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

Author

Jung, Audrey Y, Ahearn, Thomas U, Behrens, Sabine, Middha, Pooja, Bolla, Manjeet K, Wang, Qin, Arndt, Volker, Aronson, Kristan J, Augustinsson, Annelie, Beane Freeman, Laura E, Becher, Heiko, Brenner, Hermann, Canzian, Federico, Carey, Lisa A, CTS Consortium, Czene, Kamila, Eliassen, A Heather, Eriksson, Mikael, Evans, D Gareth, Figueroa, Jonine D, Fritschi, Lin, Gabrielson, Marike, Giles, Graham G, Guénel, Pascal, Hadjisavvas, Andreas, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Hoppe, Reiner, Hopper, John L, Howell, Anthony, Hunter, David J, Hüsing, Anika, Kaaks, Rudolf, Kosma, Veli-Matti, Koutros, Stella, Kraft, Peter, Lacey, James V, Le Marchand, Loic, Lissowska, Jolanta, Loizidou, Maria A, Mannermaa, Arto, Maurer, Tabea, Murphy, Rachel A, Olshan, Andrew F, Olsson, Håkan, Patel, Alpa V, Perou, Charles M, Rennert, Gad, Shibli, Rana, Shu, Xiao-Ou, Southey, Melissa C, Stone, Jennifer, Tamimi, Rulla M, Teras, Lauren R, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wang, Sophia S, Wolk, Alicja, Wu, Anna H, Yang, Xiaohong R, Zheng, Wei, Dunning, Alison M, Pharoah, Paul DP, Easton, Douglas F, Milne, Roger L, Chatterjee, Nilanjan, Schmidt, Marjanka K, García-Closas, Montserrat, Chang-Claude, Jenny, Jung, Audrey Y [0000-0003-0875-6673], Ahearn, Thomas U [0000-0003-0771-7752], Behrens, Sabine [0000-0002-9714-104X], Middha, Pooja [0000-0001-5503-8215], Wang, Qin [0000-0002-9139-0627], Arndt, Volker [0000-0001-9320-8684], Aronson, Kristan J [0000-0002-7865-7243], Becher, Heiko [0000-0002-8808-6667], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Czene, Kamila [0000-0002-3233-5695], Eliassen, A Heather [0000-0002-3961-6609], Figueroa, Jonine D [0000-0002-5100-623X], Fritschi, Lin [0000-0002-7692-3560], Gabrielson, Marike [0000-0002-3171-1556], Giles, Graham G [0000-0003-4946-9099], Guénel, Pascal [0000-0002-8359-518X], Hadjisavvas, Andreas [0000-0002-5636-0799], Håkansson, Niclas [0000-0001-7673-5554], Hall, Per [0000-0002-5640-9126], Hüsing, Anika [0000-0002-2685-9732], Koutros, Stella [0000-0001-5294-5485], Kraft, Peter [0000-0002-4472-8103], Le Marchand, Loic [0000-0001-5013-980X], Lissowska, Jolanta [0000-0003-2695-5799], Loizidou, Maria A [0000-0003-4503-7758], Mannermaa, Arto [0000-0001-8250-1930], Murphy, Rachel A [0000-0003-4383-5641], Olsson, Håkan [0000-0002-7721-4619], Patel, Alpa V [0000-0001-8834-9896], Perou, Charles M [0000-0001-9827-2247], Shu, Xiao-Ou [0000-0002-0711-8314], Southey, Melissa C [0000-0002-6313-9005], Stone, Jennifer [0000-0001-5077-0124], Tamimi, Rulla M [0000-0003-2306-8668], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Dunning, Alison M [0000-0001-6651-7166], Pharoah, Paul DP [0000-0001-8494-732X], Easton, Douglas F [0000-0003-2444-3247], Milne, Roger L [0000-0001-5764-7268], Schmidt, Marjanka K [0000-0002-2228-429X], García-Closas, Montserrat [0000-0003-1033-2650], Chang-Claude, Jenny [0000-0001-8919-1971], and Apollo - University of Cambridge Repository

Subjects
Receptors, Estrogen, Receptor, ErbB-2, Risk Factors, Case-Control Studies, Biomarkers, Tumor, Humans, Female, Breast Neoplasms, Triple Negative Breast Neoplasms, Receptors, Progesterone
Abstract

BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER)-positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear. METHODS: Analyses included up to 23 353 cases and 71 072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative breast cancer) and by invasiveness. All statistical tests were 2-sided. RESULTS: Compared with nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like, and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46 for multiparous women with luminal A-like tumors 20 to less than 25 years after last birth and 45 to less than 50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95% CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95% CI = 0.79 to 1.34, for multiparous women 25 to less than 30 years after last birth). Older age at first birth (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) and breastfeeding (Pheterogeneity < .001 for triple-negative compared with luminal A-like breast cancer) were associated with lower risk of triple-negative breast cancer but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like. CONCLUSIONS: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared with other subtypes, with implications for the understanding of disease etiology and risk prediction.

