-year risks were calculated based on lifestyle factors, family history data, and a 313-variant PRS. Discrimination was assessed using a C-statistic compared with 0.50 and calibration using the ratio of expected to observed number of cases (E/O). Results When the PRS was added to models with lifestyle factors and family history, the C-statistic (95% confidence interval [CI]) increased from 0.57 (0.54 to 0.60) to 0.62 (0.60 to 0.65) using IBIS and from 0.56 (0.53 to 0.59) to 0.62 (0.59 to 0.64) using BOADICEA. IBIS underpredicted risk (E/O = 0.62, 95% CI = 0.48 to 0.80) for women in the lowest risk category ( Conclusions Although the inclusion of a 313 genetic variant PRS doubles discriminatory accuracy (relative to reference 0.50), models with and without this PRS have relatively modest discrimination and might require recalibration before their clinical and wider use are promoted.
Published: 2021

10. Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

Author: Georgia Chenevix-Trench, Bernd Auber, Douglas F. Easton, Kristiina Aittomäki, Andy C. H. Lee, Ramunas Janavicius, Ana Vega, Paul D.P. Pharoah, Xin Yang, Liisa M. Pelttari, Malene Djursby, Eric Hahnen, Åke Borg, Mark E. Robson, Stephen B. Gruber, Susan J. Ramus, kConFab Investigators, Lisa Golmard, Ian Jacobs, Jill S. Dolinsky, Holly LaDuca, Karin Kast, Clare Turnbull, Fergus J. Couch, W. D. Foulkes, Thomas Hansen, Simon A. Gayther, Allan Jensen, Christoph Engel, Heli Nevanlinna, Ana Osorio, Jacek Gronwald, Judy Garber, Helen Hanson, Susanne K. Kjaer, Julie O. Culver, Goska Leslie, Ed Dicks, Honglin Song, Barbara Rivera, Richard S. Houlston, Anders Kvist, Estrid Høgdall, Antonis C. Antoniou, Dieter Niederacher, Nadia Traficante, Miguel de la Hoya, Rita K. Schmutzler, Alfons Meindl, Judit Horvath, Orland Diez, Adam N. Rosenthal, Laurent Castera, Chey Loveday, David D.L. Bowtell, Joe Dennis, Marc Tischkowitz, Susan M. Domchek, Judith Balmaña, Hans Ehrencrona, Usha Menon, Leslie, Goska [0000-0001-5756-6222], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Easton, Douglas [0000-0003-2444-3247], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Medicum, Research Programs Unit, Kristiina Aittomäki / Principal Investigator, HUSLAB, and Department of Medical and Clinical Genetics
Subjects: Oncology, Cancer Research, ASCERTAINMENT SAMPLING PROBLEM, 0302 clinical medicine, 3123 Gynaecology and paediatrics, Risk Factors, CONFER SUSCEPTIBILITY, Young adult, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, medicine.diagnostic_test, Articles, GERMLINE MUTATIONS, Middle Aged, 3. Good health, DNA-Binding Proteins, SUSCEPTIBILITY GENES, 030220 oncology & carcinogenesis, Female, AcademicSubjects/MED00010, Adult, medicine.medical_specialty, Heterozygote, Adolescent, Genetic counseling, 3122 Cancers, Breast Neoplasms, 03 medical and health sciences, Young Adult, Breast cancer, Internal medicine, medicine, Cancer Family, Humans, Genetic Predisposition to Disease, Genetic Testing, First-degree relatives, Genetic Association Studies, Germ-Line Mutation, 030304 developmental biology, Genetic testing, Aged, business.industry, Cancer, Complex segregation analysis, medicine.disease, BRCA2, MODEL, RESOLUTION, business
Abstract: Background The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. Methods We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. Results Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44–46% for BC, for carriers with two first-degree relatives diagnosed with BC. Conclusions These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.
Published: 2020

11. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

Author: Lee, Andrew, Mavaddat, Nasim, Wilcox, Amber N., Cunningham, Alex P., Carver, Tim, Hartley, Simon, Babb de Villiers, Chantal, Izquierdo, Angel, Simard, Jacques, Schmidt, Marjanka K., Walter, Fiona M., Chatterjee, Nilanjan, Garcia-Closas, Montserrat, Tischkowitz, Marc, Pharoah, Paul, Easton, Douglas F., Antoniou, Antonis C., Lee, Andrew [0000-0003-0677-0252], Mavaddat, Nasim [0000-0003-0307-055X], Cunningham, Alex [0000-0002-3737-9611], Babb, Chantal Louiza [0000-0003-1334-1819], Walter, Fiona [0000-0002-7191-6476], Tischkowitz, Marc [0000-0002-7880-0628], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Multifactorial Inheritance, Breast Neoplasms, Ataxia Telangiectasia Mutated Proteins, PRS, Polymorphism, Single Nucleotide, Risk Assessment, Article, risk prediction, breast cancer, Breast -- Cancer -- Prognosis, Risk Factors, Humans, Genetic Predisposition to Disease, Genetic Testing, BRCA2 Protein, Ovarian Neoplasms, BRCA1 Protein, Correction, rare variants, Checkpoint Kinase 2, rare-variants, Mutation, BOADICEA, Female, Mama -- Càncer -- Prognosi, Fanconi Anemia Complementation Group N Protein
Abstract: Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs). Methods BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information. Results Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17–
Published: 2019

12. Homeobox B13 G84E Mutation and Prostate Cancer Risk

Author: Nyberg, Tommy, Govindasami, Koveela, Leslie, Goska, Dadaev, Tokhir, Bancroft, Elizabeth, Ni Raghallaigh, Holly, Brook, Mark N, Hussain, Nafisa, Keating, Diana, Lee, Andrew, McMahon, Romayne, Morgan, Angela, Mullen, Andrea, Osborne, Andrea, Rageevakumar, Reshma, UK Genetic Prostate Cancer Study Collaborators, Kote-Jarai, Zsofia, Eeles, Rosalind, Antoniou, Antonis C, Nyberg, Tommy [0000-0002-9436-0626], Leslie, Goska [0000-0001-5756-6222], Lee, Andrew [0000-0003-0677-0252], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Genetic risk, Homeodomain Proteins, Male, Prostate cancer, Kin-cohort study, Age Factors, Prostatic Neoplasms, Risk Assessment, United Kingdom, Cohort Studies, Meta-analysis, Risk Factors, Mutation, Humans, HomeoboxB13, Medical History Taking
Abstract: BACKGROUND: The homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain. OBJECTIVE: To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. DESIGN, SETTING, AND PARTICIPANTS: Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort. RESULTS AND LIMITATIONS: A meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p
Published: 2018
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13. Evaluating clinician acceptability of the prototype CanRisk tool for predicting risk of breast and ovarian cancer: A multi-methods study

Author: Alex P Cunningham, Fiona Scheibl, Douglas F. Easton, Stephanie Archer, Fiona M Walter, Andrew Lee, Simon Hartley, Antonis C. Antoniou, Marc Tischkowitz, Jennifer McIntosh, Chantal Babb de Villiers, Tim Carver, Jon Emery, Archer, Stephanie [0000-0003-1349-7178], Babb de Villiers, Chantal [0000-0003-1334-1819], Hartley, Simon [0000-0001-7991-0581], Lee, Andrew [0000-0003-0677-0252], and Apollo - University of Cambridge Repository
Subjects: Male, GENETIC SUSCEPTIBILITY, Epidemiology, Engineering and technology, Geographical locations, User-Computer Interface, 0302 clinical medicine, Germany, SUPPORT, Breast Tumors, 030212 general & internal medicine, BOADICEA MODEL, Ovarian Neoplasms, Multidisciplinary, Cancer Risk Factors, Genomics, Middle Aged, Self Efficacy, 3. Good health, Multidisciplinary Sciences, Europe, England, Oncology, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Medicine, Female, Thematic analysis, Psychology, Research Article, Adult, Risk, General Science & Technology, Health Personnel, Science, MEDLINE, Breast Neoplasms, Genetic Counseling, Context (language use), Qualitative property, Simulated patient, 03 medical and health sciences, Breast cancer, Genomic Medicine, GENERAL-PRACTICE, Breast Cancer, Genetics, medicine, Humans, Prototypes, European Union, Primary Care, Clinical Genetics, Medicine and health sciences, Self-efficacy, Medical education, Science & Technology, Primary Health Care, Biology and life sciences, Cancers and Neoplasms, Human Genetics, medicine.disease, United Kingdom, Health Care, Technology Development, Vignette, Medical Risk Factors, People and places
Abstract: BACKGROUND: There is a growing focus on the development of multi-factorial cancer risk prediction algorithms alongside tools that operationalise them for clinical use. BOADICEA is a breast and ovarian cancer risk prediction model incorporating genetic and other risk factors. A new user-friendly Web-based tool (CanRisk.org) has been developed to apply BOADICEA. This study aimed to explore the acceptability of the prototype CanRisk tool among two healthcare professional groups to inform further development, evaluation and implementation. METHOD: A multi-methods approach was used. Clinicians from primary care and specialist genetics clinics in England, France and Germany were invited to use the CanRisk prototype with two test cases (either face-to-face with a simulated patient or via a written vignette). Their views about the tool were examined via a semi-structured interview or equivalent open-ended questionnaire. Qualitative data were subjected to thematic analysis and organised around Sekhon's Theoretical Framework of Acceptability. RESULTS: Seventy-five clinicians participated, 21 from primary care and 54 from specialist genetics clinics. Participants were from England (n = 37), France (n = 23) and Germany (n = 15). The prototype CanRisk tool was generally acceptable to most participants due to its intuitive design. Primary care clinicians were concerned about the amount of time needed to complete, interpret and communicate risk information. Clinicians from both settings were apprehensive about the impact of the CanRisk tool on their consultations and lack of opportunities to interpret risk scores before sharing them with their patients. CONCLUSIONS: The findings highlight the challenges associated with developing a complex tool for use in different clinical settings; they also helped refine the tool. This prototype may not have been versatile enough for clinical use in both primary care and specialist genetics clinics where the needs of clinicians are different, emphasising the importance of understanding the clinical context when developing cancer risk assessment tools.
Published: 2020

14. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: Olufunmilayo I. Olopade, Darcy L. Thull, Raanan Berger, Mary Beth Terry, Michel Longy, Timothy R. Rebbeck, Gord Glendon, Min Hyuk Lee, Javier Benitez, Mark T. Rogers, Mark H. Greene, Dezheng Huo, Adalgeir Arason, Carole Brewer, Siranoush Manoukian, Jackie Cook, Louise Izatt, Yuan Chun Ding, Dieter Niederacher, Nadine Tung, Sophie Giraud, Henriette Roed Nielsen, Antonis C. Antoniou, Bernhard H. F. Weber, Bruno Buecher, Goska Leslie, Amanda E. Toland, Anna Marie Mulligan, Ane Y. Schmidt, Noralane M. Lindor, Véronique Mari, Tara M. Friebel, Cecilia M. Dorfling, Ugnius Mickys, Lenka Foretova, Andrew K. Godwin, Bernd Dworniczak, Tsun Leung Chan, Monica Barile, Angela R. Solano, Susan J. Ramus, Laurence Faivre, Susan L. Neuhausen, Ana Peixoto, Julio Abugattas, Mattias Van Heetvelde, Jacqueline Eason, Muhammad Usman Rashid, Barbara Pasini, Henrique de Campos Reis Galvão, Heli Nevanlinna, Lucy Side, Nina Peruga, Marco Montagna, Amie Blanco, Alison H. Trainer, Cristina Zanzottera, Arjen R. Mensenkamp, Douglas F. Easton, Inge Søkilde Pedersen, Kenneth Offit, Judy Garber, Sook-Yee Yoon, Uffe Birk Jensen, Irene Konstantopoulou, Barbara Wappenschmidt, Stefanie Engert, Robert L. Nussbaum, Kai-ren Ong, Ros Eeles, Marinus J. Blok, Yael Laitman, Alex Teulé, Marion Gauthier-Villars, Daniel Barrowdale, Mads Thomassen, Torben A Kruse, Hanne Meijers-Heijboer, Abigail Thomas, Susan M. Domchek, Jacques Simard, Jamal Zidan, Paul A. James, Rob B. van der Luijt, Nina Ditsch, Annette Lee, Joseph Vijai, Kathleen R. Blazer, Elizabeth J. van Rensburg, János Papp, Lizet E. van der Kolk, Eitan Friedman, Pascal Pujol, Johanna Rantala, Patricia A. Ganz, Esther M. John, Conxi Lázaro, Jacek Gronwald, Paul Gesta, Jan Hauke, Simona Agata, Leo Auerbach, Paolo Radice, Fabienne Prieur, Beth Y. Karlan, Antoine De Pauw, Paolo Peterlongo, Sandrine M. Caputo, Sue K. Park, Marc Tischkowitz, Jocelyne Chiquette, Karin Kast, Annemieke H. van der Hout, Eric Hahnen, Grzegorz Sukiennicki, Debra Frost, Noura Mebirouk, Angel Izquierdo, Alex Henderson, Carolina Velázquez, Raymonda Varon-Mateeva, J. Margriet Collée, Soo-Hwang Teo, Esther Pohl, Rosa B. Barkardottir, Rita K. Schmutzler, Kim De Leeneer, Andrea Gehrig, D. Gareth Evans, Jeffrey N. Weitzel, Katherine L. Nathanson, Lesley McGuffog, Christoph Engel, Amanda B. Spurdle, Austin Miller, Edith Olah, Hans Ehrencrona, Almuth Caliebe, Zoltan Matrai, Ian G. Campbell, Christina G. Selkirk, Kirsten B. Moysich, Ella Asseryanis, Wendy K. Chung, Michael T. Parsons, Shan Wang-Gohrke, Thomas P. Slavin, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Christian F. Singer, Lesley Andrews, Jacopo Azzollini, Peter J. Hulick, Judith Balmaña, Anne-Marie Gerdes, Frans B. L. Hogervorst, Capucine Delnatte, Miguel de la Hoya, Katarzyna Kaczmarek, Angelica M. Gutierrez-Barrera, Claudine Isaacs, Lisa Walker, Doris Steinemann, Huu Phuc Nguyen, Anna von Wachenfeldt, Saundra S. Buys, Fabienne Lesueur, Kristin K. Zorn, Kerstin Rhiem, Manuel R. Teixeira, Linda Steele, Ava Kwong, Alfons Meindl, Evgeny N. Imyanitov, Giuseppe Giannini, Banu Arun, Vilius Rudaitis, Norbert Arnold, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Jacob Korach, Ana Vega, Nisha Pradhan, David E. Goldgar, Anna Jakubowska, Angela R. Bradbury, Cora M. Aalfs, kConFab Investigators, Lídia Feliubadaló, Annelie Liljegren, Ana Osorio, Sabine Topka, Julia Hentschel, Katie Snape, Fergus J. Couch, Ute Hamann, Anna Öfverholm, Edenir Inêz Palmero, Jacob Musinsky, Adriana Lasa, Silvia Tognazzo, Payal D. Shah, Drakoulis Yannoukakos, Valérie Bonadona, Laura Papi, Georgia Chenevix-Trench, Christi J. van Asperen, Hagay Sobol, Kristiina Aittomäki, Cristina Martínez-Bouzas, Jan Lubinski, Csilla Szabo, Joanne Ngeow, Hebon, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Christian Sutter, Yen Y. Tan, Trinidad Caldés, Rosemarie Davidson, Jenny Lester, Andreas Berger, Mark E. Robson, Jennifer T. Loud, Cynthia Villarreal-Garza, Eva Machackova, Leigha Senter, Irene L. Andrulis, Sandra Fert Ferrer, Diana Torres, Sung-Won Kim, Karolina Prajzendanc, Christine Lasset, Embrace, Jeffrey M. Fowler, Bernardo Bonanni, Bent Ejlertsen, Liliana Varesco, Orland Diez, Kathleen Claes, Leslie, Goska [0000-0001-5756-6222], Easton, Douglas [0000-0003-2444-3247], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Centre Léon Bérard [Lyon], Institut Curie [Paris], CRLCC René Gauducheau, Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Métropole Savoie [Chambéry], Centre Hospitalier Georges Renon [Niort] (CH Georges Renon Niort), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de génétique moléculaire des cancers d'Aquitaine, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Clinical Genetics, Human genetics, CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Fundações de Amparo à Pesquisa (Brasil), Research Foundation - Flanders, University of Helsinki, Sigrid Juselius Foundation, Dutch Cancer Society, Netherlands Organization for Scientific Research, Asociación Española Contra el Cáncer, Generalitat de Catalunya, Ministero della Salute, Istituto Oncologico Veneto, University of Tasmania, Australian Cancer Research Foundation, Ministry of Health and Welfare (South Korea), Charles University (Czech Republic), National Research Foundation Singapore, Russian Foundation for Basic Research, Istituto Toscano Tumori, Israel Cancer Association USA, Swedish Cancer Society, Foundation for Women's Cancer, University of Pittsburgh, Cancer Australia, American Cancer Society, The Ohio State University, National Institutes of Health (US), Cancer Research UK, European Commission, Canadian Institutes of Health Research, Department of Trade and Industry (UK), Susan G. Komen Foundation, Breast Cancer Research Foundation, Genome Canada, National Cancer Institute (US), Research Council of Lithuania, Cancer Association of South Africa, Consejo Nacional de Investigaciones Científicas y Técnicas (Argentina), Instituto de Salud Carlos III, Ministerio de Economía y Competitividad (España), Ministerio de Sanidad y Política Social (España), Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Ricerca sul Cancro, Ministero dell'Istruzione, dell'Università e della Ricerca, Institut Pasteur, Fondazione Cenci Bolognetti, Greek Government, Pontificia Universidad Javeriana, Royal Marsden NHS Foundation Trust, Kansas State University, Fundación Mutua Madrileña, Ligue Nationale contre le Cancer (France), Georgetown University, Human Genetics, Other departments, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, HEREDITARY BREAST, Mutation rate, Internationality, endocrine system diseases, Càncer d'ovari, Gene mutation, medicine.disease_cause, geography, Race (biology), 0302 clinical medicine, Breast cancer, FOUNDER MUTATIONS, Databases, Genetic, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], skin and connective tissue diseases, Genetics (clinical), Genetics, Mutation, medicine.diagnostic_test, Geography, RISK HISPANIC FAMILIES, BRCA1 Protein, 185DELAG MUTATION, GERMLINE MUTATIONS, 3. Good health, PROSTATE-CANCER, ovarian cancer, 030220 oncology & carcinogenesis, Medical genetics, ethnicity, BREAST-CANCER PATIENTS, BRCA1, BRCA2, breast cancer, mutation, medicine.medical_specialty, Biology, OVARIAN-CANCER, Article, Càncer de mama, BRCA2 Protein, Family, Humans, 03 medical and health sciences, Databases, Germline mutation, Genetic, Ovarian cancer, medicine, ddc:610, Genotyping, Genetic testing, PHENOTYPE ANALYSIS, BRCA1, BRCA2, Breast Cancer, HAPLOTYPE ANALYSIS, Mutació (Biologia), Mutation (Biology), 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics
Abstract: The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.
Published: 2018

