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1. The genetic background of Southern Iranian couples before marriage

Author: Nariman A, Sobhan MR, Savaei M, Aref-Eshghi E, Nourinejad R, Manoochehri M, Ghahremani S, Daliri F, and Daliri K
Subjects: genetic counseling, genetic testing, iran, Genetics, QH426-470
Abstract: Genetic service for couples plays an increasingly important role in diagnosis and risk management. This study investigated the status of consanguinity and the medical genetic history (effectiveness and coverage of medical genetic services) in couples residing in a city in southern Iran. We questioned couples who were referred to Behbahan Marital Counseling Center, Behbahan, Iran, during the period from January to November 2014, to obtain information on consanguinity, disease history, and previous referral to a medical genetics center. For the collected data was obtained descriptive statistics with STATA 11.0 software. A total of 500 couples were questioned. Mean age was 24.8 ± 5.2 years. Almost one quarter (23.4%) of the couples were consanguineous. Consanguinity was almost twice as common in rural areas as in urban areas (33.9 vs. 19.2%, p = 0.001). Only a few couples (~3.0%) had ever been referred for genetic counseling. The main reason for previous genetic counseling was consanguinity (85.7%). The majority of the participants (96.3%) had never been tested for any genetic conditions. Our findings suggest that only a small proportion of couples in Khuzestan Province, Iran (Behbahan City) were receiving adequate genetics care. This may reflect the limited accessibility of such services, and inadequate awareness and education among the care providers.
Published: 2016
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2. Comparison of sporadic and familial behavioral variant frontotemporal dementia (FTD) in a North American cohort

Author: Heuer, Hilary W, Wang, P, Rascovsky, K, Wolf, A, Appleby, B, Bove, J, Bordelon, Y, Brannelly, P, Brushaber, DE, Caso, C, Coppola, G, Dickerson, B, Dickinson, S, Domoto‐Reilly, K, Faber, K, Ferrall, J, Fields, J, Fishman, A, Fong, J, Foroud, T, Forsberg, LK, Gearhart, D, Ghazanfari, B, Ghoshal, N, Goldman, J, Graff‐Radford, J, Graff‐Radford, N, Grant, I, Grossman, M, Haley, D, Hsiung, G‐Y, Huey, E, Irwin, D, Jones, D, Kantarci, K, Karydas, A, Kaufer, D, Kerwin, D, Knopman, D, Kornak, J, Kramer, JH, Kraft, R, Kremers, WK, Kukull, W, Litvan, I, Ljubenkov, P, Mackenzie, IR, Maldonado, M, Manoochehri, M, McGinnis, S, McKinley, E, Mendez, MF, Miller, BL, Onyike, C, Pantelyat, A, Pearlman, R, Petrucelli, L, Potter, M, Rademakers, R, Ramos, EM, Rankin, KP, Roberson, ED, Rogalski, E, Sengdy, P, Shaw, L, Syrjanen, J, Tartaglia, MC, Tatton, N, Taylor, J, Toga, A, Trojanowski, J, Weintraub, S, Wong, B, Wszolek, Z, Boeve, BF, Rosen, HJ, Boxer, AL, and consortia, on behalf of the ARTFL and LEFFTDS
Subjects: Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Behavioral and Social Science, Clinical Research, Rare Diseases, Dementia, Brain Disorders, Aging, Genetics, Neurological, Age Factors, Aged, Brain, C9orf72 Protein, Female, Frontotemporal Dementia, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Neuropsychological Tests, North America, Progranulins, tau Proteins, bvFTD, C9orf72, clinical trials, frontotemporal dementia, genetics, GRN, MAPT, ARTFL and LEFFTDS consortia, Geriatrics, Clinical sciences, Biological psychology
Abstract: IntroductionBehavioral variant frontotemporal dementia (bvFTD) may present sporadically or due to an autosomal dominant mutation. Characterization of both forms will improve understanding of the generalizability of assessments and treatments.MethodsA total of 135 sporadic (s-bvFTD; mean age 63.3 years; 34% female) and 99 familial (f-bvFTD; mean age 59.9; 48% female) bvFTD participants were identified. f-bvFTD cases included 43 with known or presumed chromosome 9 open reading frame 72 (C9orf72) gene expansions, 28 with known or presumed microtubule-associated protein tau (MAPT) mutations, 14 with known progranulin (GRN) mutations, and 14 with a strong family history of FTD but no identified mutation.ResultsParticipants with f-bvFTD were younger and had earlier age at onset. s-bvFTD had higher total Neuropsychiatric Inventory Questionnaire (NPI-Q) scores due to more frequent endorsement of depression and irritability.Discussionf-bvFTD and s-bvFTD cases are clinically similar, suggesting the generalizability of novel biomarkers, therapies, and clinical tools developed in either form to the other.
Published: 2020