Published
2022

2. Within-sibship genome-wide association analyses decrease bias in estimates of direct genetic effects

Author

Howe, Laurence J, Nivard, Michel G, Morris, Tim T, Hansen, Ailin F, Rasheed, Humaira, Cho, Yoonsu, Chittoor, Geetha, Ahlskog, Rafael, Lind, Penelope A, Palviainen, Teemu, Van Der Zee, Matthijs D, Cheesman, Rosa, Mangino, Massimo, Wang, Yunzhang, Li, Shuai, Klaric, Lucija, Ratliff, Scott M, Bielak, Lawrence F, Nygaard, Marianne, Giannelis, Alexandros, Willoughby, Emily A, Reynolds, Chandra A, Balbona, Jared V, Andreassen, Ole A, Ask, Helga, Baras, Aris, Bauer, Christopher R, Boomsma, Dorret I, Campbell, Archie, Campbell, Harry, Chen, Zhengming, Christofidou, Paraskevi, Corfield, Elizabeth, Dahm, Christina C, Dokuru, Deepika R, Evans, Luke M, De Geus, Eco JC, Giddaluru, Sudheer, Gordon, Scott D, Harden, K Paige, Hill, W David, Hughes, Amanda, Kerr, Shona M, Kim, Yongkang, Kweon, Hyeokmoon, Latvala, Antti, Lawlor, Deborah A, Li, Liming, Lin, Kuang, Magnus, Per, Magnusson, Patrik KE, Mallard, Travis T, Martikainen, Pekka, Mills, Melinda C, Njølstad, Pål Rasmus, Overton, John D, Pedersen, Nancy L, Porteous, David J, Reid, Jeffrey, Silventoinen, Karri, Southey, Melissa C, Stoltenberg, Camilla, Tucker-Drob, Elliot M, Wright, Margaret J, Social Science Genetic Association Consortium, Within Family Consortium, Hewitt, John K, Keller, Matthew C, Stallings, Michael C, Lee, James J, Christensen, Kaare, Kardia, Sharon LR, Peyser, Patricia A, Smith, Jennifer A, Wilson, James F, Hopper, John L, Hägg, Sara, Spector, Tim D, Pingault, Jean-Baptiste, Plomin, Robert, Havdahl, Alexandra, Bartels, Meike, Martin, Nicholas G, Oskarsson, Sven, Justice, Anne E, Millwood, Iona Y, Hveem, Kristian, Naess, Øyvind, Willer, Cristen J, Åsvold, Bjørn Olav, Koellinger, Philipp D, Kaprio, Jaakko, Medland, Sarah E, Walters, Robin G, Benjamin, Daniel J, Turley, Patrick, Evans, David M, Davey Smith, George, Hayward, Caroline, Brumpton, Ben, Hemani, Gibran, Davies, Neil M, Howe, Laurence J [0000-0002-2819-9686], Nivard, Michel G [0000-0003-2015-1888], Morris, Tim T [0000-0001-8178-6815], Rasheed, Humaira [0000-0002-3331-5864], Cho, Yoonsu [0000-0001-6118-6652], Lind, Penelope A [0000-0002-3887-2598], Palviainen, Teemu [0000-0002-7847-8384], van der Zee, Matthijs D [0000-0003-4076-9167], Mangino, Massimo [0000-0002-2167-7470], Wang, Yunzhang [0000-0003-1165-3595], Klaric, Lucija [0000-0003-3105-8929], Bielak, Lawrence F [0000-0002-3443-8030], Nygaard, Marianne [0000-0003-0703-2665], Giannelis, Alexandros [0000-0003-4587-0336], Willoughby, Emily A [0000-0001-7559-1544], Reynolds, Chandra A [0000-0001-6502-7173], Balbona, Jared V [0000-0003-4466-248X], Andreassen, Ole A [0000-0002-4461-3568], Ask, Helga [0000-0003-0149-5319], Baras, Aris [0000-0002-6830-3396], Boomsma, Dorret I [0000-0002-7099-7972], Campbell, Archie [0000-0003-0198-5078], Chen, Zhengming [0000-0001-6423-105X], Corfield, Elizabeth [0000-0002-0119-157X], Evans, Luke M [0000-0002-7458-1720], Gordon, Scott D [0000-0001-7623-328X], Harden, K Paige [0000-0002-1557-6737], Hughes, Amanda [0000-0001-5896-7650], Kerr, Shona M [0000-0002-4137-1495], Kweon, Hyeokmoon [0000-0002-3649-0457], Lawlor, Deborah A [0000-0002-6793-2262], Magnusson, Patrik KE [0000-0002-7315-7899], Mallard, Travis T [0000-0002-3265-3001], Martikainen, Pekka [0000-0001-9374-1438], Njølstad, Pål Rasmus [0000-0003-0304-6728], Porteous, David J [0000-0003-1249-6106], Reid, Jeffrey [0000-0001-8645-4713], Southey, Melissa C [0000-0002-6313-9005], Stoltenberg, Camilla [0000-0002-8747-1985], Tucker-Drob, Elliot M [0000-0001-5599-6237], Wright, Margaret J [0000-0001-7133-4970], Keller, Matthew C [0000-0002-6075-9882], Lee, James J [0000-0001-6547-5128], Christensen, Kaare [0000-0002-5429-5292], Peyser, Patricia A [0000-0002-9717-8459], Smith, Jennifer A [0000-0002-3575-5468], Wilson, James F [0000-0001-5751-9178], Hägg, Sara [0000-0002-2452-1500], Spector, Tim D [0000-0002-9795-0365], Plomin, Robert [0000-0002-0756-3629], Havdahl, Alexandra [0000-0002-9268-0423], Bartels, Meike [0000-0002-9667-7555], Oskarsson, Sven [0000-0001-8698-2866], Willer, Cristen J [0000-0001-5645-4966], Åsvold, Bjørn Olav [0000-0003-3837-2101], Koellinger, Philipp D [0000-0001-7413-0412], Kaprio, Jaakko [0000-0002-3716-2455], Walters, Robin G [0000-0002-9179-0321], Benjamin, Daniel J [0000-0002-2642-5416], Evans, David M [0000-0003-0663-4621], Davey Smith, George [0000-0002-1407-8314], Hayward, Caroline [0000-0002-9405-9550], Brumpton, Ben [0000-0002-3058-1059], Hemani, Gibran [0000-0003-0920-1055], Davies, Neil M [0000-0002-2460-0508], and Apollo - University of Cambridge Repository