15. Cost-effectiveness of Population-Based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 Mutation Testing in Unselected General Population Women

Author: Manchanda, Ranjit, Patel, Shreeya, Gordeev, Vladimir S, Antoniou, Antonis C, Smith, Shantel, Lee, Andrew, Hopper, John L, MacInnis, Robert J, Turnbull, Clare, Ramus, Susan J, Gayther, Simon A, Pharoah, Paul DP, Menon, Usha, Jacobs, Ian, Legood, Rosa, Antoniou, Antonis [0000-0001-9223-3116], Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, BRCA2 Protein, Ovarian Neoplasms, BRCA1 Protein, Cost-Benefit Analysis, Incidence, DNA Mutational Analysis, Breast Neoplasms, Middle Aged, Fanconi Anemia Complementation Group Proteins, United Kingdom, United States, Decision Support Techniques, Mutation, Humans, Female, Genetic Testing, Fanconi Anemia Complementation Group N Protein, RNA Helicases, Aged, Mammography
Abstract: Background: The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women. Methods: A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer. Results: Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million. Conclusions: Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.
Published: 2018
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16. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects

Author: Jervis, Sarah, Song, Honglin, Lee, Andrew, Dicks, Ed, Harrington, Patricia, Baynes, Caroline, Manchanda, Ranjit, Easton, Douglas F, Jacobs, Ian, Pharoah, Paul PD, Antoniou, Antonis C, Song, Honglin [0000-0001-5076-7371], Lee, Andrew [0000-0003-0677-0252], Dicks, Ed [0000-0002-0617-0401], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Ovarian Neoplasms, Multifactorial Inheritance, endocrine system diseases, Models, Genetic, Genes, BRCA2, Genes, BRCA1, Genetic screening/counselling, Genetic Counseling, Risk Assessment, Risk prediction, Ovarian Cancer, Cancer Genetics, Humans, Genetic epidemiology, Female, Genetic Predisposition to Disease, Genome-wide, skin and connective tissue diseases, Alleles
Abstract: BACKGROUND: Although BRCA1 and BRCA2 mutations account for only ∼27% of the familial aggregation of ovarian cancer (OvC), no OvC risk prediction model currently exists that considers the effects of BRCA1, BRCA2 and other familial factors. Therefore, a currently unresolved problem in clinical genetics is how to counsel women with family history of OvC but no identifiable BRCA1/2 mutations. METHODS: We used data from 1548 patients with OvC and their relatives from a population-based study, with known BRCA1/2 mutation status, to investigate OvC genetic susceptibility models, using segregation analysis methods. RESULTS: The most parsimonious model included the effects of BRCA1/2 mutations, and the residual familial aggregation was accounted for by a polygenic component (SD 1.43, 95% CI 1.10 to 1.86), reflecting the multiplicative effects of a large number of genes with small contributions to the familial risk. We estimated that 1 in 630 individuals carries a BRCA1 mutation and 1 in 195 carries a BRCA2 mutation. We extended this model to incorporate the explicit effects of 17 common alleles that are associated with OvC risk. Based on our models, assuming all of the susceptibility genes could be identified we estimate that the half of the female population at highest genetic risk will account for 92% of all OvCs. CONCLUSIONS: The resulting model can be used to obtain the risk of developing OvC on the basis of BRCA1/2, explicit family history and common alleles. This is the first model that accounts for all OvC familial aggregation and would be useful in the OvC genetic counselling process.
Published: 2015

17. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author: Lecarpentier, J., Silvestri, V., Kuchenbaecker, K.B., Barrowdale, D., Dennis, J., McGuffog, L., Soucy, P., Leslie, G., Rizzolo, P., Navazio, A.S., Valentini, V., Zelli, V., Lee, A., Olama, A.A. al, Tyrer, J.P., Southey, M., John, E.M., Conner, T.A., Goldgar, D.E., Buys, S.S., Janavicius, R., Steele, L., Ding, Y.C., Neuhausen, S.L., Hansen, T.V.O., Osorio, A., Weitzel, J.N., Toss, A., Medici, V., Cortesi, L., Zanna, I., Palli, D., Radice, P., Manoukian, S., Peissel, B., Azzollini, J., Viel, A., Cini, G., Damante, G., Tommasi, S., Peterlongo, P., Fostira, F., Hamann, U., Evans, D.G., Henderson, A., Brewer, C., Eccles, D., Cook, J., Ong, K.R., Walker, L., Side, L.E., Porteous, M.E., Davidson, R., Hodgson, S., Frost, D., Adlard, J., Izatt, L., Eeles, R., Ellis, S., Tischkowitz, M., Godwin, A.K., Meindl, A., Gehrig, A., Dworniczak, B., Sutter, C., Engel, C., Niederacher, D., Steinemann, D., Hahnen, E., Hauke, J., Rhiem, K., Kast, K., Arnold, N., Ditsch, N., Wang-Gohrke, S., Wappenschmidt, B., Wand, D., Lasset, C., Stoppa-Lyonnet, D., Belotti, M., Damiola, F., Barjhoux, L., Mazoyer, S., Heetvelde, M. van, Poppe, B., Leeneer, K. de, Claes, K.B.M., Hoya, M. de la, Garcia-Barberan, V., Caldes, T., Perez Segura, P., Kiiski, J.I., Aittomaki, K., Khan, S., Nevanlinna, H., Asperen, C.J. van, Vaszko, T., Kasler, M., Olah, E., Balmana, J., Gutierrez-Enriquez, S., Diez, O., Teule, A., Izquierdo, A., Darder, E., Brunet, J., Valle, J. del, Feliubadalo, L., Pujana, M.A., Lazaro, C., Arason, A., Agnarsson, B.A., Johannsson, O.T., Barkardottir, R.B., Alducci, E., Tognazzo, S., Montagna, M., Teixeira, M.R., Pinto, P., Spurdle, A.B., Holland, H., Lee, J.W., Lee, M.H., Lee, J., Kim, S.W., Kang, E., Kim, Z., Sharma, P., Rebbeck, T.R., Vijai, J., Robson, M., Lincoln, A., Musinsky, J., Gaddam, P., Tan, Y.Y., Berger, A., Singer, C.F., Loud, J.T., Greene, M.H., Mulligan, A.M., Glendon, G., Andrulis, I.L., Toland, A.E., Senter, L., Bojesen, A., Nielsen, H.R., Skytte, A.B., Sunde, L., Jensen, U.B., Pedersen, I.S., Krogh, L., Kruse, T.A., Caligo, M.A., Yoon, S.Y., Teo, S.H., Wachenfeldt, A. von, Huo, D., Nielsen, S.M., Olopade, O.I., Nathanson, K.L., Domchek, S.M., Lorenchick, C., Jankowitz, R.C., Campbell, I., James, P., Mitchell, G., Orr, N., Park, S.K., Thomassen, M., Offit, K., Couch, F.J., Simard, J., Easton, D.F., Chenevix-Trench, G., Schmutzler, R.K., Antoniou, A.C., Ottini, L., EMBRACE, GEMO Study Collaborators, HEBON, KConFab Investigators, Dennis, Joe [0000-0003-4591-1214], Leslie, Goska [0000-0001-5756-6222], Lee, Andrew [0000-0003-0677-0252], Amin Al Olama, Ali [0000-0002-7178-3431], Tyrer, Jonathan [0000-0003-3724-4757], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Adult, Aged, 80 and over, Male, Heterozygote, Multifactorial Inheritance, Genes, BRCA2, Age Factors, Genes, BRCA1, Prostatic Neoplasms, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Breast Neoplasms, Male, Case-Control Studies, Mutation, Humans, Genetic Predisposition to Disease, Genetic Testing, skin and connective tissue diseases, Aged, Genome-Wide Association Study
Abstract: $\textbf{Purpose}$ $\textit{BRCA1/2}$ mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of $\textit{BRCA1/2}$ mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of $\textit{BRCA1/2}$ mutations and implications for cancer risk prediction. $\textbf{Materials and Methods}$ We genotyped 1,802 male carriers of $\textit{BRCA1/2}$ mutations from the Consortium of Investigators of Modifiers of $\textit{BRCA1/2}$ by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of $\textit{BRCA1/2}$ mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. $\textbf{Results}$ In male carriers of $\textit{BRCA1/2}$ mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; $P$ = 8.6 × 10$^{-6}$)). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; $P$ = 3.2 × 10$^{-9}$)). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of $\textit{BRCA1}$ mutations and from 19% to 61% for carriers of $\textit{BRCA2}$ mutations, respectively. $\textbf{Conclusion}$ PRSs may provide informative cancer risk stratification for male carriers of $\textit{BRCA1/2}$ mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
Published: 2017

18. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Author: Zuber, V, Bettella, F, Witoelar, A, Andreassen, OA, Mills, IG, Urbanucci, A, Eeles, R, Easton, D, Kote-Jarai, Z, Al Olama, AA, Benlloch, S, Muir, K, Giles, GG, Wiklund, F, Gronberg, H, Haiman, CA, Schleutker, J, Weischer, M, Travis, RC, Neal, D, Pharoah, P, Khaw, KT, Stanford, JL, Blot, WJ, Thibodeau, S, Maier, C, Kibel, AS, Cybulski, C, Cannon-Albright, L, Brenner, H, Park, J, Kaneva, R, Batra, J, Teixeira, MR, Pandha, H, Chenevix-Trench, G, Humphreys, M, Hung, RJ, Han, Y, Brennan, P, Bickeböller, H, Rosenberger, A, Houlston, RS, Caporaso, N, Landi, MT, Heinrich, J, Risch, A, Wu, X, Ye, Y, Christiani, DC, Amos, CI, Easton, DF, Michailidou, K, Bolla, MK, Wang, Q, Berchuck, A, Antoniou, A, McGuffog, L, Couch, F, Offit, K, Dennis, J, Dunning, AM, Lee, A, Dicks, E, Luccarini, C, Benitez, J, Gonzalez-Neira, A, Simard, J, Tessier, DC, Bacot, F, Vincent, D, LaBoissière, S, Zuber, Verena [0000-0001-9827-1877], Pharoah, Paul [0000-0001-8494-732X], Khaw, Kay-Tee [0000-0002-8802-2903], Easton, Douglas [0000-0003-2444-3247], Wang, Jean [0000-0002-9139-0627], Antoniou, Antonis [0000-0001-9223-3116], Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Dicks, Ed [0000-0002-0617-0401], and Apollo - University of Cambridge Repository
Subjects: risk loci, schizophrenia, breast cancer risk, super-enhancer, genome-wide association studies, BRD4, chromatin, functional annotation, prostate cancer risk, SNPs
Abstract: $\textbf{Background:}$ Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding sites to chromatin have been used to inform functional annotations of SNPs. $\textbf{Results:}$ Here we establish criteria for enhancer mapping which are applicable to other diseases and traits to achieve the optimal tissue-specific enrichment of PC risk SNPs. We used stratified Q-Q plots and Fisher test to assess the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC) and applied to other diseases such as schizophrenia. $\textbf{Conclusions:}$ This is the first study to evaluate the enrichment of epigenetic readers in genome-wide associations studies for SNPs within enhancers, and provides a powerful tool for enriching and prioritizing PC and BC genetic risk loci. Our study represents a proof of principle applicable to other diseases and traits that can be used to redefine molecular mechanisms of human phenotypic variation.
Published: 2017
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19. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author: Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract: The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).
Published: 2017

20. Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

Author: Kuchenbaecker, KB, McGuffog, L, Barrowdale, D, Lee, A, Soucy, P, Dennis, J, Domchek, SM, Robson, M, Spurdle, AB, Ramus, SJ, Mavaddat, N, Terry, MB, Neuhausen, SL, Schmutzler, RK, Simard, J, Pharoah, PDP, Offit, K, Couch, FJ, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Mavaddat, Nasim [0000-0003-0307-055X], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: genome-wide association study, endocrine system diseases, diagnosis, brca2 mutation, brca1 protein, receptors, cancer risk, estrogen receptor negative, brca1, brca2 gene, breast cancer, ovarian cancer, single nucleotide polymorphism, estrogen, mutation, genes, breast
Abstract: $\textbf{Background:}$ Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes $\textit{BRCA1}$ or $\textit{BRCA2}$. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. $\textbf{Methods:}$ We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through populationbased GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female $\textit{BRCA1}$ and 8211 $\textit{BRCA2}$ carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. $\textbf{Results:}$ The PRS for ER-negative BC displayed the strongest association with BC risk in $\textit{BRCA1}$ carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, $P$ = 8.2 $\times$ 10$^{-53}$). In $\textit{BRCA2}$ carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, $P$ = 7.2 $\times$ 10$^{-20}$). The OC PRS was strongly associated with OC risk for both $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom AR deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for $\textit{BRCA2}$ carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. $\textbf{Conclusions:}$ BC and OC PRS are predictive of cancer risk in $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management., Cancer Research UK
Published: 2017
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21. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

Author: Mark A. Jenkins, Steven Gallinger, John D. Potter, Noralane M. Lindor, Antonis C. Antoniou, Christophe Rosty, Robert J. MacInnis, Daniel D. Buchanan, Andy C. H. Lee, Loc Le Marchand, Graham Casey, Yingye Zheng, Aung Ko Win, Graham G. Giles, James G. Dowty, Polly A. Newcomb, John L. Hopper, Dennis J. Ahnen, Mark Clendenning, Robert W. Haile, Stephen N. Thibodeau, Antoniou, Antonis [0000-0001-9223-3116], Lee, Andrew [0000-0003-0677-0252], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Adult, Male, Multifactorial Inheritance, Epidemiology, Population, Penetrance, Biology, MLH1, DNA Mismatch Repair, Article, DNA Glycosylases, 03 medical and health sciences, 0302 clinical medicine, MUTYH, Risk Factors, medicine, PMS2, Prevalence, Humans, Genetic Predisposition to Disease, education, Aged, Genetics, education.field_of_study, Cancer, Middle Aged, medicine.disease, Lynch syndrome, MSH6, 030104 developmental biology, Oncology, MSH2, 030220 oncology & carcinogenesis, Population Surveillance, Mutation, Female, Colorectal Neoplasms, MutL Protein Homolog 1
Abstract: Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.
Published: 2017
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22. Association analysis identifies 65 new breast cancer risk loci