3. Evaluation of European-based polygenic risk score for breast cancer in Ashkenazi Jewish women in Israel

Author: Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, Elkon, R, Levi, H, Carmi, S, Rosset, S, Yerushalmi, R, Zick, A, Yablonski-Peretz, T, Wang, Q, Bolla, MK, Dennis, J, Michailidou, K, Lush, M, Ahearn, T, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Augustinsson, A, Auvinen, P, Freeman, LB, Beckmann, M, Behrens, S, Bermisheva, M, Bodelon, C, Bogdanova, NV, Bojesen, SE, Brenner, H, Byers, H, Camp, N, Castelao, J, Chang-Claude, J, Chirlaque, M-D, Chung, W, Clarke, C, Collee, MJ, Colonna, S, Couch, F, Cox, A, Cross, SS, Czene, K, Daly, M, Devilee, P, Dork, T, Dossus, L, Eccles, DM, Eliassen, AH, Eriksson, M, Evans, G, Fasching, P, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Giles, GG, Goldberg, M, Guenel, P, Hall, P, Hamann, U, He, W, Hillemanns, P, Hollestelle, A, Hoppe, R, Hopper, J, Jakovchevska, S, Jakubowska, A, Jernstrom, H, John, E, Johnson, N, Jones, M, Vijai, J, Kaaks, R, Khusnutdinova, E, Kitahara, C, Koutros, S, Kristensen, V, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lejbkowicz, F, Lindblom, A, Loibl, S, Lori, A, Lubinski, J, Mannermaa, A, Manoochehri, M, Mavroudis, D, Menon, U, Mulligan, A, Murphy, R, Nevelsteen, I, Newman, WG, Obi, N, O'Brien, K, Offit, K, Olshan, A, Plaseska-Karanfilska, D, Olson, J, Panico, S, Park-Simon, T-W, Patel, A, Peterlongo, P, Rack, B, Radice, P, Rennert, G, Rhenius, V, Romero, A, Saloustros, E, Sandler, D, Schmidt, MK, Schwentner, L, Shah, M, Sharma, P, Simard, J, Southey, M, Stone, J, Tapper, WJ, Taylor, J, Teras, L, Toland, AE, Troester, M, Truong, T, van der Kolk, LE, Weinberg, C, Wendt, C, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, P, Easton, DF, Ben-Sachar, S, Elefant, N, Shamir, R, and Elkon, R
Abstract: BACKGROUND: Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women. METHODS: We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel. RESULTS: In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28). CONCLUSIONS: Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
Published: 2023

4. A Likelihood Ratio Approach for Utilizing Case-Control Data in the Clinical Classification of Rare Sequence Variants: Application to BRCA1 and BRCA2

Author: Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, Michailidou, K, Cutting, G, Zanti, M, O'Mahony, DG, Parsons, MT, Li, H, Dennis, J, Aittomakkiki, K, Andrulis, IL, Anton-Culver, H, Aronson, KJ, Augustinsson, A, Becher, H, Bojesen, SE, Bolla, MK, Brenner, H, Brown, MA, Buys, SS, Canzian, F, Caputo, SM, Castelao, JE, Chang-Claude, J, Czene, K, Daly, MB, De Nicolo, A, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Eccles, DM, Engel, C, Evans, DG, Fasching, PA, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Gentry-Maharaj, A, Geurts-Giele, WRR, Giles, GG, Glendon, G, Goldberg, MS, Garcia, EBG, Guendert, M, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Hopper, JL, Houdayer, C, Houlston, RS, Howell, A, Investigators, A, Jakimovska, M, Jakubowska, A, Jernstrom, H, John, EM, Kaaks, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Leone, M, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Menon, U, Milne, RL, Monteiro, AN, Murphy, RA, Neuhausen, SL, Nevanlinna, H, Newman, WG, Offit, K, Park, SK, James, P, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Punie, K, Radice, P, Rashid, MU, Rennert, G, Romero, A, Rosenberg, EH, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Shu, X-O, Simard, J, Southey, MC, Stone, J, Stoppa-Lyonnet, D, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Thomassen, M, Troester, MA, Vachon, CM, Vega, A, Vreeswijk, MPG, Wang, Q, Wappenschmidt, B, Weinberg, CR, Wolk, A, Zheng, W, Feng, B, Couch, FJ, Spurdle, AB, Easton, DF, Goldgar, DE, and Michailidou, K
Abstract: A large number of variants identified through clinical genetic testing in disease susceptibility genes, are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion), can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analyses of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC), and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity - findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared to classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and pre-formatted excel calculators for implementation of the method for rare variants in BRCA1, BRCA2 and other high-risk genes with known penetrance.
Published: 2023

5. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author: Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, Kuchenbaecker, KB, Mueller, SH, Lai, AG, Valkovskaya, M, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Abu-Ful, Z, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baert, T, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Brucker, SY, Buys, SS, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Chung, WK, Colonna, S, Cornelissen, S, Couch, FJ, Czene, K, Daly, MB, Devilee, P, Dork, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Gago-Dominguez, M, Gao, Y-T, Garcia-Closas, M, Garcia-Saenz, JA, Genkinger, J, Gentry-Maharaj, A, Grassmann, F, Guenel, P, Gundert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Harkness, EF, Harrington, PA, Hartikainen, JM, Hartman, M, Hein, A, Ho, W-K, Hooning, MJ, Hoppe, R, Hopper, JL, Houlston, RS, Howell, A, Hunter, DJ, Huo, D, Investigators, A, Ito, H, Iwasaki, M, Jakubowska, A, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kang, D, Khusnutdinova, EK, Kim, S-W, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Linet, M, Lo, W-Y, Long, J, Lophatananon, A, Mannermaa, A, Manoochehri, M, Margolin, S, Matsuo, K, Mavroudis, D, Menon, U, Muir, K, Murphy, RA, Nevanlinna, H, Newman, WG, Niederacher, D, O'Brien, KM, Obi, N, Offit, K, Olopade, O, Olshan, AF, Olsson, H, Park, SK, Patel, A, Perou, CM, Peto, J, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Ramachandran, D, Rashid, MU, Rennert, G, Romero, A, Ruddy, KJ, Ruebner, M, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneider, MO, Scott, C, Shah, M, Sharma, P, Shen, C-Y, Shu, X-O, Simard, J, Surowy, H, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Toland, AE, Tollenaar, RAEM, Torres, D, Torres-Mejia, G, Troester, MA, Truong, T, Vachon, CM, Vijai, J, Weinberg, CR, Wendt, C, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Yang, XR, Yu, J-C, Zheng, W, Ziogas, A, Ziv, E, Dunning, AM, Easton, DF, Hemingway, H, Hamann, U, and Kuchenbaecker, KB
Abstract: BACKGROUND: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. METHODS: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. RESULTS: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10-6) and AC058822.1 (P = 1.47 × 10-4), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. CONCLUSIONS: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10-5), demonstrating the importance of diversifying study cohorts.
Published: 2023

6. Deep-drawing of thermoplastic metal-composite structures: Experimental investigations, statistical analyses and finite element modeling

Author: Rajabi, A., Kadkhodayan, M., Manoochehri, M., and Farjadfar, R.
Published: 2015
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7. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