Subjects
Multifactorial Inheritance, Phenotype, 631/208/205/2138, article, Humans, 631/208/457, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, Genome-Wide Association Study
Abstract

Funder: Jacobs Foundation; doi: https://doi.org/10.13039/501100003986, Estimates from genome-wide association studies (GWAS) of unrelated individuals capture effects of inherited variation (direct effects), demography (population stratification, assortative mating) and relatives (indirect genetic effects). Family-based GWAS designs can control for demographic and indirect genetic effects, but large-scale family datasets have been lacking. We combined data from 178,086 siblings from 19 cohorts to generate population (between-family) and within-sibship (within-family) GWAS estimates for 25 phenotypes. Within-sibship GWAS estimates were smaller than population estimates for height, educational attainment, age at first birth, number of children, cognitive ability, depressive symptoms and smoking. Some differences were observed in downstream SNP heritability, genetic correlations and Mendelian randomization analyses. For example, the within-sibship genetic correlation between educational attainment and body mass index attenuated towards zero. In contrast, analyses of most molecular phenotypes (for example, low-density lipoprotein-cholesterol) were generally consistent. We also found within-sibship evidence of polygenic adaptation on taller height. Here, we illustrate the importance of family-based GWAS data for phenotypes influenced by demographic and indirect genetic effects.

Published
2022
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3. Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

Author

Anne-Laure Renault, James G. Dowty, Jason A. Steen, Shuai Li, Ingrid M. Winship, Graham G. Giles, John L. Hopper, Melissa C. Southey, Tú Nguyen-Dumont, Southey, Melissa C [0000-0002-6313-9005], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, Age-specific cumulative risk, Tumor Suppressor Proteins, Short Report, Age Factors, Australia, Penetrance, Breast Neoplasms, Ataxia Telangiectasia Mutated Proteins, Breast cancer predisposition, ATM, Humans, Female, Genetic Predisposition to Disease, Genetic risk factors
Abstract

BackgroundMultigene panel tests for breast cancer predisposition routinely includeATMas it is now a well-established breast cancer predisposition gene.MethodsWe includedATMin a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygousATMpathogenic variants from the family data, using segregation analysis.ResultsThe estimated breast cancer hazard ratio for carriers of pathogenicATMvariants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87;P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATMpathogenic variant carriers was estimated to be 13% (95% CI 4.6–30).ConclusionsAlthoughATMhas been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