Author: Michael Jones, Dong-Young Noh, Martha J. Shrubsole, Chen-Yang Shen, Xiaoqing Chen, Esther M. John, Patricia Harrington, Quinten Waisfisz, Sue K. Park, Miriam Dwek, Christa Stegmaier, Sibylle Loibl, Wing-Yee Lo, Suleeporn Sangrajrang, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Christof Sohn, Keun-Young Yoo, Arja Jukkola-Vuorinen, Kathrin Thöne, James McKay, John J. Spinelli, Brian D. Carter, Elza Khusnutdinova, Francois Bacot, Paul L. Auer, Anna H. Wu, Christopher I. Amos, Johanna I. Kiiski, Hans Wildiers, Manjeet K. Bolla, Soo Hwang Teo, Julie M. Cunningham, Zhaoming Wang, Dieter Flesch-Janys, Argyrios Ziogas, Ann Smeets, Min Hyuk Lee, Xiaohong R. Yang, Carl Blomqvist, Natalia Antonenkova, Vassilios Georgoulias, Siranoush Manoukian, Anne Lise Børresen-Dale, Montserrat Garcia-Closas, Priyanka Sharma, Michael J. Kerin, Loic Le Marchand, Yoshio Kasuga, Michael Untch, Thomas Brüning, Natalia Bogdanova, Juliet D. French, Mark E. Sherman, Diana Eccles, Don M. Conroy, Marcia Adams, Pascal Guénel, Jonine D. Figueroa, Somchai Thanasitthichai, Jonathan Beesley, Paolo Peterlongo, Angela Cox, Graham G. Giles, Hans Christiansen, Irene L. Andrulis, Caroline Baynes, V. Shane Pankratz, Kristine Jones, Wei Zheng, Motoki Iwasaki, Rita K. Schmutzler, Julian Peto, Sara Margolin, Hedy S. Rennert, Hidemi Ito, Caroline Seynaeve, Jirong Long, Rachel Lloyd, Mark S. Goldberg, Javier Benitez, Børge G. Nordestgaard, Kathleen E. Malone, A. Heather Eliassen, Valerie Rhenius, Kristan J. Aronson, Maartje J. Hooning, Ursula Eilber, Christopher A. Haiman, Ji Yeob Choi, Jaana M. Hartikainen, Ian W. Brock, Barbara Burwinkel, Brigitte Rack, Mitul Shah, Matthias W. Beckmann, Belynda Hicks, Bernardo Bonanni, Alexander Hein, Leslie Bernstein, Christine L. Clarke, Emilie Cordina-Duverger, Sabine Behrens, Hoda Anton-Culver, Angela Brooks-Wilson, Bin Zhu, Gord Glendon, Banu Arun, José A. García-Sáenz, Jose Ignacio Arias Perez, Anne Grundy, Ans M.W. van den Ouweland, Nadege Presneau, Volker Arndt, Mikael Eriksson, Simon S. Cross, Craig Luccarini, Anthony J. Swerdlow, Veli-Matti Kosma, Hui Miao, Ming-Feng Hou, Hiroji Iwata, Christi J. van Asperen, Henrik Flyger, Jennifer Stone, Qin Wang, Penny Soucy, Heli Nevanlinna, Jane Heyworth, Shoichiro Tsugane, Annika Lindblom, Curtis Olswold, Trinidad Caldés, Laura Fachal, Ed Dicks, Shirley Hui, Katja Butterbach, Alison M. Dunning, Peter Devilee, Qiuyin Cai, Antonis C. Antoniou, Diether Lambrechts, Katarzyna Kaczmarek, Katri Pylkäs, Fredrick R. Schumacher, Arif B. Ekici, Aaron D. Norman, Jolanta Lissowska, Daniel C. Tessier, N Hamel, Paolo Radice, Håkan Olsson, Vessela N. Kristensen, Ling Tong, Harald Surowy, Rulla M. Tamimi, Jonathan Tyrer, Michael P. Lux, Stacey L. Edwards, Kathryn J. Ruddy, Giske Ursin, Myrto Barrdahl, Xiao-Ou Shu, Primitiva Menéndez, Sara Y. Brucker, Elad Ziv, Kenneth Muir, Eric Hahnen, Andy C. H. Lee, Rodney J. Scott, Lothar Haeberle, Darya Prokofyeva, Isabel dos-Santos-Silva, Peter Kraft, David G. Cox, Jong Won Lee, Sunil R. Lakhani, Kelly-Anne Phillips, Douglas F. Easton, Melissa C. Southey, Jan Lubinski, Jose E. Castelao, Hanne Meijers-Heijboer, Ivana Maleva Kostovska, Siddhartha Kar, Renske Keeman, Celine M. Vachon, Diana Torres, Stephen J. Chanock, Jack A. Taylor, Emiel J. Th. Rutgers, Chuen Neng Lee, Jason Vollenweider, Gadi Rennert, Jane Romm, Amy E. McCart Reed, Kee Seng Chia, Thomas Rüdiger, Anja Rudolph, Catriona McLean, David Van Den Berg, Christopher G. Scott, Mervi Grip, Lucy Xia, Georgia Chenevix-Trench, Robert Winqvist, Mary Beth Terry, Jenny Chang-Claude, Hans-Ulrich Ulmer, Mikael Hartman, Dona N. Ho, Maria Kabisch, Christoph Engel, Claire Mulot, Grethe I. Grenaker Alnæs, Arto Mannermaa, Nazneen Rahman, Tjoung-Won Park-Simon, Atocha Romero, Lin Fritschi, Manuela Gago-Dominguez, Matthias Ruebner, Valerie Gaborieau, Keitaro Matsuo, Asha Rostamianfar, Emmanouil Saloustros, Dijana Plaseska-Karanfilska, J.-P. Meyer, Sara Lindström, Annegien Broeks, Audrey Lemaçon, Tsun Leung Chan, Tongguang Cheng, Robert J. MacInnis, Habibul Ahsan, Federico Canzian, Paul Brennan, Mia M. Gaudet, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Jacek Gronwald, Sung-Won Kim, Daehee Kang, Daniel O. Stram, Nichola Johnson, Rob B. van der Luijt, Sten Cornelissen, Camilla Wendt, Dylan M. Glubb, Olufunmilayo I. Olopade, Usha Menon, David J. Hunter, Kristiina Aittomäki, Jamie Allen, Chiu-Chen Tseng, Keith Humphreys, Edmond S. K. Ma, Peter Hillemanns, Hiltrud Brauch, Chia-Ni Hsiung, Sheila Seal, Junko Ishiguro, Dale P. Sandler, Peter Schürmann, Gary D. Bader, Sarah Stewart-Brown, Flavio Lejbkowicz, Marike Gabrielson, Wolfgang Janni, Judith S. Brand, Jingmei Li, Ava Kwong, Stig E. Bojesen, Ying Zheng, Mila Pinchev, Yu Tang Gao, Susan E. Hankinson, Elinor J. Sawyer, Per Broberg, Sofia Khan, Grace Sheng, Alfons Meindl, Margriet Collée, Jyh-Cherng Yu, Ute Krüger, Louise A. Brinton, Elizabeth W. Pugh, Thilo Dörk, Hilary K. Finucane, Peter A. Fasching, Shan Wang-Gohrke, Jenna Lilyquist, Muriel A. Adank, Marjanka K. Schmidt, Susan M. Gapstur, Sune F. Nielsen, Maya Ghoussaini, Minouk J. Schoemaker, Roger L. Milne, Jacques Simard, Clarice R. Weinberg, Kyriaki Michailidou, Shivaani Mariapun, Rob A. E. M. Tollenaar, Lizet E. van der Kolk, Nicola Miller, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Ross L. Prentice, Anna Marie Mulligan, Jason S. Carroll, Taiki Yamaji, Carolina Ellberg, Mingajeva Elvira, Olivia Fletcher, Arnaud Droit, Per Hall, Maria Elena Martinez, Maria Tengström, Hui Cai, Xia Jiang, Janet E. Olson, Julia A. Knight, Nick Orr, Angel Carracedo, Guanmengqian Huang, Martine Dumont, Cheng Har Yip, Tom Maishman, Mary B. Daly, Artitaya Lophatananon, Niclas Håkansson, Steven N. Hart, Nur Aishah Taib, Andreas Schneeweiss, Daniel F. Schmidt, Daniel Vincent, Antoinette Hollestelle, Dimitrios Mavroudis, JoAnn E. Manson, Joe Dennis, Walter C. Willett, Rudolf Kaaks, Karen McCue, Enes Makalic, Kimberly F. Doheny, Eunjung Lee, Robert N. Hoover, Fergus J. Couch, Ute Hamann, Alice S. Whittemore, Hermann Brenner, Lorraine Durcan, Kamila Czene, Patrick Neven, John L. Hopper, Clinical Genetics, Medical Oncology, Human Genetics, CCA - Cancer biology and immunology, Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Tyrer, Jonathan [0000-0003-3724-4757], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Allen, Jamie [0000-0002-8677-2225], Fachal Vilar, Laura [0000-0002-7256-9752], Carroll, Jason [0000-0003-3643-0080], Rhenius, Valerie [0000-0003-4215-3235], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Multifactorial Inheritance, Genome-wide association study, Regulatory Sequences, Nucleic Acid, skin and connective tissue diseases, Cancer genetics, Genetics, Multidisciplinary, medicine.diagnostic_test, 3. Good health, Europe, annotation, Medical genetics, Female, Asian Continental Ancestry Group, medicine.medical_specialty, Asia, architecture, European Continental Ancestry Group, ABCTB Investigators, Locus (genetics), Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, White People, NBCS Collaborators, 03 medical and health sciences, Breast cancer, Asian People, SDG 3 - Good Health and Well-being, Genetic variation, ConFab/AOCS Investigators, expression, medicine, Genetic predisposition, Journal Article, Humans, Computer Simulation, Genetic Predisposition to Disease, biological pathways, Genetic association, Genetic testing, Genetic association study, Binding Sites, interaction networks, medicine.disease, comprehensive molecular portraits, mutations, susceptibility loci, 030104 developmental biology, Genetic Loci, genome-wide association, protein, Transcription Factors, Genome-Wide Association Study
Abstract: Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P
Published: 2017

23. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers

Author: Katja Butterbach, Daniel C. Tessier, Dennis J. Hazelett, Stephen J. Chanock, Paul Brennan, Zhaoming Wang, Marc T. Goodman, Ali Amin Al Olama, Daniela Seminara, Tracy A. O'Mara, Craig Luccarini, Lesley McGuffog, David Van Den Berg, Andy C. H. Lee, James McKay, Stephen B. Gruber, Sue K. Park, Jack A. Taylor, Graham G. Giles, Michael F. Seldin, Alison M. Dunning, Zsofia Kote-Jarai, Sara Lindström, David E. Goldgar, Irene Brüske-Hohlfeld, Stig E. Bojesen, Paul D.P. Pharoah, Jonathan Marchini, Rosalind A. Eeles, Karoline Kuchenbaecker, Laura Fachal, Penny Soucy, Rayjean J. Hung, Ahsan Kamal, Marjorie J. Riggan, Xiangjun Xiao, Fergus J. Couch, Francois Bacot, Georgia Chenevix-Trench, John K. Field, Amanda B. Spurdle, Christopher A. Haiman, Julie M. Cunningham, Andrew Berchuck, Fredrick R. Schumacher, Elizabeth M. Gillanders, Simon A. Gayther, Belynda Hicks, Laura Ottini, David J. Hunter, Peter Kraft, Charlisse Caga-Anan, Jane Romm, Sylvie Laboissiere, Heike Bickeböller, Catherine M. Phelan, Jacques Simard, Graham Casey, Stephanie L. Schmit, Yafang Li, Sune F. Nielsen, Thomas A. Sellers, Hua Ling, Christopher K. Edlund, Yongyong Shi, Liesel M. FitzGerald, Stefanie A. Nelson, Rita K. Schmutzler, Gerhard A. Coetzee, Linda E. Kelemen, Kimberly F. Doheny, Elizabeth W. Pugh, Antonis C. Antoniou, Melanie Waldenberger, Judith L. Forman, Angela Risch, Ulrike Peters, Joe Dennis, David V. Conti, Daniel Vincent, Stephen Demetriades, Jinyoung Byun, Sara Benlloch, Tameka Shelford, Hongbing Shen, Douglas F. Easton, Mads Thomassen, Marcia Adams, Christopher I. Amos, Kenneth Offit, Kyriaki Michailidou, Judith Manz, Deborah J. Thompson, Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Fachal Vilar, Laura [0000-0002-7256-9752], Lee, Andrew [0000-0003-0677-0252], Thompson, Deborah [0000-0003-1465-5799], Amin Al Olama, Ali [0000-0002-7178-3431], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Male, 0301 basic medicine, epistasis, genetic epidemiology, Genotype, Epidemiology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Genetic Predisposition to Disease/epidemiology, Genetic variation, Mendelian randomization, Prevalence, Humans, cancer, Genetic Predisposition to Disease, Selection, Genetic, Genotyping, Genetics, ancestry, Genetic Variation, Polymorphism, Single Nucleotide/genetics, Prognosis, Genetic architecture, 3. Good health, 030104 developmental biology, Genetic Variation/genetics, Oncology, 030220 oncology & carcinogenesis, OncoArray Consortium, genetic architecture, cancers, Genome-Wide Association Study/methods, Female, DNA microarray, Neoplasms/epidemiology, Genome-Wide Association Study, genetic susceptibility
Abstract: Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (C.I. Amos, J. Byun, Y. Li, X. Xiao, J. L. Forman, A. Risch, H. Bickeböller, M. Waldenberger, I. Brüske, J. Manz, P. Brennan, R. Hung, H. Shen, Y. Shi, A. Kamal, C. I. Amos, J.K. Field), Canadian Cancer Society Research Institute (no. 020214, R. Hung). DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065 (D.J. Hazelett, D. F. Easton, S. Lindström, P. Kraft, J. Dennis, A. Dunning, K. Michailidou, L. Fachal, S. Benlloch, J. Cunningham, K. Butterbach, K. Offit, R. Schmutzler, L. Ottini, D. Vincent). CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089 (S. Gruber, U. Peters, G. Casey). ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by U19 CA148537(F. Schumacher, S.A. Gayther, S.L. Schmit, C.K. Edlund, D.J. Hazelett, G.A. Coetzee, C. Haiman, S. Demetriades, D. Van Den Berg). FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112- 01 (T.A. Sellers, C. Phelan), R01-CA122443(B. Hicks) ) P50-CA116201, CA192393 (F. Couch), P50-CA136393(J. Cunningham, F. Couch), OCAC - CA-149429 (C. Phelan). , P30-CA15083 (B. Hicks), Cancer Research UK (C490/A8339(A. Antoniou, P. Pharoah, A. Dunning), C490/A16561(P. Pharoah, A. Dunning), C490/A10119 (A. Dunning, P. Pharoah), C490/A10124 (A. Dunning, P. Pharoah)). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC) (F. Bacot). DACHS: German Research Council (Deutsche Downloaded from cebp.aacrjournals.org on October 31, 2016. © 2016 American Association for Cancer Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 3, 2016; DOI: 10.1158/1055-9965.EPI-16-0106 Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1, C.K. Edlund), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Prostate Lung Colon Ovarian Screening trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: R. Schmutzler, Cologne). The PERSPECTIVE (J. Simard) project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (MOP-86727, L.E. Kelemen), the Ministère de l’Économie, Innovation et Exportation du Québec through Genome Québec, and thee Quebec Breast Cancer Foundation, including additional funding from the Canadian Breast Cancer Foundation and the National Cancer Institute USA through Breast Cancer Family Registry Cohort (#1UM1CA164920-01A1). European Union Framework Programme for Research and Innovation (MSCA-IF-2014-EF-656144)(L. Fachal). The Breast Cancer Research Foundation, P30 CA08748, Andrew Sabin Foundation (K. Offit). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I to K.Doheny and through grant 1X01HG007491- 01 to C.I. Amos. This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-0106
Published: 2016

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

Author: Sten Cornelissen, Richard van Hien, Muriel A. Adank, Argyrios Ziogas, Amy Trentham-Dietz, Frans B. L. Hogervorst, Hiltrud Brauch, Alison M. Dunning, Qin Wang, Stig E. Bojesen, Natalia Bogdanova, Hoda Anton-Culver, Sara Margolin, Elza Khusnutdinova, Marjanka K. Schmidt, Elinor J. Sawyer, Kenneth Offit, Lothar Haeberle, Veli-Matti Kosma, Natalia Antonenkova, Taru A. Muranen, Heli Nevanlinna, Polly A. Newcomb, Manjeet K. Bolla, Mieke Schutte, Vessela N. Kristensen, Andy C. H. Lee, Melissa C. Southey, Jenny Chang-Claude, Douglas F. Easton, Marina Bermisheva, Henrik Flyger, Lizet E. van der Kolk, Antonis C. Antoniou, Anna Jakubowska, Paul D.P. Pharoah, Ans M.W. van den Ouweland, Jan Lubinski, Angela Cox, Maartje J. Hooning, Graham G. Giles, Rita K. Schmutzler, Julian Peto, Anthony J. Swerdlow, Volker Arndt, Thilo Dörk, Barbara Burwinkel, Harald Surowy, Ian Tomlinson, Celine M. Vachon, Peter Hillemanns, Mark E. Robson, Michael Jones, Roger L. Milne, Esther M. John, Olivia Fletcher, Julie Soens, Per Hall, Quinten Waisfisz, Jonine D. Figueroa, Julia A. Knight, Rob A. E. M. Tollenaar, Irene L. Andrulis, Annika Lindblom, Annegien Broeks, Alfons Meindl, Peter A. Fasching, Montserrat Garcia-Closas, Georgia Chenevix-Trench, Thomas Brüning, Alice S. Whittemore, Caroline M. Seynaeve, Tjoung-Won Park-Simon, Eva Galle, Hermann Brenner, Hanne Meijers, Amanda B. Spurdle, Antoinette Hollestelle, Kamila Czene, Anja Rudolph, John L. Hopper, Arto Mannermaa, Simon S. Cross, Fergus J. Couch, Human genetics, CCA - Cancer biology, Antoniou, Antonis [0000-0001-9223-3116], Dunning, Alison [0000-0001-6651-7166], Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], Wang, Jean [0000-0002-9139-0627], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Clinical Genetics, and Medical Oncology
Subjects: 0301 basic medicine, Oncology, Cancer Research, Estrogen receptor, Disease, 0302 clinical medicine, Receptors, 80 and over, Odds Ratio, 2.1 Biological and endogenous factors, Aetiology, skin and connective tissue diseases, Progesterone, Cancer, Sequence Deletion, Aged, 80 and over, education.field_of_study, Homozygote, Age Factors, ORIGINAL REPORTS, Middle Aged, 3. Good health, Receptors, Estrogen, 030220 oncology & carcinogenesis, Female, Risk assessment, Receptors, Progesterone, Adult, medicine.medical_specialty, Heterozygote, Clinical Sciences, Oncology and Carcinogenesis, Population, Breast Neoplasms, Risk Assessment, 03 medical and health sciences, Breast cancer, SDG 3 - Good Health and Well-being, Clinical Research, Internal medicine, Breast Cancer, Genetics, medicine, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, education, CHEK2, Aged, business.industry, Case-control study, Odds ratio, medicine.disease, Estrogen, Checkpoint Kinase 2, 030104 developmental biology, Case-Control Studies, business
Abstract: Purpose CHEK2*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 Methods CHEK2*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. Results Proportions 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. Conclusion These 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

25. Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families

Author: Nasim Mavaddat, Carl Blomqvist, Liisa M. Pelttari, Andy C. H. Lee, Douglas F. Easton, Heli Nevanlinna, Rainer Fagerholm, Taru A. Muranen, Kristiina Aittomäki, Sofia Khan, Department of Obstetrics and Gynecology, Clinicum, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Department of Oncology, HUS Gynecology and Obstetrics, Mavaddat, Nasim [0000-0003-0307-055X], Lee, Andrew [0000-0003-0677-0252], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Gerontology, Oncology, Multifactorial Inheritance, Cancer Research, Genotyping Techniques, LOCI, Disease, SUSCEPTIBILITY, PRS, Preclinical Study, 0302 clinical medicine, Breast cancer, 3123 Gynaecology and paediatrics, HISTORY, Medicine, Family history, skin and connective tissue diseases, MUTATION, Finland, WOMEN, Pedigree, 3. Good health, Hereditary, 030220 oncology & carcinogenesis, Female, Algorithms, Risk, EXPRESSION, medicine.medical_specialty, 3122 Cancers, Breast Neoplasms, 03 medical and health sciences, Internal medicine, Genetic variation, Humans, Genetic Predisposition to Disease, business.industry, Common variants, Case-control study, Genetic Variation, Odds ratio, medicine.disease, BRCA2, MODEL, 030104 developmental biology, Case-Control Studies, Polygenic risk score, business, Ovarian cancer
Abstract: The risk of developing breast cancer is increased in women with family history of breast cancer and particularly in families with multiple cases of breast or ovarian cancer. Nevertheless, many women with a positive family history never develop the disease. Polygenic risk scores (PRSs) based on the risk effects of multiple common genetic variants have been proposed for individual risk assessment on a population level. We investigate the applicability of the PRS for risk prediction within breast cancer families. We studied the association between breast cancer risk and a PRS based on 75 common genetic variants in 52 Finnish breast cancer families including 427 genotyped women and pedigree information on ~4000 additional individuals by comparing the affected to healthy family members, as well as in a case–control dataset comprising 1272 healthy population controls and 1681 breast cancer cases with information on family history. Family structure was summarized using the BOADICEA risk prediction model. The PRS was associated with increased disease risk in women with family history of breast cancer as well as in women within the breast cancer families. The odds ratio (OR) for breast cancer within the family dataset was 1.55 [95 % CI 1.26–1.91] per unit increase in the PRS, similar to OR in unselected breast cancer cases of the case–control dataset (1.49 [1.38–1.62]). High PRS-values were informative for risk prediction in breast cancer families, whereas for the low PRS-categories the results were inconclusive. The PRS is informative in women with family history of breast cancer and should be incorporated within pedigree-based clinical risk assessment. Electronic supplementary material The online version of this article (doi:10.1007/s10549-016-3897-6) contains supplementary material, which is available to authorized users.
Published: 2016

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

Author: Jirong Long, Simon S. Cross, Marc Tischkowitz, Beth Y. Karlan, Trinidad Caldés, Fergus J. Couch, Charlotte Sagne, Ute Hamann, Olga M. Sinilnikova, Maria Kabisch, Richard C Sallari, Gad Rennert, Daniel Barrowdale, Elinor J. Sawyer, Anthony J. Swerdlow, Jenny Lester, Åke Borg, Anders Bojesen, Rosa B. Barkardottir, Simon A. Gayther, Heli Nevanlinna, Judy Garber, Norbert Arnold, Vilde Drageset Haakensen, Vessela N. Kristensen, Christopher G. Scott, Daehee Kang, Gillian Mitchell, Eitan Friedman, Laura Ottini, Diether Lambrechts, Manjeet K. Bolla, Robert L. Nussbaum, Tomasz Huzarski, Dieter Niederacher, Angela Cox, Rachel Laframboise, Maartje J. Hooning, Volker Arndt, Penny Soucy, Marjanka K. Schmidt, William Blot, Soo Hwang Teo, Anne Lise Børresen-Dale, Maria A. Caligo, Ana Osorio, Orland Diez, Gertraud Maskarinec, Johanna Rantala, Kelly-Anne Phillips, Pascal Guénel, Hidemi Ito, Miquel Angel Pujana, Anna H. Wu, Christy G. Woolcott, Maya Ghoussaini, Hatef Darabi, Sander Canisius, Kay-Tee Khaw, Irene Konstantopoulou, Carl Blomqvist, Christine Rappaport, Joan Brunet, Hermann Brenner, Sylvie Mazoyer, Irene L. Andrulis, Nicholas A Sinnott-Armstrong, Javier Benitez, Claudine Isaacs, Mahdi Moradi Marjaneh, Joseph Vijai, Jennifer Stone, Qin Wang, Caroline Seynaeve, Patricia A. Ganz, Sara Margolin, Paolo Radice, Janet E. Olson, Soo-Chin Lee, Mark H. Greene, Laura Papi, Carmel Apicella, Ava Kwong, Mitul Shah, Matthias W. Beckmann, Yael Laitman, Hoda Anton-Culver, Ans M.W. van den Ouweland, Sue K. Park, Annegien Broeks, Georgia Chenevix-Trench, Jonathan Beesley, Nadja Bogdanova-Markov, Paolo Peterlongo, Paraskevi Apostolou, Bernardo Bonanni, Frederik Marmé, Veli-Matti Kosma, Alfons Meindl, Brian E. Henderson, Rulla M. Tamimi, Siranoush Manoukian, Bent Ejlertsen, Miroslav Kapuscinski, Juliet D. French, Mark E. Sherman, Ji Yeob Choi, Graham G. Giles, Stacey L. Edwards, Evgeny N. Imyanitov, Kamila Czene, Thomas Hansen, Nick Orr, Susanne Kaufmann, Lenka Foretova, Celine M. Vachon, Edith Olah, Anja Rudolph, Arto Mannermaa, Phuong L. Mai, Isabel dos-Santos-Silva, Haran Sivakumaran, Francesca Damiola, Christian F. Singer, Muhammad Usman Rashid, Ed Dicks, Mikael Hartman, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Douglas F. Easton, Alison M. Dunning, John L. Hopper, Nadine Tung, Annika Lindblom, Kristiina Aittomäki, Kenneth Muir, Sue Healey, Cheng Har Yip, Mads Thomassen, Melissa C. Southey, Ramunas Janavicius, Cecilia M. Dorfling, Christine B. Ambrosone, Siddhartha Kar, Mary B. Daly, Artitaya Lophatananon, Rachel Rando, Banu Arun, Christopher A. Haiman, Catherine M. Phelan, Margaret Hills, Manuel R. Teixeira, Diana Torres, Hans Wildiers, Andrew K. Godwin, Keith Humphreys, Katri Pylkäs, Monika Jarosz, Susan L. Neuhausen, Montserrat Garcia-Closas, Robert Winqvist, Joe Dennis, Sook-Yee Yoon, Wei Zheng, Mitch Dowsett, Gord Glendon, Natasha Bogdanova, Suleeporn Sangrajrang, Steve Ellis, Paul Brennan, Lee Eunjung, Keitaro Matsuo, Jacek Gronwald, David E. Goldgar, Debra Frost, Chiu-Chen Tseng, Henrik Flyger, Kristine M. Hillman, Susan M. Domchek, Elena Lopez-Knowles, Bernard Peissel, Anna von Wachenfeldt, Karoline Kuchenbaecker, Anna Jakubowska, Paul D.P. Pharoah, Jose Ignacio Arias Perez, Kim De Leeneer, Roger L. Milne, Peter A. Fasching, Louise Izatt, Saundra S. Buys, Lesley McGuffog, Elizabeth J. van Rensburg, Pei-Ei Wu, Peter Devilee, Åslaug Helland, Qiuyin Cai, Peter J. Hulick, Miguel de la Hoya, Esther M. John, Kerstin Rhiem, Jan Lubinski, Karen A. Pooley, Marion Piedmonte, Catherine S. Healey, Mark S. Goldberg, Xiao-Ou Shu, Antoinette Hollestelle, Mary Beth Terry, Jenny Chang-Claude, Silje Nord, Chen-Yang Shen, Hiltrud Brauch, Kathleen Claes, Jason Sang Hun Lee, Sofia Khan, Katherine L. Nathanson, Hans Ehrencrona, Olufunmilayo I. Olopade, Stig E. Bojesen, Matti A. Rookus, Andrew Lee, Rita K. Schmutzler, Julian Peto, Jeffrey N. Weitzel, Barbara Burwinkel, Arjen R. Mensenkamp, Jacques Simard, Yu-Tang Gao, Robert Luben, S. Drury, Thilo Dörk, Laima Tihomirova, Per Hall, Barbara Perkins, Simona Agata, Jonine D. Figueroa, Julia A. Knight, Kenneth Offit, Kyriaki Michailidou, Anna González-Neira, Ian Tomlinson, Thérèse Truong, Amanda E. Toland, Anna Marie Mulligan, Noralane M. Lindor, Deborah J. Thompson, Marco Montagna, Clinical Genetics, Medical Oncology, Obstetrics & Gynecology, Dunning, Alison [0000-0001-6651-7166], Thompson, Deborah [0000-0003-1465-5799], Pooley, Karen [0000-0002-1274-9460], Dicks, Ed [0000-0002-0617-0401], Dennis, Joe [0000-0003-4591-1214], Wang, Jean [0000-0002-9139-0627], Ghoussaini, Maya [0000-0002-2415-2143], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Luben, Robert [0000-0002-5088-6343], Khaw, Kay-Tee [0000-0002-8802-2903], Pharoah, Paul [0000-0001-8494-732X], Antoniou, Antonis [0000-0001-9223-3116], Easton, Douglas [0000-0003-2444-3247], Apollo - University of Cambridge Repository, Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), and [ 1 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge, England [ 2 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England [ 3 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld, Australia [ 4 ] Breakthrough Breast Canc Res Ctr, Breast Canc Res, London, England [ 5 ] Royal Marsden Hosp, Acad Biochem, London SW3 6JJ, England [ 6 ] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA [ 7 ] MIT, Comp Sci & Artificial Intelligence Lab, 77 Massachusetts Ave, Cambridge, MA 02139 USA [ 8 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands [ 9 ] Univ Melbourne, Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic, Australia [ 10 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 11 ] Univ Warwick, Warwick Med Sch, Div Hlth Sci, Coventry CV4 7AL, W Midlands, England [ 12 ] Univ Manchester, Inst Populat Hlth, Manchester, Lancs, England [ 13 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Gynecol & Obstet, Comprehens Canc Ctr Erlangen Nuremberg Metropolit, D-91054 Erlangen, Germany [ 14 ] Univ Calif Los Angeles, David Geffen Sch Med, Div Hematol & Oncol, Dept Med, Los Angeles, CA 90095 USA [ 15 ] London Sch Hyg & Trop Med, Dept Noncommunicable Dis Epidemiol, London WC1, England [ 16 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London, England [ 17 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England [ 18 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford, England [ 19 ] German Canc Res Ctr, Div Mol Genet Epidemiol, Heidelberg, Germany [ 20 ] German Canc Res Ctr, Mol Epidemiol Grp, Heidelberg, Germany [ 21 ] Heidelberg Univ, Natl Ctr Tumor Dis, Heidelberg, Germany [ 22 ] Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany [ 23 ] INSERM, Ctr Res Epidemiol & Populat Hlth, Environm Epidemiol Canc, Villejuif, France [ 24 ] Univ Paris Sud, Villejuif, France [ 25 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, Herlev, Denmark [ 26 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev, Denmark [ 27 ] Univ Copenhagen, Fac Hlth & Med Sci, Copenhagen, Denmark [ 28 ] Copenhagen Univ Hosp, Herlev Hosp, Dept Breast Surg, Herlev, Denmark [ 29 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Madrid, Spain [ 30 ] Hosp Monte Naranco, Serv Cirugia Gen & Especialidades, Oviedo, Spain [ 31 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA USA [ 32 ] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 33 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany [ 34 ] German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany [ 35 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-80290 Munich, Germany [ 36 ] Univ Hosp Cologne, Dept Obstet & Gynaecol, Div Mol Gynecooncol, Cologne, Germany [ 37 ] Univ Hosp Cologne, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 38 ] Univ Hosp, Ctr Integrated Oncol, Cologne, Germany [ 39 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, Stuttgart, Germany [ 40 ] Univ Tubingen, Tubingen, Germany [ 41 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany [ 42 ] Helsinki Univ Cent Hosp, Dept Clin Genet, Helsinki, Finland [ 43 ] Univ Helsinki, Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland [ 44 ] Aichi Canc Ctr Res Inst, Div Epidemiol & Prevent, Aichi, Japan [ 45 ] Aichi Canc Ctr Res Inst, Div Mol Med, Nagoya, Aichi, Japan [ 46 ] Hannover Med Sch, Radiat Oncol Res Unit, Hannover, Germany [ 47 ] Hannover Med Sch, Gynaecol Res Unit, Hannover, Germany [ 48 ] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden [ 49 ] Karolinska Univ Hosp, Dept Oncol Pathol, Stockholm, Sweden [ 50 ] Kuopio Univ Hosp, Ctr Canc, SF-70210 Kuopio, Finland [ 51 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Kuopio, Finland [ 52 ] Kuopio Univ Hosp, Dept Clin Pathol, Imaging Ctr, SF-70210 Kuopio, Finland [ 53 ] Vesalius Res Ctr, Leuven, Belgium [ 54 ] Univ Leuven, Dept Oncol, Lab Translat Genet, Leuven, Belgium [ 55 ] Univ Hosp Leuven, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, Leuven, Belgium [ 56 ] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany [ 57 ] Univ Med Ctr Hamburg Eppendorf, UCCH, Hamburg, Germany [ 58 ] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy [ 59 ] Fdn IRCCS Ist Nazl Tumori, Dept Prevent & Predict Med, Unit Mol Basis Genet Risk & Genet Testing, Milan, Italy [ 60 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA [ 61 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia [ 62 ] McGill Univ, Dept Med, Montreal, PQ, Canada [ 63 ] McGill Univ, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H3A 1A1, Canada [ 64 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia [ 65 ] Univ Malaya, Med Ctr, Canc Res Inst, Breast Canc Res Unit, Kuala Lumpur, Malaysia [ 66 ] Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Genet, Oslo, Norway [ 67 ] Univ Oslo, Inst Clin Med, Oslo, Norway [ 68 ] Univ Oslo, Oslo Univ Hosp, Dept Clin Mol Biol, Oslo, Norway [ 69 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA [ 70 ] Univ Oulu, NordLab Oulu Univ Hosp, Dept Clin Chem, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 71 ] Univ Oulu, NordLab Oulu Univ Hosp, Bioctr Oulu, Oulu, Finland [ 72 ] Northern Finland Lab Ctr NordLab, Lab Canc Genet & Tumor Biol, Oulu, Finland [ 73 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 74 ] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada [ 75 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 76 ] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Epidemiol, Toronto, ON, Canada [ 77 ] Leiden Univ Med Ctr, Dept Pathol, Leiden, Netherlands [ 78 ] Leiden Univ Med Ctr, Dept Human Genet, Leiden, Netherlands [ 79 ] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands [ 80 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA [ 81 ] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden [ 82 ] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands [ 83 ] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China [ 84 ] Univ Sheffield, Sheffield Canc Res, Dept Oncol, Sheffield, S Yorkshire, England [ 85 ] Univ Sheffield, Dept Neurosci, Acad Unit Pathol, Sheffield, S Yorkshire, England [ 86 ] Int Epidemiol Inst, Rockville, MD USA [ 87 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea [ 88 ] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul, South Korea [ 89 ] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea [ 90 ] Natl Univ Hlth Syst, Dept Haematol Oncol, Singapore, Singapore [ 91 ] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore [ 92 ] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore 117548, Singapore [ 93 ] Natl Univ Hlth Syst, Dept Surg, Singapore, Singapore [ 94 ] Pontificia Univ Javerianar, Inst Human Genet, Bogota, Colombia [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France [ 97 ] Natl Canc Inst, Bangkok, Thailand [ 98 ] Roswell Pk Canc Inst, Buffalo, NY 14263 USA [ 99 ] Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 100 ] China Med Univ, Sch Publ Hlth, Taichung, Taiwan [ 101 ] Acad Sinica, Inst Biomed Sci, Taiwan Biobank, Taipei, Taiwan [ 102 ] Inst Canc Res, Breakthrough Breast Canc Res Ctr, Div Canc Studies, London SW3 6JB, England [ 103 ] Inst Canc Res, Div Genet & Epidemiol, London SW3 6JB, England [ 104 ] Inst Canc Res, Div Breast Canc Res, London SW3 6JB, England [ 105 ] Univ Melbourne, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia [ 106 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA USA [ 107 ] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA [ 108 ] Fox Chase Canc Ctr, Dept Clin Genet, 7701 Burholme Ave, Philadelphia, PA 19111 USA [ 109 ] Univ Utah, Sch Med, Dept Dermatol, Huntsman Canc Inst, Salt Lake City, UT USA [ 110 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT USA [ 111 ] State Res Inst Ctr Innovat Med, Vilnius, Lithuania [ 112 ] 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Florence, Dept Biomed Expt & Clin Sci, Unit Med Genet, Florence, Italy [ 126 ] Univ Roma La Sapienza, Dept Mol Med, Piazzale Aldo Moro 5, I-00185 Rome, Italy [ 127 ] Aghia Paraskevi Attikis, Natl Ctr Sci Res Demokritos, INRASTES Inst Nucl & Radiol Sci & Technol, Mol Diagnost Lab, Athens, Greece [ 128 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02115 USA [ 129 ] Shaukat Khanum Mem Canc Hosp & Res Ctr, Dept Basic Sci, Lahore, Pakistan [ 130 ] Guys & St Thomas Natl Hlth Serv NHS Fdn Trust, Clin Genet, London, England [ 131 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66103 USA [ 132 ] Univ Kiel, Univ Hosp Schleswig Holstein, Dept Gynaecol & Obstet, Campus Kiel, Kiel, Germany [ 133 ] Univ Dusseldorf, Dusseldorf, Germany [ 134 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Dept Obstet & Gynaecol, Ctr Familial Breast & Ovarian Canc, Cologne, Germany [ 135 ] Univ Hosp Cologne, Ctr Mol Med Cologne, Ctr Integrated Oncol, Cologne, Germany [ 136 ] Univ Munster, Inst 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Dis, Perth, WA 6009, Australia [ 202 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 203 ] Harvard Univ, Sch Med, Boston, MA USA [ 204 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 205 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, 665 Huntington Ave, Boston, MA 02115 USA [ 206 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Clin Gerontol, Cambridge, England
Subjects: 0301 basic medicine, Genes, BRCA2, Estrogen receptor, MODIFIERS, Gene Expression, Genome-wide association study, Cell Cycle Proteins, DISEASE, Breast cancer, Risk Factors, Brjóstakrabbamein, BRCA2 MUTATION CARRIERS, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], SUSCEPTIBILITY LOCUS, MAMMOGRAPHIC DENSITY, Regulation of gene expression, Genetics, Research Support, Non-U.S. Gov't, Estrogen Receptor alpha/genetics, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Medical genetics, Chromosomes, Human, Pair 6, Female, BONE-MINERAL DENSITY, NAF12, Protein Binding, EXPRESSION, medicine.medical_specialty, Locus (genetics), Breast Neoplasms, Estrògens, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Research Support, N.I.H., Extramural, SDG 3 - Good Health and Well-being, REVEALS, medicine, Journal Article, cancer, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, breast, Genetic Association Studies, Base Sequence, Estrogen Receptor alpha, Genetic Variation, Arfgengi, medicine.disease, Estrogen, 030104 developmental biology, breast cancer, BRCA1, BRCA2, Carrier Proteins, Estrogen receptor alpha, Research Support, U.S. Gov't, Non-P.H.S, Meta-Analysis
Abstract: To access publisher's full text version of this article click on the hyperlink at the bottom of the page We analyzed 3,872 common genetic variants across the ESR1 locus (encoding estrogen receptor α) in 118,816 subjects from three international consortia. We found evidence for at least five independent causal variants, each associated with different phenotype sets, including estrogen receptor (ER(+) or ER(-)) and human ERBB2 (HER2(+) or HER2(-)) tumor subtypes, mammographic density and tumor grade. The best candidate causal variants for ER(-) tumors lie in four separate enhancer elements, and their risk alleles reduce expression of ESR1, RMND1 and CCDC170, whereas the risk alleles of the strongest candidates for the remaining independent causal variant disrupt a silencer element and putatively increase ESR1 and RMND1 expression. National Institute for Health Research (NIHR) info:eu-repo/grantAgreement/EC/FP7/223175 Cancer Research UK C1287/A10118 C1287/A10710 C12292/A11174 C1281/A12014 C5047/A8384 C5047/A15007 C5047/A10692 C8197/A16565 US National Institutes of Health (NIH) CA128978 CA192393 CA116167 CA176785 US National Institutes of Health (NIH Specialized Program of Research Excellence (SPORE) in Breast Cancer) CA116201 Post-Cancer GWAS initiative 1U19 CA148537 1U19 CA148065 1U19 CA148112 Post-Cancer GWAS initiative (GAME-ON initiative) US Department of Defense W81XWH-10-1-0341 Canadian Institutes of Health Research (CIHR) Komen Foundation for the Cure Breast Cancer Research Foundation Ovarian Cancer Research Fund
Published: 2016

27. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

Author: Blein, Sophie, Bardel, Claire, Danjean, Vincent, Mcguffog, Lesley, Healey, Sue, Barrowdale, Daniel, Lee, Andrew, Dennis, Joe, Kuchenbaecker, Karoline B., Soucy, Penny, Terry, Mary Beth, Chung, Wendy K., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Neuhausen, Susan L., Ding, Yuan Chun, Gerdes, Anne Marie, Ejlertsen, Bent, Nielsen, Finn C., Hansen, Thomas V. O., Osorio, Ana, Benitez, Javier, Conejero, Raquel Andrés, Segota, Ena, Weitzel, Jeffrey N., Thelander, Margo, Peterlongo, Paolo, Radice, Paolo, Pensotti, Valeria, Dolcetti, Riccardo, Bonanni, Bernardo, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Manoukian, Siranoush, Varesco, Liliana, Capone, Gabriele L., Papi, Laura, Ottini, Laura, Yannoukakos, Drakoulis, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brady, Angela, Brewer, Carole, Foo, Claire, Evans, D. Gareth, Frost, Debra, Eccles, Diana, Douglas, Fiona, Cook, Jackie, Adlard, Julian, Barwell, Julian, Walker, Lisa, Izatt, Louise, Side, Lucy E., Kennedy, M. John, Tischkowitz, Marc, Rogers, Mark T., Porteous, Mary E., Morrison, Patrick J., Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Cole, Trevor, Godwin, Andrew K., Isaacs, Claudine, Claes, Kathleen, De Leeneer, Kim, Meindl, Alfons, Gehrig, Andrea, Wappenschmidt, Barbara, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Plendl, Hansjoerg, Kast, Karin, Rhiem, Kerstin, Ditsch, Nina, Arnold, Norbert, Varon Mateeva, Raymonda, Schmutzler, Rita K., Preisler Adams, Sabine, Markov, Nadja Bogdanova, Wang Gohrke, Shan, de Pauw, Antoine, Lefol, Cédrick, Lasset, Christine, Leroux, Dominique, Rouleau, Etienne, Damiola, Francesca, Dreyfus, Hélène, Barjhoux, Laure, Golmard, Lisa, Uhrhammer, Nancy, Bonadona, Valérie, Sornin, Valérie, Bignon, Yves Jean, Carter, Jonathan, Van Le, Linda, Piedmonte, Marion, Disilvestro, Paul A., de la Hoya, Miguel, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Jager, Agnes, van den Ouweland, Ans M. W., Kets, Carolien M., Aalfs, Cora M., van Leeuwen, Flora E., Hogervorst, Frans B. L., Meijers Heijboer, Hanne E. J., Oosterwijk, Jan C., van Roozendaal, Kees E. P., Rookus, Matti A., Devilee, Peter, van der Luijt, Rob B., Olah, Edith, Diez, Orland, Teulé, Alex, Lazaro, Conxi, Blanco, Ignacio, Del Valle, Jesús, Jakubowska, Anna, Sukiennicki, Grzegorz, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska Bieniek, Katarzyna, Agnarsson, Bjarni A., Maugard, Christine, Amadori, Alberto, Montagna, Marco, Teixeira, Manuel R., Spurdle, Amanda B., Foulkes, William, Olswold, Curtis, Lindor, Noralane M., Pankratz, Vernon S., Szabo, Csilla I., Lincoln, Anne, Jacobs, Lauren, Corines, Marina, Robson, Mark, Vijai, Joseph, Berger, Andreas, Fink Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Kaulich, Daphne Geschwantler, Pfeiler, Georg, Tea, Muy Kheng, Greene, Mark H., Mai, Phuong L., Rennert, Gad, Imyanitov, Evgeny N., Mulligan, Anna Marie, Glendon, Gord, Andrulis, Irene L., Tchatchou, Sandrine, Toland, Amanda Ewart, Pedersen, Inge Sokilde, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Caligo, Maria A., Friedman, Eitan, Zidan, Jamal, Laitman, Yael, Lindblom, Annika, Melin, Beatrice, Arver, Brita, Loman, Niklas, Rosenquist, Richard, Olopade, Olufunmilayo I., Nussbaum, Robert L., Ramus, Susan J., Nathanson, Katherine L., Domchek, Susan M., Rebbeck, Timothy R., Arun, Banu K., Mitchell, Gillian, Karlan, Beth Y., Lester, Jenny, Orsulic, Sandra, Stoppa Lyonnet, Dominique, Thomas, Gilles, Simard, Jacques, Couch, Fergus J., Offit, Kenneth, Easton, Douglas F., Chenevix Trench, Georgia, Antoniou, Antonis C., Mazoyer, Sylvie, Phelan, Catherine M., Sinilnikova, Olga M., Cox, David G., Angelakos, Maggie, Maskiell, Judi, Dite, Gillian, Tsimiklis, Helen, Rudaitis, Vilius, Griškevicius, Laimonas, Eglitis, Drs Janis, Krilova, Anna, Stengrevics, Aivars, Ding, Chun, Steele, Linda, Barroso, Alicia, Alonso, Rosario, Pita, Guillermo, Viel, Alessandra, della Puppa, Lara, Barile, Monica, Tommasi, Stefania, Pilato, Brunella, Lambo, Rossana, Martayan, Aline, Tibiletti, Maria Grazia, Ellis, Steve, Fineberg, Elena, Miedzybrodzka, Zosia, Gregory, Helen, Jeffers, Lisa, Ong, Kai Ren, Hoffman, Jonathan, James, Margaret, Paterson, Joan, Taylor, Amy, Murray, Alexandra, Mccann, Emma, Barton, David, Drummond, Sarah, Kivuva, Emma, Searle, Anne, Goodman, Selina, Hill, Kathryn, Murday, Victoria, Bradshaw, Nicola, Snadden, Lesley, Longmuir, Mark, Watt, Catherine, Gibson, Sarah, Haque, Eshika, Tobias, Ed, Duncan, Alexis, Jacobs, Chris, Langman, Caroline, Dorkins, Huw, Serra Feliu, Gemma, Ellis, Ian, Houghton, Catherine, Lalloo, Fiona, Taylor, Jane, Male, Alison, Berlin, Cheryl, Eason, Jacqueline, Collier, Rebecca, Claber, Oonagh, Jobson, Irene, Mcleod, Diane, Halliday, Dorothy, Durell, Sarah, Stayner, Barbara, Shanley, Susan, Rahman, Nazneen, Houlston, Richard, Bancroft, Elizabeth, Page, Elizabeth, Ardern Jones, Audrey, Kohut, Kelly, Wiggins, Jennifer, Castro, Elena, Killick, Emma, Martin, Sue, Rea, Gillian, Kulkarni, Anjana, Quarrell, Oliver, Bardsley, Cathryn, Goff, Sheila, Brice, Glen, Winchester, Lizzie, Eddy, Charlotte, Tripathi, Vishakha, Attard, Virginia, Lehmann, Anna, Lucassen, Anneke, Crawford, Gillian, Mcbride, Donna, Smalley, Sarah, Weaver, Jo Ellen, Bove, Betsy, Verny Pierre, Carole, Calender, Alain, Giraud, Sophie, Léone, Mélanie, Gauthier Villars, Marion, Buecher, Bruno, Houdayer, Claude, Moncoutier, Virginie, Belotti, Muriel, Tirapo, Carole, Bressac de Paillerets, Brigitte, Caron, Olivier, Handallou, Sandrine, Hardouin, Agnès, Berthet, Pascaline, Sobol, Hagay, Bourdon, Violaine, Noguchi, Tetsuro, Remenieras, Audrey, Eisinger, François, Coupier, Isabelle, Pujol, Pascal, Peyrat, Jean Philippe, Fournier, Joëlle, Révillion, Françoise, Vennin, Philippe, Adenis, Claude, Lidereau, Rosette, Demange, Liliane, Nogues, Catherine, Muller, Danièle, Fricker, Jean Pierre, Barouk Simonet, Emmanuelle, Bonnet, Françoise, Bubien, Virginie, Sevenet, Nicolas, Longy, Michel, Toulas, Christine, Guimbaud, Rosine, Gladieff, Laurence, Feillel, Viviane, Rebischung, Christine, Peysselon, Magalie, Coron, Fanny, Faivre, Laurence, Prieur, Fabienne, Lebrun, Marine, Kientz, Caroline, Ferrer, Sandra Fert, Frénay, Marc, Vénat Bouvet, Laurence, Delnatte, Capucine, Mortemousque, Isabelle, Coulet, Florence, Colas, Chrystelle, Soubrier, Florent, Sokolowska, Johanna, Bronner, Myriam, Collonge Rame, Marie Agnès, Damette, Alexandre, Lynch, Henry T., Snyder, Carrie L., Muranen, Taru A., Blomqvist, Drs Carl, Aaltonen, Kirsimari, Erkkilä, Irja, Palola, Virpi, Verhoef, S., Schmidt, M. K., de Lange, J. L., Wijnands, R., Collée, J. M., Hooning, M. J., Seynaeve, C., van Deurzen, C. H. M., Obdeijn, I. M., van Asperen, C. J., Wijnen, J. T., Tollenaar, R. A. E. M., van Cronenburg, T. C. T. E. F., Mensenkamp, A. R., Ausems, M. G. E. M., van Os, T. A. M., Gille, J. J. P., Waisfisz, Q., Gómez Garcia, E. B., Blok, M. J., van der Hout, A. H., Mourits, M. J., de Bock, G. H., Vasen, H. F., Siesling, S., Overbeek, L. I. 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P., Gayther, Simon, Pye, Carole, Harrington, Patricia, Wozniak, Eva, Lindeman, Geoffrey, Harris, Marion, Delatycki, Martin, Sawyer, Sarah, Driessen, Rebecca, Thompson, Ella, Breast Cancer Family Registry, Null, Embrace, Null, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Medical Oncology, Clinical Genetics, Radiotherapy, MUMC+: DA KG Lab Specialisten (9), Klinische Genetica, Genetica & Celbiologie, RS: FHML non-thematic output, [ 1 ] Univ Lyon 1, Ctr Rech Cancerol Lyon, CNRS, INSERM U1052,UMR5286, F-69365 Lyon, France [ 2 ] Univ Lyon, F-69000 Lyon, France [ 3 ] Univ Lyon 1, F-69100 Villeurbanne, France [ 4 ] Univ Lyon 1, CNRS, Lab Biometrie & Biol Evolut LBBE Biometrie & Bio, UMR 5558, F-69622 Villeurbanne, France [ 5 ] Univ Grenoble Alpes, Lab Informat 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Subjects: Genetic modifiers, Dna haplogroups, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], ADN mitocondrial, SUSCEPTIBILITY, VARIANTS, 0302 clinical medicine, Breast Cancer Family Registry, Brjóstakrabbamein, MULTIPLE, Aetiology, skin and connective tissue diseases, Phylogeny, Cancer, ddc:616, 0303 health sciences, Mutation, education.field_of_study, Variants, SINGLE-NUCLEOTIDE POLYMORPHISMS, Subclade, Mitochondrial DNA, 3. Good health, ddc, Damage, Oncology, Ovarian, 030220 oncology & carcinogenesis, DISEASES, Multiple, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Single-nucleotide polymorphism, Breast Neoplasms/genetics, EMBRACE, GEMO Study Collaborators, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15], Genetics, Humans, education, Cancer och onkologi, Haplotype, BRCA2, Genes, mitochondrial haplogroup T1a1, breast cancer, BRCA2, Cancer and Oncology, GENETIC MODIFIERS, Polymorphisms, Cancer Research, [SDV]Life Sciences [q-bio], medicine.disease_cause, Haplogroup, 610 Medical sciences Medicine, 3123 Gynaecology and paediatrics, Medicine and Health Sciences, 2.1 Biological and endogenous factors, OXIDATIVE STRESS, Non-U.S. Gov't, Medicine(all), Gen, BRCA1 Protein, Research Support, Non-U.S. Gov't, Cohort, OVARIAN, Mitochondria, Mitochondrial, Genes, Mitochondrial, Female, Research Article, Risk, Heterozygote, BRCA1 protein, breast neoplasms, female, genetic predisposition to disease, haplotypes, humans, phylogeny, risk, genes, BRCA2, genes, mitochondrial, heterozygote, mutation, cancer research, oncology, Population, 3122 Cancers, Oncology and Carcinogenesis, Breast Neoplasms, Biology, Research Support, Càncer de mama, Breast Cancer, medicine, Journal Article, Genetic Predisposition to Disease, ddc:610, Oncology & Carcinogenesis, HEBON, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CONSORTIUM, African, DNA HAPLOGROUPS, Arfgengi, Haplotypes, Susceptibility, BRCA1 Protein/genetics, Human mitochondrial DNA haplogroup
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects. European Commission Seventh Framework Program 223175: HEALTH-F2-2009-223175 Cancer Research UK C12292/A11174 C1287/A10118 C1287/A11990 C5047/A8385 National Health and Medical Research Council (NHMRC) program National Health and Medical Research Council (NHMRC) American Cancer Society Early Detection Professorship SIOP-06-258-01-COUN Intramural Research Program of the National Cancer Institute, National Institutes of Health National Cancer Institute, National Institutes of Health UM1 CA164920 Lithuania (BFBOCC-LT): Research Council of Lithuania LIG-07/2012 LSC 10.0010.08 European Social Fund 2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016 Liepaja City Council, Liepaja, Latvia Breast Cancer Research Foundation Cancer Association of South Africa (CANSA) Morris and Horowitz Families Professorship in Cancer Etiology and Outcomes Research NEYE Foundation Spanish Association against Cancer (Asociacion Espanola Contra el Cancer) AECC08 Thematic Network Cooperative Research in Cancer (Red Tematica Investigacion Cooperativa en Cancer (RTICC), Centro de Investigacion Cancer, Salamanca, Spain) RTICC 06/0020/1060 Spanish Ministry of Science and Innovation FIS PI08 1120 Fondo de Investigacion Sanitaria (FIS) SAF2010-20493 Fundacion Mutua Madrilena (FMMA) City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry (COH-CCGCRN) National Cancer Institute and the Office of the Director, National Institutes of Health RC4CA153828 Italian citizens Fondazione IRCCS Istituto Nazionale Tumori Italian Association for Cancer Research (AIRC) European Union (European Social Fund (ESF) Greek national funds through the "Education and Lifelong Learning" operational program of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research and Technology: ARISTEIA "Heracleitus II: Investing in knowledge society through the European Social Fund" Deutsches Krebsforschungszentrum (DKFZ) National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester, UK NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London University of Kansas Cancer Center P30 CA168524 Kansas Bioscience Authority Eminent Scholar Program Chancellors Distinguished Chair in Biomedical Sciences Professorship German Cancer Aid 109076 Center for Molecular Medicine Cologne (CMMC) Ligue National Contre le Cancer Association "Le cancer du sein, parlons-en!" Award Canadian Institutes of Health Research for the CIHR Team in Familial Risks of Breast Cancer program GOA BOF10/GOA/019 Ghent University Hospital National Cancer Institute grants to the GOG Administrative Office and Tissue Bank CA 27469 GOG Statistical and Data Center CA 37517 GOG's Cancer Prevention and Control Committee CA 101165 Instituto de Salud Carlos III (ISCIII), Madrid, Spain RD12/00369/0006 12/00539 European Regional Development Fund (Fonds europeen de developpement regional (FEDER)) funds Helsinki University Central Hospital Research Fund Academy of Finland 266528 Finnish Cancer Society Sigrid Juselius Foundation Dutch Cancer Society NKI1998-1854 NKI2004-3088 NKI2007-3756 Netherlands Organization of Scientific Research NWO 91109024 Pink Ribbon grant 110005 Biobanking and Molecular Resource Infrastructure (BBMRI) NWO 184.021.007/CP46 Hungarian Research and Technological Innovation Fund (KTIA)/Hungarian Scientific Research Fund (Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA)) KTIA-OTKA CK-80745 KTIA-OTKA K-112228 Institut Catala d'Oncologia (ICO): contract grant sponsor: Asociacion Espanola Contra el Cancer Spanish Health Research Foundation Ramon Areces Foundation Instituto de Salud Carlos III (ISCIII) Catalan Health Institute Autonomous Government of Catalonia International Hereditary Cancer Center (Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland) PBZ_KBN_122/P05/2004 Icelandic Association "Walking for Breast Cancer Research" Landspitali University Hospital Research Fund Canadian Institutes of Health Research (CIHR) for the "CIHR Team in Familial Risks of Breast Cancer" program, Canadian Breast Cancer Research Alliance 019511 Ministry of Economic Development, Innovation and Export Trade PSR-SIIRI-701 Ministero della Salute and a "5 x 1,000" Istituto Oncologico Veneto grant Liga Portuguesa Contra o Cancro National Breast Cancer Foundation Queensland Cancer Fund Cancer Councils of New South Wales, Victoria, Tasmania and South Australia Cancer Foundation of Western Australia National Institutes of Health (NIH) through the National Cancer Institute (NCI) CA 116167 CA 128978 CA 176785 NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer CA116201 US Department of Defense Ovarian Cancer Idea award W81XWH-10-1-0341 Ministry of Health of the Czech Republic to Masaryk Memorial Cancer Institute MMCI 00209805 European Regional Development Fund State Budget of the Czech Republic (RECAMO) CZ. 1.05/2.1.00/03.0101 Charles University in Prague project UNCE204024 Robert and Kate Niehaus Clinical Cancer Genetics Initiative Intramural Research Program of the National Cancer Institute Westat, Inc, Rockville, MD, USA N02-CP-11019-50 N02-CP-65504 Clalit Health Services in Israel Israel Cancer Association Breast Cancer Research Foundation (BCRF), New York, NY, USA Russian Federation for Basic Research 11-04-00227 12-04-00928 12-04-01490 Federal Agency for Science and Innovations, Russia 02.740.11.0780 Ohio State University Comprehensive Cancer Center Istituto Toscano Tumori (ITT) Israeli Inherited Breast Cancer Consortium Swedish Breast Cancer Swedish Cancer Society Ralph and Marion Falk Medical Research Trust Entertainment Industry Fund National Women's Cancer Research Alliance University of California, Los Angeles Jonsson Comprehensive Cancer Center Foundation: Breast Cancer Research Foundation University of California, San Francisco Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center Cancer Research UK University of Pennsylvania: National Institutes of Health (NIH) R01 CA102776 R01 CA083855 Susan G Komen for the Cure, Basser Center for BRCA Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation 5U01 CA113916 R01 CA140323 ISCIIIRETIC RD06/0020/1051 PI09/02483 PI10/01422 PI10/00748 PI13/00285 PI13/00189 2009SGR290 PI13/00189 2009SGR283 CA125183 R01 CA142996 1U01CA161032
Published: 2015

28. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Author: Osorio, Ana, Milne, Roger L., Kuchenbaecker, Karoline, Vaclová, Tereza, Pita, Guillermo, Alonso, Rosario, Peterlongo, Paolo, Blanco Guillermo, Ignacio, De la Hoya, Miguel, Durán, Mercedes, Diez, Orland, Ramon y Cajal, Teresa, Konstantopoulou, Irene, Martínez-Bouzas, Cristina, Andrés Conejero, Raquel, Soucy, Penny, McGuffog, Lesley, Barrowdale, Daniel, Lee, Andrew, SWE-BRCA, None, Arver, Brita, Rantala, Johanna, Loman, Niklas, Ehrencrona, Hans, Olopade, Olufunmilayo I., Beattie, Mary S., Domchek, Susan M., Nathanson, Katherine, Rebbeck, Timothy R., Arun, Banu K., Karlan, Beth Y., Walsh, Christine, Lester, Jenny, John, Esther M., Whittemore, Alice S., Daly, Mary B., Southey, Melissa, Hopper, John L, Terry, Mary Beth, Buys, Saundra, Janavicius, Ramunas, Dorfling, Cecilia M., van Rensburg, Elizabeth J., Steele, Linda, Neuhausen, Susan L., Ding, Yuan Chun, Hansen, Thomas v. O., Jønson, Lars, Ejlertsen, Bent, Gerdes, Anne-Marie, Infante, Mar, Herráez, Belén, Moreno, Leticia Thais, Weitzel, Jeffrey N., Herzog, Josef, Weeman, Kisa, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Scuvera, Giulietta, Bonanni, Bernardo, Mariette, Frederique, Volorio, Sara, Viel, Alessandra, Varesco, Liliana, Papi, Laura, Ottini, Laura, Tibiletti, Maria Grazia, Radice, Paolo, Yannoukakos, Drakoulis, Garber, Judy, Ellis, Steve, Frost, Debra, Platte, Radka, Fineberg, Elena, Evans, Gareth, Lalloo, Fiona, Izatt, Louise, Eeles, Ros, Adlard, Julian, Davidson, Rosemarie, Cole, Trevor, Eccles, Diana M, Cook, Jackie, Hodgson, Shirley, Brewer, Carole, Tischkowitz, Marc, Douglas, Fiona, Porteous, Mary, Side, Lucy, Walker, Lisa, Morrison, Patrick, Donaldson, Alan, Kennedy, John, Foo, Claire, Godwin, Andrew K., Schmutzler, Rita Katharina, Wappenschmidt, Barbara, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hans Jörg, Niederacher, Dieter, Sutter, Christian, Wang-Gohrke, Shan, Steinemann, Doris, Preisler-Adams, Sabine, Kast, Karin, Varon-Mateeva, Raymonda, Gehrig, Andrea, Stoppa-Lyonnet, Dominique, Sinilnikova, Olga M., Mazoyer, Sylvie, Damiola, Francesca, Poppe, Bruce, Claes, Kathleen, Piedmonte, Marion, Tucker, Kathy, Backes, Floor, Rodríguez, Gustavo, Brewster, Wendy, Wakeley, Katie, Rutherford, Thomas, Caldes, Trinidad, Nevanlinna, Heli, Aittomäki, Kristiina, Rookus, Matti A., van Os, Theo A. M., van der Kolk, Lizet, de Lange, J. L., Meijers-Heijboer, Hanne E. J., van der Hout, A. H., van Asperen, Christi J., Gómez Garcia, Encarna B., Hoogerbrugge, Nicoline, Collée, J. Margriet, van Deurzen, Carolien H. M., van der Luijt, Rob B., Devilee, Peter, HEBON, None, Olah, Edith, Lázaro, Conxi, Teulé, Alex, Menéndez, Mireia, Jakubowska, Anna, Cybulski, Cezary, Gronwald, Jacek, Lubinski, Jan, Durda, Katarzyna, Jaworska-Bieniek, Katarzyna, Johannsson, Oskar Th., Maugard, Christine, Montagna, Marco, Tognazzo, Silvia, Teixeira, Manuel R., Healey, Sue, Investigators, kConFab, Olswold, Curtis, Guidugli, Lucia, Lindor, Noralane, Slager, Susan, Szabo, Csilla I., Vijai, Joseph, Robson, Mark, Kauff, Noah, Zhang, Liying, Rau-Murthy, Rohini, Fink-Retter, Anneliese, Singer, Christian F., Rappaport, Christine, Geschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Berger, Andreas, Phelan, Catherine M., Greene, Mark H., Mai, Phuong L., Lejbkowicz, Flavio, Andrulis, Irene L., Mulligan, Anna Marie, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Sunde, Lone, Thomassen, Mads, Kruse, Torben A., Jensen, Uffe Birk, Friedman, Eitan, Laitman, Yael, Shimon, Shani Paluch, Simard, Jacques, Easton, Douglas F., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia, Antoniou, Antonis C., Benitez, Javier, Universitat Autònoma de Barcelona, Pediatric Surgery, Clinical Genetics, Pathology, Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. 2Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia. 3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom. 4Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain. 5Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain. 6IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. 7Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 8Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain. 9Institute of 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University Hospital, Stockholm, Sweden. 19Department of Oncology, Lund University Hospital, Lund, Sweden. 20Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. 21Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America. 22Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America. 23Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America. 24Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America. 25University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. 26Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, 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center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania. 35Department of Genetics, University of Pretoria, Pretoria, South Africa. 36Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America. 37Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 38Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 39Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 40Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America. 41Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 42Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy. 43IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy. 44Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy. 45Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy. 46Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy. 47Department of Molecular Medicine, 'Sapienza' University, Rome, Italy. 48UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy. 49Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. 50Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. 51Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom. 52South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom. 53Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom. 54Yorkshire Regional Genetics Service, Leeds, United Kingdom. 55Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom. 56West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom. 57Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom. 58Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom. 59Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom. 60Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom. 61Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom. 62Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom. 63South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom. 64North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom. 65Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom. 66Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom. 67South West Regional Genetics Service, Bristol, United Kingdom. 68Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire. 69Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom. 70Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America. 71Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany. 72Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany. 73Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany. 74Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 75Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 76Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. 77Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany. 78Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany. 79Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany. 80Institute of Human Genetics, University of Münster, Münster, Germany. 81Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany. 82Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany. 83Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany. 84Institut Curie, Department of Tumour Biology, Paris, France, Institut Curie, INSERM U830, Paris, France, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 85Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France, INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 86INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. 87Center for Medical Genetics, Ghent University, Ghent, Belgium. 88Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America. 89Prince of Wales Hospital. Sydney, Australia. 90Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America. 91Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America. 92Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America. 93For Tufts Medical Center, Boston, Massachusetts, United States of America. 94Yale University School of Medicine, New Haven, Connecticut, United States of America. 95Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. 96Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. 97Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands. 98Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands. 99Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands. 100University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 101Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands. 102Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands. 103Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. 104Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 105Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands. 106Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 107Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands. 108The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands. 109Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary. 110Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain. 111Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. 112Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland, Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland. 113Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland. 114Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France. 115Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy. 116Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. 117Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia. 118Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia. 119Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America. 120Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 121Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America. 122Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America. 123Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America, Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 124Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 125Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America. 126Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria. 127Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America. 128Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America. 129Clalit National Israeli Cancer Control Center, Haifa, Israel. 130Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. 131Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada, Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada. 132Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. 133Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America. 134Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark. 135Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark. 136Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark. 137Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 138Sheba Medical Center, Tel Aviv, Israel. 139Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada. 140Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America. 141Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain, Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain., SWE-BRCA, Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Unión Europea, Cancer Research UK (Reino Unido), United States of Department of Health & Human Services, Canadian Institutes of Health Research, Susan G. Komen Breast Cancer Foundation, Ralph and Marion Falk Medical Research Trust, Research Council (Lituania), University of Kansas. Cancer Center (Estados Unidos), National Institute for Health Research (Reino Unido), Deutsche Krebshilfe, Finlands Akademi (Finlandia), Dutch Cancer Society (Holanda), Dutch Research Council (Holanda), Pink Ribbons Project, Hungarian Scientific Research Fund (Hungría), Canadian Breast Cancer Network, Ministère du Développement économique, de Innovation et de Exportation (Canadá), Westat (Estados Unidos), Department of Obstetrics and Gynecology, Clinicum, Universitat de Barcelona, Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, CCA - Oncogenesis, Fundación Mutua Madrileña Automovilista, Fundacion Asociacion Espanola Contra el Cancer (AECC), Instituto de Salud Carlos III - ISCIII, European Union (EU), Cancer Research UK, United States Department of Health & Human Services National Institutes of Health (NIH) - USA, Canadian Institutes of Health Research (CIHR), Research Council of Lithuania, University of Kansas Cancer Center, National Institute for Health Research (NIHR), Academy of Finland, KWF Kankerbestrijding, Netherlands Organization for Scientific Research (NWO), Pink Ribbon grant, Orszagos Tudomanyos Kutatasi Alapprogramok (OTKA), Canadian Breast Cancer Research Alliance-grant, Ministry of Economic Development, Innovation and Export Trade, and Westat, Inc, Rockville, MD
Subjects: Cancer Research, 24 Ciencias de la Vida, DNA Repair, endocrine system diseases, ADN, Càncer d'ovari, Synthetic lethality, BRCA1 Protein/genetics, DNA Glycosylases, 0302 clinical medicine, DNA Glycosylases/genetics, Brjóstakrabbamein, Genotype, Medicine and Health Sciences, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Glicosilasas, INVESTIGATORS, skin and connective tissue diseases, OGG1, Genetics (clinical), Genetics, DAMAGE, Aged, 80 and over, Ovarian Neoplasms, 0303 health sciences, BRCA1 Protein, SINGLE-NUCLEOTIDE POLYMORPHISMS, COMMON VARIANTS, Base excision repair, Middle Aged, BRCA2 Protein, 3. Good health, 030220 oncology & carcinogenesis, NEIL2, Female, Medical Genetics, Research Article, BRCA1, BRCA2, Adult, Risk, Ovarian Neoplasms/genetics, lcsh:QH426-470, Adolescent, DNA repair, education, Single-nucleotide polymorphism, Breast Neoplasms, DNA Repair/genetics, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, OVARIAN-CANCER, 03 medical and health sciences, Polymorphism, Single Nucleotide/genetics, SDG 3 - Good Health and Well-being, Ovarian cancer, Cancer Genetics, BREAST-CANCER, Humans, Genetic Predisposition to Disease, ddc:610, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Aged, BRCA2 Protein/genetics, CONSORTIUM, Biology and Life Sciences, Arfgengi, lcsh:Genetics, DNA glycosylase, Cancer research, 3111 Biomedicine, GENETIC MODIFIERS, Genètica
Abstract: Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p, Author Summary Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
Published: 2014

29. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

Author: Mulligan, Anna Marie, Couch, Fergus J, Barrowdale, Daniel, Domchek, Susan M, Eccles, Diana, Nevanlinna, Heli, Ramus, Susan J, Robson, Mark, Sherman, Mark, Spurdle, Amanda B, Wappenschmidt, Barbara, Lee, Andrew, McGuffog, Lesley, Healey, Sue, Sinilnikova, Olga M, Janavicius, Ramunas, Hansen, Thomas vO, Nielsen, Finn C, Ejlertsen, Bent, Osorio, Ana, Muñoz-Repeto, Iván, Durán, Mercedes, Godino, Javier, Pertesi, Maroulio, Benítez, Javier, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Zaffaroni, Daniela, Cattaneo, Elisa, Bonanni, Bernardo, Viel, Alessandra, Pasini, Barbara, Papi, Laura, Ottini, Laura, Savarese, Antonella, Bernard, Loris, Radice, Paolo, Hamann, Ute, Verheus, Martijn, Meijers-Heijboer, Hanne EJ, Wijnen, Juul, Gómez García, Encarna B, Nelen, Marcel R, Kets, C Marleen, Seynaeve, Caroline, Tilanus-Linthorst, Madeleine MA, van der Luijt, Rob B, van Os, Theo, Rookus, Matti, Frost, Debra, Jones, J Louise, Evans, D Gareth, Lalloo, Fiona, Eeles, Ros, Izatt, Louise, Adlard, Julian, Davidson, Rosemarie, Cook, Jackie, Donaldson, Alan, Dorkins, Huw, Gregory, Helen, Eason, Jacqueline, Houghton, Catherine, Barwell, Julian, Side, Lucy E, McCann, Emma, Murray, Alex, Peock, Susan, Godwin, Andrew K, Schmutzler, Rita K, Rhiem, Kerstin, Engel, Christoph, Meindl, Alfons, Ruehl, Ina, Arnold, Norbert, Niederacher, Dieter, Sutter, Christian, Deissler, Helmut, Gadzicki, Dorothea, Kast, Karin, Preisler-Adams, Sabine, Varon-Mateeva, Raymonda, Schoenbuchner, Ines, Fiebig, Britta, Heinritz, Wolfram, Schäfer, Dieter, Gevensleben, Heidrun, Caux-Moncoutier, Virginie, Fassy-Colcombet, Marion, Cornelis, François, Mazoyer, Sylvie, Léoné, Mélanie, Boutry-Kryza, Nadia, Hardouin, Agnès, Berthet, Pascaline, Muller, Danièle, Fricker, Jean-Pierre, Mortemousque, Isabelle, Pujol, Pascal, Coupier, Isabelle, Lebrun, Marine, Kientz, Caroline, Longy, Michel, Sevenet, Nicolas, Stoppa-Lyonnet, Dominique, Isaacs, Claudine, Caldes, Trinidad, de la Hoya, Miguel, Heikkinen, Tuomas, Aittomäki, Kristiina, Blanco, Ignacio, Lazaro, Conxi, Barkardottir, Rosa B, Soucy, Penny, Dumont, Martine, Simard, Jacques, Montagna, Marco, Tognazzo, Silvia, D'Andrea, Emma, Fox, Stephen, Yan, Max, Rebbeck, Tim, Olopade, Olufunmilayo, Weitzel, Jeffrey N, Lynch, Henry T, Ganz, Patricia A, Tomlinson, Gail E, Wang, Xianshu, Fredericksen, Zachary, Pankratz, Vernon S, Lindor, Noralane M, Szabo, Csilla, Offit, Kenneth, Sakr, Rita, Gaudet, Mia, Bhatia, Jasmine, Kauff, Noah, Singer, Christian F, Tea, Muy-Kheng, Gschwantler-Kaulich, Daphne, Fink-Retter, Anneliese, Mai, Phuong L, Greene, Mark H, Imyanitov, Evgeny, O'Malley, Frances P, Ozcelik, Hilmi, Glendon, Gordon, Toland, Amanda E, Gerdes, Anne-Marie, Thomassen, Mads, Kruse, Torben A, Jensen, Uffe Birk, Skytte, Anne-Bine, Caligo, Maria A, Soller, Maria, Henriksson, Karin, Wachenfeldt, von Anna, Arver, Brita, Stenmark-Askmalm, Marie, Karlsson, Per, Ding, Yuan Chun, Neuhausen, Susan L, Beattie, Mary, Pharoah, Paul DP, Moysich, Kirsten B, Nathanson, Katherine L, Karlan, Beth Y, Gross, Jenny, John, Esther M, Daly, Mary B, Buys, Saundra M, Southey, Melissa C, Hopper, John L, Terry, Mary Beth, Chung, Wendy, Miron, Alexander F, Goldgar, David, Chenevix-Trench, Georgia, Easton, Douglas F, Andrulis, Irene L, Antoniou, Antonis C, Breast Cancer Family Registry, EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Ontario Cancer Genetics Network, SWE-BRCA, CIMBA, Pediatric Surgery, Neurology, Medical Oncology, Surgery, Clinical Genetics, Department of Laboratory Medicine, St Michael's Hospital-Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Department of Laboratory Medicine and Pathobiology, University of Toronto, Department of Laboratory Medicine and Pathology, Mayo Clinic, Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Department of Medicine, University of Pennsylvania [Philadelphia]-Abramson Cancer Center, Faculty of Medicine, University of Southampton-University Hospital Southampton, Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Department of Preventive Medicine, University of Southern California (USC)-Keck School of Medicine [Los Angeles], University of Southern California (USC), Memorial Sloane Kettering Cancer Center [New York]-Weill Medical College of Cornell University [New York], Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Queensland Institute of Medical Research, Department of Gynaecology and Obstetrics, University Hospital of Cologne [Cologne]-Centre of Familial Breast and Ovarian Cancer-Centre for Integrated Oncology (CIO), Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Léon Bérard [Lyon]-Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santariskiu Clinics, State Research Institute Innovative Medicine Center, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Oncology, Human Genetics Group, Spanish National Cancer Research Centre-Spain and the Spanish Network on Rare Diseases, Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Instituto de investigación sanitaria de Aragón (IIS), Hospital clinico Universitario 'Lozano Blesa', Molecular Diagnostics Laboratory, National Center for Scientific Research 'Demokritos' (NCSR)-IRRP, Unit of Molecular Bases of Genetic Risk and Genetic Testing, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Fondazione Istituto FIRC di Oncologia Molecolare, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Unit of Medical Genetics, Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Unit of Experimental Oncology 1, Centro di Riferimento Oncologico, Department of Genetics, Biology and Biochemistry, University of Turin, Medical Genetics Unit, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Division of Medical Oncology, Regina Elena Cancer Institute, Department of Experimental Oncology, Consortium for Genomics Technology (Cogentech)-Istituto Europeo di Oncologia. Milan, Molecular Genetics of Breast Cancer, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Epidemiology, Netherlands Cancer Institute, Department of Clinical Genetics, VU Medical Center, Department of Human Genetics and Department of Clinical Genetics, Leiden University Medical Center (LUMC), Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, Department of Human Genetics, Radboud University Medical Center [Nijmegen], Department of Medical Oncology, Erasmus University Medical Center [Rotterdam] (Erasmus MC)-Family Cancer Clinic, Department of Surgical Oncology, Department of Clinical Molecular Genetics, University Medical Center [Utrecht], Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Barts Cancer Institute, Queen Mary University of London (QMUL), Genetic Medicine, Manchester Academic Health Sciences Centre-Central Manchester University Hospitals, Oncogenetics Team, The Institute of Cancer Research and Royal Marsden, Guy's and St. Thomas' NHS Foundation Trust, Yorkshire Regional Genetics Service, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Clinical Genetics Department, St Michael's Hospital, North West Thames Regional Genetics Service, Kennedy-Galton Centre, North of Scotland Regional Genetics Service, University of Aberdeen-NHS Grampian, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Cheshire and Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Leicestershire Clinical Genetics Service, University Hospitals Leicester, North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children [London] (GOSH), All Wales Medical Genetics Services, Singleton Hospital, Department of Pathology and Laboratory Medicine, University of Kansas Medical Center [Lawrence], Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] (IMISE), Universität Leipzig [Leipzig], Klinikum Rechts der Isar, Ludwig-Maximillians University, University Hospital of Schleswig-Holstein (UKSH), University Hospital Düsseldorf, Institute of Human Genetics, Heidelberg University Hospital [Heidelberg], Universitätsklinikum Ulm - University Hospital of Ulm, Institute of Cell and Molecular Pathology, Hannover Medical School [Hannover] (MHH), University Hospital Carl Gustav Carus, Westfälische Wilhelms-Universität Münster (WWU), Campus Virchov Klinikum, Department of Medical Genetic, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU)-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, Universität Regensburg (UR), University Hospital, Frankfurt, Breakthrough Breast Cancer Research Centre, Institute of cancer research, Service de Génétique Oncologique, Institut Curie [Paris], Service de génétique [Avicenne], Université Paris 13 (UP13)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Sud Francilien, CH Evry-Corbeil, CHU Clermont-Ferrand, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), Unité d'oncogénétique, CRLCC Paul Strauss, Service de génétique [Tours], Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de Génétique Clinique Chromosomique et Moléculaire, CHU Saint-Etienne, Validation et identification de nouvelles cibles en oncologie (VINCO), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Lombardi Comprehensive Cancer Center, Georgetown University, Molecular Oncology Laboratory, Hospital Clínico San Carlos, Hereditary Cancer Program, Institut Català d'Oncologia-Hospital Duran i Reynals, Department of Pathology, Landspitali University Hospital, University of Iceland [Reykjavik], Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, Research Chair in Oncogenetics, Université Laval [Québec] (ULaval), Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Department of Oncology and Surgical Sciences, Universita degli Studi di Padova, Peter MacCallum Cancer Centre, Peter MacCallum Cancer Center, Department of Anatomical Pathology, Prince of Wales Hospital, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], University of Chicago, City of Hope Comprehensive Cancer Center and Department of Population Sciences, Beckman Research Institute, Departments of Medicine, and Preventive Medicine and Public Health, Creighton University, Jonsson Comprehensive Cancer Center, University of California [Los Angeles] (UCLA), University of California-University of California, Department of Internal Medicine, The University of Texas Health Science Center at Houston (UTHealth)-Harold C. Simmons Comprehensive Cancer Center, Department of Pediatrics, The University of Texas Health Science Center at Houston (UTHealth), Department of Medical Genetics, University of Delaware [Newark], Epidemiology Research Program, American Cancer Society, Department of Obstetrics/Gynaecology and Comprehensive Cancer Center, Medizinische Universität Wien = Medical University of Vienna, Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital [Toronto, Canada] (MSH), Prevention & Cancer Control, Cancer Care Ontario, Departments of Molecular VirologyImmunology and Medical Genetics and Internal Medicine, Ohio State University [Columbus] (OSU), University of Copenhagen = Københavns Universitet (KU)-Rigshospital, Odense University Hospital, Aarhus University Hospital, Vejle Hospital, Section of Genetic Oncology, University of Pisa - Università di Pisa, Lund University Hospital, Oncological Centre, Karolinska University Hospital [Stockholm], Department of Clinical and Experimental Medicine, Linköping University (LIU), Sahlgrenska University Hospital [Gothenburg], Department of Population Sciences, Beckman Research Institute of the City of Hope, UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), Department of Cancer Prevention and Control, Roswell Park Cancer Institute [Buffalo], Women's Cancer Program, Samuel Oschin Comprehensive Cancer Institute, Cancer Prevention Institute of California, Fox Chase Cancer Center, Department of Oncological Sciences, University of Utah-Huntsman Cancer Institute, Genetic Epidemiology Laboratory, University of Melbourne, Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, Columbia University [New York], Department of Cancer Biology, Dana-Farber Cancer Institute [Boston], Department of Dermatology, University of Utah School of Medicine [Salt Lake City], This work was supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The research leading to these results has received funding from the European Community's Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175). ACA is a CR-UK Senior Cancer Research Fellow, DFE is CR-UK Principal Research Fellow., for Breast Cancer Family Registry, for EMBRACE, for Ontario Cancer Genetics Network, for SWE-BRCA, for CIMBA, European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), BMC, Ed., Collaborative Oncological Gene-environment Study - COGS - - EC:FP7:HEALTH2009-05-01 - 2014-01-31 - 223175 - VALID, University of Pennsylvania-Abramson Cancer Center, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Consortium for Genomics Technology (Cogentech)-Istituto Europeo di Oncologia [Milano] (IEO), University of Kansas Medical Center [Kansas City, KS, USA], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Julius-Maximilians-Universität Würzburg (JMU)-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Georgetown University [Washington] (GU), Università degli Studi di Padova = University of Padua (Unipd), University of Pennsylvania-University of Pennsylvania, University of California (UC)-University of California (UC), Rigshospital-University of Copenhagen = Københavns Universitet (UCPH), Vejle Hospital [Danemark], University of California [San Francisco] (UC San Francisco), Lee, Andrew [0000-0003-0677-0252], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, University of Cambridge [UK] ( CAM ), University of Southampton [Southampton]-University Hospital Southampton, University of Southern California ( USC ) -Keck School of Medicine [Los Angeles], Memorial Sloan-Kettering Cancer Center-Weill Medical College of Cornell University [New York], National Cancer Institute ( NIH ), Centre Léon Bérard [Lyon]-Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon ( CRCL ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Instituto de investigación sanitaria de Aragón ( IIS ), National Center for Scientific Research 'Demokritos' ( NCSR ) -IRRP, IFOM, University of Florence, Università degli Studi di Roma 'La Sapienza' [Rome], Deutsches Krebsforschungszentrum ( DKFZ ), Erasmus University Medical Center-Family Cancer Clinic, University Medical Center Utrecht, Academic Medical Center [Amsterdam] ( AMC ), University of Amsterdam [Amsterdam] ( UvA ) -University of Amsterdam [Amsterdam] ( UvA ), Queen Mary University of London ( QMUL ), Sheffield Children's Hospital, University Hospitals of Leicester, Great Ormond Street Hospital for Children [London] ( GOSH ), University of Kansas Medical Center, Institute for Medical Informatics, Statistics and Epidemiology [Leipzig] ( IMISE ), University of Leipzig, University Hospital Ulm, Hannover Medical School [Hannover] ( MHH ), Westfälische Wilhelms-Universität Münster ( WWU ), University Wurzburg-Institute of Human Genetics-Centre of Familial Breast and Ovarian Cancer, University Regensburg, INSTITUT CURIE, Université Paris 13 ( UP13 ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Avicenne, Centre Hospitalier Universitaire Clermont-Ferrand, Centre François Baclesse, Hôpital Bretonneau-CHRU Tours, Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ) -Hôpital Arnaud de Villeneuve, Validation et identification de nouvelles cibles en oncologie ( VINCO ), Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié - CRLCC Bordeaux-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Unité de génétique et biologie des cancers ( U830 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut Curie-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laval University [Québec], University of Padua and Istituto Oncologico Veneto IOV - IRCCS, University of Pennsylvania Perelman School of Medicine, University of California at Los Angeles [Los Angeles] ( UCLA ), University of Texas at Houston [Houston] ( UTHealth ) -Harold C. Simmons Comprehensive Cancer Center, University of Texas Health Science, Medical University of Vienna, Mount Sinai Hospital, The Ohio State University Comprehensive Cancer Center, University of Copenhagen ( KU ) -Rigshospital, University of Pisa [Pisa], Linköping University ( LIU ), Sahlgrenska University Hospital, the Beckman Research Institute of the City of Hope, University of California [San Francisco] ( UCSF ), European Project : 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS ( 2009 ), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris 13 (UP13), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2, Human Genetics, Universiteit Leiden-Universiteit Leiden, Nottingham University Hospitals NHS Trust (NUH), Universität Leipzig, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), and Roswell Park Cancer Institute [Buffalo] (RPCI)
Subjects: Risk, Heterozygote, endocrine system diseases, Population, Genes, BRCA2, Genes, BRCA1, Social Sciences, Estrogen receptor, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, Biology, Polymorphism, Single Nucleotide, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, 610 Medical sciences Medicine, 0302 clinical medicine, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, Genotype, medicine, Humans, Genetic Predisposition to Disease, education, skin and connective tissue diseases, Estrogen Receptor Status, Alleles, 030304 developmental biology, Medicine(all), 0303 health sciences, education.field_of_study, Samhällsvetenskap, medicine.disease, 3. Good health, TOX3, Receptors, Estrogen, Cancer and Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer research, Female, Ovarian cancer, Receptors, Progesterone, Research Article
Abstract: [Introduction]: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. [Methods]: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. [Results]: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. [Conclusions]: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.
Published: 2011