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

8. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, L., Carvalho, S., Allen, J., Parsons, M.T., Fortuno, C., Gonzalez-Neira, A., Heijl, S.M., Adank, M.A., Ahearn, T.U., Andrulis, I.L., Auvinen, P., Becher, H., Beckmann, M.W., Behrens, S., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bremer, M., Briceno, I., Camp, N.J., Campbell, A., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Collee, J.M., Czene, K., Dennis, J., Dork, T., Eriksson, M., Evans, D.G., Fasching, P.A., Figueroa, J., Flyger, H., Gabrielson, M., Gago-Dominguez, M., Garcia-Closas, M., Giles, G.G., Glendon, G., Guenel, P., Gundert, M., Hadjisavvas, A., Hahnen, E., Hall, P., Hamann, U., Harkness, E.F., Hartman, M., Hogervorst, F.B.L., Hollestelle, A., Hoppe, R., Howell, A., Jakubowska, A., Jung, A., Khusnutdinova, E., Kim, S.W., Ko, Y.D., Kristensen, V.N., Lakeman, I.M.M., Li, J.M., Lindblom, A., Loizidou, M.A., Lophatananon, A., Lubinski, J., Luccarini, C., Madsen, M.J., Mannermaa, A., Manoochehri, M., Margolin, S., Mavroudis, D., Milne, R.L., Taib, N.A.M., Muir, K., Nevanlinna, H., Newman, W.G., Oosterwijk, J.C., Park, S.K., Peterlongo, P., Radice, P., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Shah, M.T., Sim, X., Southey, M.C., Surowy, H., Suvanto, M., Tomlinson, I., Torres, D., Truong, T., Asperen, C.J. van, Waltes, R., Wang, Q., Yang, X.H.R., Pharoah, P.D.P., Schmidt, M.K., Benitez, J., Vroling, B., Dunning, A.M., Teo, S.H., Kvist, A., Hoya, M. de la, Devilee, P., Spurdle, A.B., Vreeswijk, M.P.G., Easton, D.F., NBCS Collaborators, KConFab Investigators, SGBCC Investigators, Clinical Genetics, Medical Oncology, Apollo - University of Cambridge Repository, Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Targeted Gynaecologic Oncology (TARGON), Damage and Repair in Cancer Development and Cancer Treatment (DARE), University of Helsinki, Clinicum, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Wellcome Trust, WT: 633784, v203477/Z/16/Z, Horizon 2020 Framework Programme, H2020, Cancer Research UK, CRUK: C1287/A16563, The sequencing and analysis for this project was funded by the European Union’s Horizon 2020 Research and Innovation Programme (BRIDGES: grant number 634935) and the Wellcome Trust [grant no: v203477/Z/16/Z]. BCAC co-ordination was additionally funded by the European Union’s Horizon 2020 Research and Innovation Programme (BRIDGES: grant number 634935, BCAST: grant number 633784) and by Cancer Research UK [C1287/A16563]. Study specific funding is given in the Additional Note., and HAL UVSQ, Équipe
Subjects: Mutation, Missense, Breast Neoplasms, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Breast Neoplasms/genetics, Breast Cancer, Genetic Epidemiology, Missense Variants, Risk Prediction, CLASSIFICATION, Breast cancer, Missense variants, SDG 3 - Good Health and Well-being, 3123 Gynaecology and paediatrics, SEQUENCE VARIANTS, Genetics, Humans, Genetic Predisposition to Disease, Genetic epidemiology, ddc:610, skin and connective tissue diseases, Molecular Biology, Genetics (clinical), MUTATIONS, Research, UNKNOWN CLINICAL-SIGNIFICANCE, 1184 Genetics, developmental biology, physiology, FRAMEWORK, BRCA1, Risk prediction, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, SUBSTITUTIONS, Case-Control Studies, Mutation, Molecular Medicine, Female, Missense, PATHOGENICITY
Abstract: Background Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47–2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022

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

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, Chatterjee, N, Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Borresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Bruening, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Collee, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dork, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Alnaes, GIG, Grip, M, Guenel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Kruger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkas, K, Radice, P, Rennert, G, Romero, A, Ruediger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schottker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, Garcia-Closas, M, and Chatterjee, N
Abstract: BACKGROUND: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. METHODS: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. RESULTS: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. CONCLUSION: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