Published
2021

4. 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

5. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Author

Morra, Anna, Jung, Audrey Y, Behrens, Sabine, Keeman, Renske, Ahearn, Thomas U, Anton-Culver, Hoda, Arndt, Volker, Augustinsson, Annelie, Auvinen, Päivi K, Beane Freeman, Laura E, Becher, Heiko, Beckmann, Matthias W, Blomqvist, Carl, Bojesen, Stig E, Bolla, Manjeet K, Brenner, Hermann, Briceno, Ignacio, Brucker, Sara Y, Camp, Nicola J, Campa, Daniele, Canzian, Federico, Castelao, Jose E, Chanock, Stephen J, Choi, Ji-Yeob, Clarke, Christine L, Couch, Fergus J, Cox, Angela, Cross, Simon S, Czene, Kamila, Dörk, Thilo, Dunning, Alison M, Dwek, Miriam, Easton, Douglas F, Eccles, Diana M, Egan, Kathleen M, Evans, D Gareth, Fasching, Peter A, Flyger, Henrik, Gago-Dominguez, Manuela, Gapstur, Susan M, García-Sáenz, José A, Gaudet, Mia M, Giles, Graham G, Grip, Mervi, Guénel, Pascal, Haiman, Christopher A, Håkansson, Niclas, Hall, Per, Hamann, Ute, Han, Sileny N, Hart, Steven N, Hartman, Mikael, Heyworth, Jane S, Hoppe, Reiner, Hopper, John L, Hunter, David J, Ito, Hidemi, Jager, Agnes, Jakimovska, Milena, Jakubowska, Anna, Janni, Wolfgang, Kaaks, Rudolf, Kang, Daehee, Kapoor, Pooja Middha, Kitahara, Cari M, Koutros, Stella, Kraft, Peter, Kristensen, Vessela N, Lacey, James V, Lambrechts, Diether, Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lubiński, Jan, Lush, Michael, Mannermaa, Arto, Manoochehri, Mehdi, Margolin, Sara, Mariapun, Shivaani, Matsuo, Keitaro, Mavroudis, Dimitrios, Milne, Roger L, Muranen, Taru A, Newman, William G, Noh, Dong-Young, Nordestgaard, Børge G, Obi, Nadia, Olshan, Andrew F, Olsson, Håkan, Park-Simon, Tjoung-Won, Petridis, Christos, Pharoah, Paul DP, Plaseska-Karanfilska, Dijana, Presneau, Nadege, Rashid, Muhammad U, Rennert, Gad, Rennert, Hedy S, Rhenius, Valerie, Romero, Atocha, Saloustros, Emmanouil, Sawyer, Elinor J, Schneeweiss, Andreas, Schwentner, Lukas, Scott, Christopher, Shah, Mitul, Shen, Chen-Yang, Shu, Xiao-Ou, Southey, Melissa C, Stram, Daniel O, Tamimi, Rulla M, Tapper, William, Tollenaar, Rob AEM, Tomlinson, Ian, Torres, Diana, Troester, Melissa A, Truong, Thérèse, Vachon, Celine M, Wang, Qin, Wang, Sophia S, Williams, Justin A, Winqvist, Robert, Wolk, Alicja, Wu, Anna H, Yoo, Keun-Young, Yu, Jyh-Cherng, Zheng, Wei, Ziogas, Argyrios, Yang, Xiaohong R, Eliassen, A Heather, Holmes, Michelle D, García-Closas, Montserrat, Teo, Soo Hwang, Schmidt, Marjanka K, Chang-Claude, Jenny, ABCTB Investigators, NBCS Collaborators, Behrens, Sabine [0000-0002-9714-104X], Keeman, Renske [0000-0002-5452-9933], Ahearn, Thomas U [0000-0003-0771-7752], Arndt, Volker [0000-0001-9320-8684], Augustinsson, Annelie [0000-0003-3415-0536], Brenner, Hermann [0000-0002-6129-1572], Camp, Nicola J [0000-0002-4788-1998], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Dunning, Alison M [0000-0001-6651-7166], Evans, D Gareth [0000-0002-8482-5784], Fasching, Peter A [0000-0003-4885-8471], Gago-Dominguez, Manuela [0000-0001-6713-4351], García-Sáenz, José A [0000-0001-6880-0301], Gaudet, Mia M [0000-0002-6429-4007], Giles, Graham G [0000-0003-4946-9099], Guénel, Pascal [0000-0002-8359-518X], Hall, Per [0000-0002-5640-9126], Hart, Steven N [0000-0001-7714-2734], Hartman, Mikael [0000-0001-5726-9965], Ito, Hidemi [0000-0002-8023-4581], Jager, Agnes [0000-0002-7713-1450], Jakubowska, Anna [0000-0002-5650-0501], Janni, Wolfgang [0000-0001-5911-2400], Kaaks, Rudolf [0000-0003-3751-3929], Kapoor, Pooja Middha [0000-0001-5503-8215], Koutros, Stella [0000-0001-5294-5485], Lambrechts, Diether [0000-0002-3429-302X], Li, Jingmei [0000-0001-8587-7511], Matsuo, Keitaro [0000-0003-1761-6314], Milne, Roger L [0000-0001-5764-7268], Muranen, Taru A [0000-0002-5895-1808], Newman, William G [0000-0002-6382-4678], Park-Simon, Tjoung-Won [0000-0002-2863-3040], Pharoah, Paul DP [0000-0001-8494-732X], Rennert, Gad [0000-0002-8512-068X], Rennert, Hedy S [0000-0001-5772-2977], Rhenius, Valerie [0000-0003-4215-3235], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Schneeweiss, Andreas [0000-0002-2429-4512], Scott, Christopher [0000-0003-1340-0647], Southey, Melissa C [0000-0002-6313-9005], Stram, Daniel O [0000-0001-7099-9022], Tamimi, Rulla M [0000-0003-2306-8668], Tomlinson, Ian [0000-0003-3037-1470], Torres, Diana [0000-0002-9879-9775], Vachon, Celine M [0000-0002-1962-9322], Wolk, Alicja [0000-0001-7387-6845], Ziogas, Argyrios [0000-0003-4529-3727], Holmes, Michelle D [0000-0002-8664-2172], García-Closas, Montserrat [0000-0003-1033-2650], Teo, Soo Hwang [0000-0002-0444-590X], Schmidt, Marjanka K [0000-0002-2228-429X], Chang-Claude, Jenny [0000-0001-8919-1971], and Apollo - University of Cambridge Repository

Subjects
Adult, Risk Factors, Cause of Death, Humans, Breast Neoplasms, Female, Neoplasm Invasiveness, Prospective Studies, Middle Aged, Life Style, Survival Analysis, Aged, Neoplasm Staging
Abstract

BACKGROUND: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (P adj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus 0

Published
2021
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6. Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer

Author

Rosalind A. Eeles, Christopher A. Haiman, David V. Conti, Xin Sheng, Zsofia Kote-Jarai, Peggy Wan, Burcu F. Darst, Kurt N. Hetrick, Demetrius Albanes, Roger L. Milne, Melissa C. Southey, Fredrik Wiklund, Lucy Xia, Lorelei A. Mucci, Loreall Pooler, Robert J. MacInnis, Graham G. Giles, Sonja I. Berndt, William J. Catalona, Vincent Gnanapragasam, Stephanie J. Weinstein, Stephen J. Chanock, Kimberly F. Doheny, Mark Pomerantz, Susan M. Gapstur, Julie A. Schmidt, Ed Saunders, Victoria L. Stevens, Tokhir Dadaev, Tu Nguyen-Dumont, Darst, Burcu F [0000-0002-6205-4632], Chanock, Stephen [0000-0002-2324-3393], Stevens, Victoria [0000-0003-0259-4407], Albanes, Demetrius [0000-0001-8330-4293], Weinstein, Stephanie J [0000-0002-3834-1535], Pomerantz, Mark [0000-0003-4914-1157], Schmidt, Julie A [0000-0002-7733-8750], Southey, Melissa C [0000-0002-6313-9005], and Apollo - University of Cambridge Repository

Subjects
Male, Oncology, Cancer Research, medicine.medical_specialty, DNA Repair, DNA repair, PALB2, Genes, BRCA2, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, P-Chloroamphetamine, Germ-Line Mutation, 030304 developmental biology, 0303 health sciences, business.industry, Prostatic Neoplasms, Cancer, Articles, Odds ratio, medicine.disease, Minor allele frequency, Germ Cells, 030220 oncology & carcinogenesis, business
Abstract

Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. Methods Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