30. CanRisk Tool—A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants

Author: Antonis C. Antoniou, Jonathan Roberts, Simon Hartley, Tim Carver, Chantal Babb de Villiers, Douglas F. Easton, Andy C. H. Lee, Marc Tischkowitz, Stephanie Archer, Fiona M Walter, Rod Ruston, Alex P Cunningham, Lee, Andrew [0000-0003-0677-0252], Cunningham, Alex P [0000-0002-3737-9611], Archer, Stephanie [0000-0003-1349-7178], Babb de Villiers, Chantal [0000-0003-1334-1819], Walter, Fiona M [0000-0002-7191-6476], Antoniou, Antonis C [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Epidemiology, Computer science, Interface (Java), MEDLINE, Breast Neoplasms, computer.software_genre, Article, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Health care, medicine, Humans, Genetic Predisposition to Disease, Family history, Graphical user interface, Ovarian Neoplasms, Internet, business.industry, medicine.disease, Data science, 3. Good health, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, Web service, User interface, business, Ovarian cancer, computer
Abstract: Background: The CanRisk Tool (https://canrisk.org) is the next-generation web interface for the latest version of the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) state-of-the-art risk model and a forthcoming ovarian cancer risk model. Methods: The tool captures information on family history, rare pathogenic variants in cancer susceptibility genes, polygenic risk scores, lifestyle/hormonal/clinical features, and imaging risk factors to predict breast and ovarian cancer risks and estimate the probabilities of carrying pathogenic variants in certain genes. It was implemented using modern web frameworks, technologies, and web services to make it extensible and increase accessibility to researchers and third-party applications. The design of the graphical user interface was informed by feedback from health care professionals and a formal evaluation. Results: This freely accessible tool was designed to be user friendly for clinicians and to boost acceptability in clinical settings. The tool incorporates a novel graphical pedigree builder to facilitate collection of the family history data required by risk calculations. Conclusions: The CanRisk Tool provides health care professionals and researchers with a user-friendly interface to carry out multifactorial breast and ovarian cancer risk predictions. It is the first freely accessible cancer risk prediction program to carry the CE marking. Impact: There have been over 3,100 account registrations, and 98,000 breast and ovarian cancer risk calculations have been run within the first 9 months of the CanRisk Tool launch.
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31. pedigreejs: a web-based graphical pedigree editor

Author: Carver, Tim, Cunningham, Alex P, Babb De Villiers, Chantal, Lee, Andrew, Hartley, Simon, Tischkowitz, Marc, Walter, Fiona M, Easton, Douglas F, Antoniou, Antonis C, Cunningham, Alex [0000-0002-3737-9611], Babb, Chantal Louiza [0000-0003-1334-1819], Lee, Andrew [0000-0003-0677-0252], Tischkowitz, Marc [0000-0002-7880-0628], Walter, Fiona [0000-0002-7191-6476], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Male, Internet, Genetics and Population Analysis, Humans, Female, Web Browser, Medical History Taking, Applications Notes, Software, Pedigree
Abstract: Motivation The collection, management and visualization of clinical pedigree (family history) data is a core activity in clinical genetics centres. However, clinical pedigree datasets can be difficult to manage, as they are time consuming to capture, and can be difficult to build, manipulate and visualize graphically. Several standalone graphical pedigree editors and drawing applications exist but there are no freely available lightweight graphical pedigree editors that can be easily configured and incorporated into web applications. Results We developed ‘pedigreejs’, an interactive graphical pedigree editor written in JavaScript, which uses standard pedigree nomenclature. Pedigreejs provides an easily configurable, extensible and lightweight pedigree editor. It makes use of an open-source Javascript library to define a hierarchical layout and to produce images in scalable vector graphics (SVG) format that can be viewed and edited in web browsers. Availability and implementation The software is freely available under GPL licence (https://ccge-boadicea.github.io/pedigreejs/). Contact tjc29@cam.ac.uk Supplementary information Supplementary data are available at Bioinformatics online.
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32. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

Author: Kuchenbaecker, Karoline B, Neuhausen, Susan L, Robson, Mark, Barrowdale, Daniel, McGuffog, Lesley, Mulligan, Anna Marie, Andrulis, Irene L, Spurdle, Amanda B, Schmidt, Marjanka K, Schmutzler, Rita K, Engel, Christoph, Wappenschmidt, Barbara, Nevanlinna, Heli, Thomassen, Mads, Southey, Melissa, Radice, Paolo, Ramus, Susan J, Domchek, Susan M, Nathanson, Katherine L, Lee, Andrew, Healey, Sue, Nussbaum, Robert L, Rebbeck, Timothy R, Arun, Banu K, James, Paul, Karlan, Beth Y, Lester, Jenny, Cass, Ilana, Breast Cancer Family Registry, the, Terry, Mary Beth, Daly, Mary B, Goldgar, David E, Buys, Saundra S, Janavicius, Ramunas, Tihomirova, Laima, Tung, Nadine, Dorfling, Cecilia M, van Rensburg, Elizabeth J, Steele, Linda, v O Hansen, Thomas, Ejlertsen, Bent, Gerdes, Anne-Marie, Nielsen, Finn C, Dennis, Joe, Cunningham, Julie, Hart, Steven, Slager, Susan, Osorio, Ana, Benitez, Javier, Duran, Mercedes, Weitzel, Jeffrey N, Tafur, Isaac, Hander, Mary, Peterlongo, Paolo, Manoukian, Siranoush, Peissel, Bernard, Roversi, Gaia, Scuvera, Giulietta, Bonanni, Bernardo, Mariani, Paolo, Volorio, Sara, Dolcetti, Riccardo, Varesco, Liliana, Papi, Laura, Tibiletti, Maria Grazia, Giannini, Giuseppe, Fostira, Florentia, Konstantopoulou, Irene, Garber, Judy, Hamann, Ute, Donaldson, Alan, Brewer, Carole, Foo, Claire, Evans, D Gareth, Frost, Debra, Eccles, Diana, EMBRACE Study, the, Douglas, Fiona, Brady, Angela, Cook, Jackie, Tischkowitz, Marc, Adlard, Julian, Barwell, Julian, Ong, Kai-ren, Walker, Lisa, Izatt, Louise, Side, Lucy E, Kennedy, M John, Rogers, Mark T, Porteous, Mary E, Morrison, Patrick J, Platte, Radka, Eeles, Ros, Davidson, Rosemarie, Hodgson, Shirley, Ellis, Steve, Godwin, Andrew K, Rhiem, Kerstin, Meindl, Alfons, Ditsch, Nina, Arnold, Norbert, Plendl, Hansjoerg, Niederacher, Dieter, Sutter, Christian, Steinemann, Doris, Bogdanova-Markov, Nadja, Kast, Karin, Varon-Mateeva, Raymonda, Wang-Gohrke, Shan, Gehrig, Andrea, Markiefka, Birgid, Buecher, Bruno, Lefol, Cédrick, Stoppa-Lyonnet, Dominique, Rouleau, Etienne, Prieur, Fabienne, Damiola, Francesca, GEMO Study Collaborators, the, Barjhoux, Laure, Faivre, Laurence, Longy, Michel, Sevenet, Nicolas, Sinilnikova, Olga M, Mazoyer, Sylvie, Bonadona, Valérie, Caux-Moncoutier, Virginie, Isaacs, Claudine, Van Maerken, Tom, Claes, Kathleen, Piedmonte, Marion, Andrews, Lesley, Hays, John, Rodriguez, Gustavo C, Caldes, Trinidad, de la Hoya, Miguel, Khan, Sofia, Hogervorst, Frans BL, Aalfs, Cora M, de Lange, JL, Meijers-Heijboer, Hanne EJ, van der Hout, Annemarie H, Wijnen, Juul T, van Roozendaal, KEP, Mensenkamp, Arjen R, van den Ouweland, Ans MW, van Deurzen, Carolien HM, van der Luijt, Rob B, HEBON, ., Olah, Edith, Diez, Orland, Lazaro, Conxi, Blanco, Ignacio, Teulé, Alex, Menendez, Mireia, Jakubowska, Anna, Lubinski, Jan, Cybulski, Cezary, Gronwald, Jacek, Jaworska-Bieniek, Katarzyna, Durda, Katarzyna, Arason, Adalgeir, Maugard, Christine, Soucy, Penny, Montagna, Marco, Agata, Simona, Teixeira, Manuel R, KConFab Investigators, the, Olswold, Curtis, Lindor, Noralane, Pankratz, Vernon S, Hallberg, Emily, Wang, Xianshu, Szabo, Csilla I, Vijai, Joseph, Jacobs, Lauren, Corines, Marina, Lincoln, Anne, Berger, Andreas, Fink-Retter, Anneliese, Singer, Christian F, Rappaport, Christine, Gschwantler Kaulich, Daphne, Pfeiler, Georg, Tea, Muy-Kheng, Phelan, Catherine M, Mai, Phuong L, Greene, Mark H, Rennert, Gad, Imyanitov, Evgeny N, Glendon, Gord, Toland, Amanda Ewart, Bojesen, Anders, Pedersen, Inge Sokilde, Jensen, Uffe Birk, Caligo, Maria A, Friedman, Eitan, Berger, Raanan, Laitman, Yael, Rantala, Johanna, Arver, Brita, Loman, Niklas, Borg, Ake, Ehrencrona, Hans, Olopade, Olufunmilayo I, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Offit, Kenneth, Couch, Fergus J, Antoniou, Antonis C, CIMBA, on behalf of, Kuchenbaecker, K, Neuhausen, S, Robson, M, Barrowdale, D, Mcguffog, L, Mulligan, A, Andrulis, I, Spurdle, A, Schmidt, M, Schmutzler, R, Engel, C, Wappenschmidt, B, Nevanlinna, H, Thomassen, M, Southey, M, Radice, P, Ramus, S, Domchek, S, Nathanson, K, Lee, A, Healey, S, Nussbaum, R, Rebbeck, T, Arun, B, James, P, Karlan, B, Lester, J, Cass, I, Breast Cancer Family, R, Terry, M, Daly, M, Goldgar, D, Buys, S, Janavicius, R, Tihomirova, L, Tung, N, Dorfling, C, van Rensburg, E, Steele, L, v. O. Hansen, T, Ejlertsen, B, Gerdes, A, Nielsen, F, Dennis, J, Cunningham, J, Hart, S, Slager, S, Osorio, A, Benitez, J, Duran, M, Weitzel, J, Tafur, I, Hander, M, Peterlongo, P, Manoukian, S, Peissel, B, Roversi, G, Scuvera, G, Bonanni, B, Mariani, P, Volorio, S, Dolcetti, R, Varesco, L, Papi, L, Tibiletti, M, Giannini, G, Fostira, F, Konstantopoulou, I, Garber, J, Hamann, U, Donaldson, A, Brewer, C, Foo, C, Evans, D, Frost, D, Eccles, D, Embrace, S, Douglas, F, Brady, A, Cook, J, Tischkowitz, M, Adlard, J, Barwell, J, Ong, K, Walker, L, Izatt, L, Side, L, Kennedy, M, Rogers, M, Porteous, M, Morrison, P, Platte, R, Eeles, R, Davidson, R, Hodgson, S, Ellis, S, Godwin, A, Rhiem, K, Meindl, A, Ditsch, N, Arnold, N, Plendl, H, Niederacher, D, Sutter, C, Steinemann, D, Bogdanova Markov, N, Kast, K, Varon Mateeva, R, Wang Gohrke, S, Gehrig, A, Markiefka, B, Buecher, B, Lefol, C, Stoppa Lyonnet, D, Rouleau, E, Prieur, F, Damiola, F, GEMO Study, C, Barjhoux, L, Faivre, L, Longy, M, Sevenet, N, Sinilnikova, O, Mazoyer, S, Bonadona, V, Caux Moncoutier, V, Isaacs, C, Van Maerken, T, Claes, K, Piedmonte, M, Andrews, L, Hays, J, Rodriguez, G, Caldes, T, de la Hoya, M, Khan, S, Hogervorst, F, Aalfs, C, de Lange, J, Meijers Heijboer, H, van der Hout, A, Wijnen, J, van Roozendaal, K, Mensenkamp, A, van den Ouweland, A, van Deurzen, C, van der Luijt, R, Hebon, Olah, E, Diez, O, Lazaro, C, Blanco, I, Teulé, A, Menendez, M, Jakubowska, A, Lubinski, J, Cybulski, C, Gronwald, J, Jaworska Bieniek, K, Durda, K, Arason, A, Maugard, C, Soucy, P, Montagna, M, Agata, S, Teixeira, M, Kconfab, I, Olswold, C, Lindor, N, Pankratz, V, Hallberg, E, Wang, X, Szabo, C, Vijai, J, Jacobs, L, Corines, M, Lincoln, A, Berger, A, Fink Retter, A, Singer, C, Rappaport, C, Kaulich, D, Pfeiler, G, Tea, M, Phelan, C, Mai, P, Greene, M, Rennert, G, Imyanitov, E, Glendon, G, Toland, A, Bojesen, A, Pedersen, I, Jensen, U, Caligo, M, Friedman, E, Berger, R, Laitman, Y, Rantala, J, Arver, B, Loman, N, Borg, A, Ehrencrona, H, Olopade, O, Simard, J, Easton, D, Chenevix Trench, G, Offit, K, Couch, F, Antoniou, A, Cimba, Lee, Andrew [0000-0003-0677-0252], Dennis, Joe [0000-0003-4591-1214], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository
Subjects: Cancer Research, Receptor, ErbB-2, Genes, BRCA2, BRCA, LOCI, Genes, BRCA1, MODIFIERS, VARIANTS, ErbB-2, 610 Medical sciences Medicine, Ductal, Receptors, Medicine and Health Sciences, INVESTIGATORS, Breast, skin and connective tissue diseases, Progesterone, Medicine(all), Carcinoma, Ductal, Breast, Middle Aged, Adult, Aged, Alleles, Breast Neoplasms, Carcinoma, Carcinoma, Lobular, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Neoplasm Grading, Neoplasm Staging, Receptors, Estrogen, Receptors, Progesterone, Oncology, TUMOR SUBTYPES, Receptor, Research Article, MEDULLARY CARCINOMA, OVARIAN-CANCER, Lobular, GENOME-WIDE ASSOCIATION, CONSORTIUM, BRCA1, Estrogen, BRCA2, ESTROGEN-RECEPTOR, Genes
Abstract: Introduction More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC) = 0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC = 0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC = 0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P
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32 results on '"Lee, Andrew [0000-0003-0677-0252]"'

1. Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases

2. Prospective validation of the BOADICEA multifactorial breast cancer risk prediction model in a large prospective cohort study

3. Incorporating alternative Polygenic Risk Scores into the BOADICEA breast cancer risk prediction model

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

5. Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence

6. Comprehensive epithelial tubo-ovarian cancer risk prediction model incorporating genetic and epidemiological risk factors

7. Prospective Evaluation over 15 Years of Six Breast Cancer Risk Models

8. Should Age-Dependent Absolute Risk Thresholds Be Used for Risk Stratification in Risk-Stratified Breast Cancer Screening?

9. Prospective Evaluation of the Addition of Polygenic Risk Scores to Breast Cancer Risk Models

10. Ovarian and Breast Cancer Risks Associated with Pathogenic Variants in RAD51C and RAD51D

11. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors

12. Homeobox B13 G84E Mutation and Prostate Cancer Risk

13. Evaluating clinician acceptability of the prototype CanRisk tool for predicting risk of breast and ovarian cancer: A multi-methods study

14. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

15. Cost-effectiveness of Population-Based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 Mutation Testing in Unselected General Population Women

16. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects

17. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

18. Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

19. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

20. Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

21. Prevalence and Penetrance of Major Genes and Polygenes for Colorectal Cancer

22. Association analysis identifies 65 new breast cancer risk loci

23. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers

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

25. Polygenic risk score is associated with increased disease risk in 52 Finnish breast cancer families

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

27. An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers

28. DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

29. Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2

30. CanRisk Tool—A Web Interface for the Prediction of Breast and Ovarian Cancer Risk and the Likelihood of Carrying Genetic Pathogenic Variants

31. pedigreejs: a web-based graphical pedigree editor

32. Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers

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32 results on '"Lee, Andrew [0000-0003-0677-0252]"'

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