Published
2020

7. Association of genomic domains in BRCA1 and BRCA2 with prostate cancer risk and aggressiveness

Author

Henriette Roed Nielsen, Judith Balmaña, Anne-Marie Gerdes, Ellen Honisch, Melissa C. Southey, Ramunas Janavicius, Finn Cilius Nielsen, Douglas F. Easton, Linda Steele, Ava Kwong, Sung Won Kim, Bjarni A. Agnarsson, Piera Rizzolo, Angela R. Solano, Mads Thomassen, Johannes Lemke, Grazia Artioli, Heli Nevanlinna, Johanna I. Kiiski, Frans B. L. Hogervorst, Jong Won Lee, Diana Eccles, Mark H. Greene, Marc Tischkowitz, David E. Goldgar, Angela R. Bradbury, Javier Benitez, Marie Navratilova, Dominique Stoppa-Lyonnet, Arjen R. Mensenkamp, Alfons Meindl, Zisun Kim, Nadine Tung, Agnes Jager, Matthew L. Freedman, Ana Osorio, Norbert Arnold, Doris Steinemann, Inge Søkilde Pedersen, Patricia Llovet, Rob B. van der Luijt, Vivek L Patel, Munaza Ahmed, Lidia Moserle, Irene Konstantopoulou, Jackie Cook, Jacques Simard, Joan Brunet, Johanna Rantala, Kai-ren Ong, Carole Brewer, Joe Dennis, Sook-Yee Yoon, Hanne Meijers-Heijboer, Roberta Villa, Katie Snape, Louise Izatt, Ana Peixoto, Susan M. Domchek, Nina Ditsch, D. Gareth Evans, Tara M. Friebel, Sue K. Park, Katherine L. Nathanson, Lenka Foretova, Miguel Angel Pujana, Edith Olah, Hélène Schuster, Raymonda Varon-Mateeva, Silvia Tognazzo, Payal D. Shah, Oskar T. Johannsson, Hans Ehrencrona, Paul Gesta, Ian G. Campbell, Drakoulis Yannoukakos, Mirjam Larsen, Anthony V. D'Amico, Liene Nikitina-Zake, Davide Bondavalli, Valérie Bonadona, Paul A. James, Alan Donaldson, Antonis C. Antoniou, Bernd Auber, Andrew K. Godwin, Denise Molina Gomes, Jihyoun Lee, Laurence Faivre, Almuth Caliebe, Pilar Garre, Siddhartha Yadav, Julika Borde, Pedro Pérez-Segura, Birgitte Bertelsen, Paolo Peterlongo, Michael T. Parsons, John L. Hopper, Bruno Buecher, Goska Leslie, Shan Wang-Gohrke, Amanda B. Spurdle, T.M. Mooij, Juliane Ramser, kConFab Investigators, Lídia Feliubadaló, Susanne E. Boonen, Bernard Peissel, Anna von Wachenfeldt, Timothy R. Rebbeck, Christi J. van Asperen, Víctor Lorca, Estela Carrasco, Elisa Alducci, Ulrike Faust, Karin Kast, Gord Glendon, Saundra S. Buys, Fergus J. Couch, Mariarosaria Calvello, Istvan Bodrogi, Kathryn J. Ruddy, Philipp Wagner, Fabienne Lesueur, Evan L. Busch, Hebon Investigators, Laura Cortesi, Christian F. Singer, Ute Hamann, Giuseppe Damante, Stefania Tommasi, Esther M. John, Jacopo Azzollini, Cristina Zanzottera, Angelica M. Gutierrez-Barrera, Emmanuelle Mouret-Fourme, Claire Saule, Rosa B. Barkardottir, Kristin K. Zorn, Kerstin Rhiem, Uffe Birk Jensen, Mark Pomerantz, Yuan Chun Ding, Alison H. Trainer, Marco Montagna, Vijai Joseph, Domenico Palli, Kwang-Pil Ko, Angel M. Cronin, Susan L. Neuhausen, Dieter Niederacher, Laura Ottini, Angela Toss, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Caroline M. Seynaeve, Ileana Carnevali, Adalgeir Arason, Rosalind A. Eeles, Annie T W Chu, Florentia Fostira, Greet Wieme, Brita Arver, Charlotte Kvist Lautrup, Christoph Engel, Marion Gauthier-Villars, Daniel Barrowdale, Caroline Maria Rossing, Kenneth Offit, Kathleen Claes, Olufunmilayo I. Olopade, Penny Soucy, Alicia Barroso, Manuel R. Teixeira, Wendy K. Chung, Gero Kramer, Tsun Leung Chan, Agostina Stradella, Debra Frost, Noura Mebirouk, Liselotte P. van Hest, Esther Darder, Valentina Silvestri, Annabeth Høgh Petersen, Lesley McGuffog, Andrea Gehrig, Mary Porteous, Matti A. Rookus, Lizet E. van der Kolk, Siranoush Manoukian, Lone Sunde, Conxi Lázaro, Maria A. Caligo, Priyanka Sharma, Anne-Bine Skytte, Claus-Eric Ott, Christian Sutter, Paolo Radice, Veronica Medici, Georgia Chenevix-Trench, Vanesa García-Barberán, Kristiina Aittomäki, Amanda E. Toland, Anna Marie Mulligan, Véronique Mari, Bernd Dworniczak, Lynn Martin, Lara Della Puppa, Phuong L. Mai, George Fountzilas, Yen Y. Tan, Simona Agata, Torben A Kruse, Trinidad Caldés, Rosemarie Davidson, Daniel R. Barnes, Thomas Dyrso Jensen, Åke Borg, Mark E. Robson, Jennifer T. Loud, Vivian Y. Shin, Irene López-Perolio, Leigha Senter, Irene L. Andrulis, Rosa Scarpitta, Angela F. Brady, Annika Lindblom, Diana Torres, Lotte Nylandsted Krogh, Barbara Wappenschmidt, Muhammad Rashid, Jeroen Vierstraete, Mary B. Daly, Annelie Liljegren, Frederieke H. van der Baan, Eunyoung Kang, Alessandra Viel, Santiago Cabezas-Camarero, Eric Hahnen, Laura Matricardi, Marinus J. Blok, Edmond S. K. Ma, Maria Grazia Tibiletti, Catarina Santos, Julian Adlard, Soo Hwang Teo, Giuseppe Giannini, Jan Hauke, Peter J. Hulick, Miguel de la Hoya, Clare Miller, Bernardo Bonanni, Bent Ejlertsen, Lajos Géczi, Liliana Varesco, Orland Diez, N Herold, Christine Lasset, Adrià López-Fernández, Min Hyuk Lee, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, Clinicum, Department of Obstetrics and Gynecology, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), Medical Oncology, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Leslie, Goska [0000-0001-5756-6222], Adlard, Julian [0000-0002-1693-0435], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barnes, Daniel R [0000-0002-3781-7570], Brunet, Joan [0000-0003-1945-3512], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian G [0000-0002-7773-4155], Claes, Kathleen BM [0000-0003-0841-7372], Darder, Esther [0000-0002-7764-1397], Dennis, Joe [0000-0003-4591-1214], Dworniczak, Bernd [0000-0003-4981-7903], Eeles, Rosalind A [0000-0002-3698-6241], Ehrencrona, Hans [0000-0002-5589-3622], Ejlertsen, Bent [0000-0001-8761-714X], Evans, D Gareth [0000-0002-8482-5784], Garre, Pilar [0000-0001-8285-4138], Greene, Mark H [0000-0003-1852-9239], Hulick, Peter J [0000-0001-8397-4078], Jager, Agnes [0000-0002-7713-1450], James, Paul [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Joseph, Vijai [0000-0002-7933-151X], Kim, Sung-Won [0000-0002-1413-2800], Kim, Zisun [0000-0002-1413-2800], Konstantopoulou, Irene [0000-0002-0470-0309], Lesueur, Fabienne [0000-0001-7404-4549], Matricardi, Laura [0000-0002-0241-1810], Gomes, Denise Molina [0000-0002-2836-9008], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Palli, Domenico [0000-0002-5558-2437], Park, Sue K [0000-0001-5002-9707], Parsons, Michael T [0000-0003-3242-8477], Peterlongo, Paolo [0000-0001-6951-6855], Petersen, Annabeth Høgh [0000-0002-4503-6942], Pujana, Miguel Angel [0000-0003-3222-4044], Ruddy, Kathryn J [0000-0001-6298-332X], Scarpitta, Rosa [0000-0001-7590-3827], Shah, Payal D [0000-0001-5874-3390], Silvestri, Valentina [0000-0003-0712-9379], Southey, Melissa C [0000-0002-6313-9005], Spurdle, Amanda B [0000-0003-1337-7897], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Sunde, Lone [0000-0002-8479-165X], Teixeira, Manuel R [0000-0002-4896-5982], Teo, Soo Hwang [0000-0002-0444-590X], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], van der Luijt, Rob B [0000-0002-0018-1089], Vierstraete, Jeroen [0000-0001-7909-6620], Wieme, Greet [0000-0003-2718-5300], Yadav, Siddhartha [0000-0003-4630-9903], Antoniou, Antonis C [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Human genetics, and CCA - Cancer biology and immunology

Subjects
Male, 0301 basic medicine, Oncology, Cancer Research, endocrine system diseases, PHENOTYPE, INCREASE, Prostate cancer, 0302 clinical medicine, Risk Factors, Young adult, skin and connective tissue diseases, Aged, 80 and over, Prostate cancer risk, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], MESSENGER-RNA DECAY, BRCA1 Protein, Genomics, GERMLINE MUTATIONS, Middle Aged, Prognosis, OVARIAN, CARRIERS, 3. Good health, 030220 oncology & carcinogenesis, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Tumor suppressor gene, Urology, Association (object-oriented programming), 3122 Cancers, MEDLINE, Article, Young Adult, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, BRCA1, BRCA2, Prostate Cancer, Pathogenic sequence variant location, Risk estimation, Journal Article, Genetic predisposition, medicine, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Risk factor, Genetic Association Studies, Aged, BRCA2 Protein, IDENTIFICATION, business.industry, Prostatic Neoplasms, medicine.disease, GENE, Confidence interval, APC, 030104 developmental biology, Mutation, 3111 Biomedicine, business
Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Published
2020

8. Reproductive profiles and risk of breast cancer subtypes: a multi-center case-only study

Author

Javier Benitez, Sara Margolin, Diether Lambrechts, Alexandra J. van den Broek, Chen-Yang Shen, Veli-Matti Kosma, Matthias W. Beckmann, Siranoush Manoukian, Antoinette Hollestelle, Montserrat Garcia-Closas, Paul Brennan, Chiu-Chen Tseng, Marjanka K. Schmidt, Carolien H.M. van Deurzen, Peter A. Fasching, Melissa C. Southey, Manjeet K. Bolla, Robert Winqvist, Keitaro Matsuo, Douglas F. Easton, Carl Blomqvist, Adelheid Soubry, Paul D.P. Pharoah, Pascal Guénel, Jenna Lilyquist, Anna González-Neira, Hidemi Ito, Daehee Kang, Thérèse Truong, Fergus J. Couch, Renske Keeman, Kenneth Muir, Caroline Seynaeve, Katri Pylkäs, Simon S. Cross, Per Hall, Olivier Brouckaert, Roger L. Milne, Cheng Har Yip, Qin Wang, Sten Cornelissen, Anja Rudolph, Kamila Czene, Artitaya Lophatananon, Mikael Eriksson, Xiao-Ou Shu, Jonine D. Figueroa, Julia A. Knight, Arto Mannermaa, Jyh-Cherng Yu, Hans Wildiers, John L. Hopper, Wei Zheng, Jingmei Li, Rob A. E. M. Tollenaar, Anthony J. Swerdlow, Hermann Brenner, Henrik Flyger, Patrick Neven, Georgia Chenevix-Trench, Irene L. Andrulis, Paolo Peterlongo, Ji Yeob Choi, Annouschka Laenen, Annika Lindblom, Hiltrud Brauch, Anna H. Wu, Heli Nevanlinna, Michael Jones, Angela Cox, Volker Arndt, Soo-Hwang Teo, Jenny Chang-Claude, Stig E. Bojesen, Graham G. Giles, Suleeporn Saajrang, School of Medicine / Clinical Medicine, Wang, Jean [0000-0002-9139-0627], Benitez, Javier [0000-0002-0923-7202], Blomqvist, Carl [0000-0003-3041-1938], Brauch, Hiltrud [0000-0001-7531-2736], Brenner, Hermann [0000-0002-6129-1572], Chenevix-Trench, Georgia [0000-0002-1878-2587], Cox, Angela [0000-0002-5138-1099], Eriksson, Mikael [0000-0001-8135-4270], González-Neira, Anna [0000-0002-5421-2020], Guénel, Pascal [0000-0002-8359-518X], Jones, Michael [0000-0001-7479-3451], Li, Jingmei [0000-0001-8587-7511], Matsuo, Keitaro [0000-0003-1761-6314], Peterlongo, Paolo [0000-0001-6951-6855], Pylkäs, Katri [0000-0002-2449-0521], Southey, Melissa C [0000-0002-6313-9005], Swerdlow, Anthony [0000-0001-5550-4159], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Lambrechts, Diether [0000-0002-3429-302X], Apollo - University of Cambridge Repository, Medical Oncology, Pathology, Department of Oncology, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, HUS Comprehensive Cancer Center, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), NIH - National Cancer Institute (NCI) (Estados Unidos), National Health and Medical Research Council (Australia), New South Wales Cancer Council (Reino Unido), Victorian Health Promotion Foundation, Dutch Cancer Society (Holanda), Agence Nationale de la Recherche (Francia), French Agency for Food, Environmental and Occupational Health & Safety (Francia), Asociación Española Contra el Cáncer, Instituto de Salud Carlos III, Centro de Investigación Biomedica en Red - CIBER, Federal Ministry of Education & Research (Alemania), Cancer Society of Finland, Ministry of Education, Culture, Sports, Science, and Technology (Japón), Japan Agency for Medical Research and Development, United States Army Medical Research and Development Command, California Breast Cancer Research Program, German Cancer Aid, Ministry of Higher Education (Malasia), Biomedical Research Council (Singapore), National Institutes of Health (Estados Unidos), and National Research Foundation of Korea

Subjects
0301 basic medicine, Oncology, Triple Negative Breast Neoplasms, Cohort Studies, 0302 clinical medicine, HORMONE-RECEPTOR STATUS, Medizinische Fakultät, Risk Factors, Odds Ratio, Young adult, Reproductive History, POPULATION, Age at menarche, education.field_of_study, WOMEN, ASSOCIATION, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Parity, PREGNANCY, 030220 oncology & carcinogenesis, Age at breast cancer diagnosis, kConFab, Menarche, Female, Cohort study, Research Article, Adult, medicine.medical_specialty, 3122 Cancers, Population, Breast Neoplasms, DIAGNOSIS, lcsh:RC254-282, Risk Assessment, MENARCHE, 1ST BIRTH, 03 medical and health sciences, Young Adult, AGE, Breast cancer, SDG 3 - Good Health and Well-being, Internal medicine, Journal Article, medicine, Biomarkers, Tumor, Humans, ddc:610, education, Aged, Gynecology, Pregnancy, business.industry, Odds ratio, medicine.disease, 030104 developmental biology, Age at first full-time pregnancy, Breast cancer subtype, business
Abstract

Background Previous studies have shown that reproductive factors are differentially associated with breast cancer (BC) risk by subtypes. The aim of this study was to investigate associations between reproductive factors and BC subtypes, and whether these vary by age at diagnosis. Methods We used pooled data on tumor markers (estrogen and progesterone receptor, human epidermal growth factor receptor-2 (HER2)) and reproductive risk factors (parity, age at first full-time pregnancy (FFTP) and age at menarche) from 28,095 patients with invasive BC from 34 studies participating in the Breast Cancer Association Consortium (BCAC). In a case-only analysis, we used logistic regression to assess associations between reproductive factors and BC subtype compared to luminal A tumors as a reference. The interaction between age and parity in BC subtype risk was also tested, across all ages and, because age was modeled non-linearly, specifically at ages 35, 55 and 75 years. Results Parous women were more likely to be diagnosed with triple negative BC (TNBC) than with luminal A BC, irrespective of age (OR for parity = 1.38, 95% CI 1.16–1.65, p = 0.0004; p for interaction with age = 0.076). Parous women were also more likely to be diagnosed with luminal and non-luminal HER2-like BCs and this effect was slightly more pronounced at an early age (p for interaction with age = 0.037 and 0.030, respectively). For instance, women diagnosed at age 35 were 1.48 (CI 1.01–2.16) more likely to have luminal HER2-like BC than luminal A BC, while this association was not significant at age 75 (OR = 0.72, CI 0.45–1.14). While age at menarche was not significantly associated with BC subtype, increasing age at FFTP was non-linearly associated with TNBC relative to luminal A BC. An age at FFTP of 25 versus 20 years lowered the risk for TNBC (OR = 0.78, CI 0.70–0.88, p, published version, peerReviewed

Published
2017

9. Breast cancer risk prediction using a polygenic risk score in the familial setting: a prospective study from the Breast Cancer Family Registry and kConFab

Author

Li, Hongyan, Feng, Bingjian, Miron, Alexander, Chen, Xiaoqing, Beesley, Jonathan, Bimeh, Emmanuella, Barrowdale, Daniel, John, Esther M, Daly, Mary B, Andrulis, Irene L, Buys, Saundra S, Kraft, Peter, kConFab investigators, Thorne, Heather, Chenevix-Trench, Georgia, Southey, Melissa C, Antoniou, Antonis C, James, Paul A, Terry, Mary Beth, Phillips, Kelly-Anne, Hopper, John L, Mitchell, Gillian, Goldgar, David E, Beesley, Jonathan [0000-0003-1942-325X], Barrowdale, Daniel [0000-0003-1661-3939], Southey, Melissa C [0000-0002-6313-9005], James, Paul A [0000-0002-4361-4657], Hopper, John L [0000-0002-8567-173X], Goldgar, David E [0000-0003-0697-9347], and Apollo - University of Cambridge Repository

Subjects
Adult, Multifactorial Inheritance, Risk Factors, Humans, Breast Neoplasms, Female, Genetic Predisposition to Disease, Registries, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, Early Detection of Cancer, Aged
Abstract

PURPOSE: This study examined the utility of sets of single-nucleotide polymorphisms (SNPs) in familial but non-BRCA-associated breast cancer (BC). METHODS: We derived a polygenic risk score (PRS) based on 24 known BC risk SNPs for 4,365 women from the Breast Cancer Family Registry and Kathleen Cuningham Consortium Foundation for Research into Familial Breast Cancer familial BC cohorts. We compared scores for women based on cancer status at baseline; 2,599 women unaffected at enrollment were followed-up for an average of 7.4 years. Cox proportional hazards regression was used to analyze the association of PRS with BC risk. The BOADICEA risk prediction algorithm was used to measure risk based on family history alone. RESULTS: The mean PRS at baseline was 2.25 (SD, 0.35) for affected women and was 2.17 (SD, 0.35) for unaffected women from combined cohorts (P < 10-6). During follow-up, 205 BC cases occurred. The hazard ratios for continuous PRS (per SD) and upper versus lower quintiles were 1.38 (95% confidence interval: 1.22-1.56) and 3.18 (95% confidence interval: 1.84-5.23) respectively. Based on their PRS-based predicted risk, management for up to 23% of women could be altered. CONCLUSION: Including BC-associated SNPs in risk assessment can provide more accurate risk prediction than family history alone and can influence recommendations for cancer screening and prevention modalities for high-risk women.Genet Med 19 1, 30-35.

Published
2017

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