10. Pathology of Tumors Associated With Pathogenic Germline Variants in 9 Breast Cancer Susceptibility Genes

Author: Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, Easton, DF, Mavaddat, N, Dorling, L, Carvalho, S, Allen, J, Gonzalez-Neira, A, Keeman, R, Bolla, MK, Dennis, J, Wang, Q, Ahearn, TU, Andrulis, IL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Briceno, I, Bruning, T, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Christiansen, H, Czene, K, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, JD, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Geisler, J, Giles, GG, Guenel, P, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Hartikainen, JM, Hartman, M, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, EK, Kristensen, VN, Li, J, Lim, SH, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Taib, NAM, Morra, A, Muir, K, Obi, N, Osorio, A, Park-Simon, T-W, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Thorne, H, Tomlinson, I, Torres, D, Truong, T, Yip, CH, Spurdle, AB, Vreeswijk, MPG, Dunning, AM, Garcia-Closas, M, Pharoah, PDP, Kvist, A, Muranen, TA, Nevanlinna, H, Teo, SH, Devilee, P, Schmidt, MK, and Easton, DF
Abstract: IMPORTANCE: Rare germline genetic variants in several genes are associated with increased breast cancer (BC) risk, but their precise contributions to different disease subtypes are unclear. This information is relevant to guidelines for gene panel testing and risk prediction. OBJECTIVE: To characterize tumors associated with BC susceptibility genes in large-scale population- or hospital-based studies. DESIGN, SETTING, AND PARTICIPANTS: The multicenter, international case-control analysis of the BRIDGES study included 42 680 patients and 46 387 control participants, comprising women aged 18 to 79 years who were sampled independently of family history from 38 studies. Studies were conducted between 1991 and 2016. Sequencing and analysis took place between 2016 and 2021. EXPOSURES: Protein-truncating variants and likely pathogenic missense variants in ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53. MAIN OUTCOMES AND MEASURES: The intrinsic-like BC subtypes as defined by estrogen receptor, progesterone receptor, and ERBB2 (formerly known as HER2) status, and tumor grade; morphology; size; stage; lymph node involvement; subtype-specific odds ratios (ORs) for carrying protein-truncating variants and pathogenic missense variants in the 9 BC susceptibility genes. RESULTS: The mean (SD) ages at interview (control participants) and diagnosis (cases) were 55.1 (11.9) and 55.8 (10.6) years, respectively; all participants were of European or East Asian ethnicity. There was substantial heterogeneity in the distribution of intrinsic subtypes by gene. RAD51C, RAD51D, and BARD1 variants were associated mainly with triple-negative disease (OR, 6.19 [95% CI, 3.17-12.12]; OR, 6.19 [95% CI, 2.99-12.79]; and OR, 10.05 [95% CI, 5.27-19.19], respectively). CHEK2 variants were associated with all subtypes (with ORs ranging from 2.21-3.17) except for triple-negative disease. For ATM variants, the association was strongest for the hormone receptor (HR)+ERBB2- high-grade subt
Published: 2022

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

Author: Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, Pharoah, PDP, Grootes, I, Keeman, R, Blows, FM, Milne, RL, Giles, GG, Swerdlow, AJ, Fasching, PA, Abubakar, M, Andrulis, IL, Anton-Culver, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Bonanni, B, Briceno, I, Burwinkel, B, Camp, NJ, Castelao, JE, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Eriksson, M, Ernst, K, Evans, DG, Figueroa, JD, Fink, V, Floris, G, Fox, S, Gabrielson, M, Gago-Dominguez, M, Garcia-Saenz, JA, Gonzalez-Neira, A, Haeberle, L, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hein, A, Hooning, MJ, Hou, M-F, Howell, SJ, Ito, H, Jakubowska, A, Janni, W, John, EM, Jung, A, Kang, D, Kristensen, VN, Kwong, A, Lambrechts, D, Li, J, Manoochehri, M, Margolin, S, Matsuo, K, Taib, NAM, Mulligan, AM, Nevanlinna, H, Newman, WG, Offit, K, Osorio, A, Park, SK, Park-Simon, T-W, Patel, A, Presneau, N, Pylkas, K, Rack, B, Radice, P, Rennert, G, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schochter, F, Schoemaker, MJ, Shen, C-Y, Shibli, R, Sinn, P, Tapper, WJ, Tawfiq, E, Teo, SH, Teras, LR, Torres, D, Vachon, CM, van Deurzen, CHM, Wendt, C, Williams, JA, Winqvist, R, Elwood, M, Schmidt, MK, and Pharoah, PDP
Abstract: BACKGROUND: Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2). METHOD: The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance. RESULTS: Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10-6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted. CONCLUSION: The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
Published: 2022

12. Breast cancer risks associated with missense variants in breast cancer susceptibility genes

Author: Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, Easton, DF, Dorling, L, Carvalho, S, Allen, J, Parsons, MT, Fortuno, C, Gonzalez-Neira, A, Heijl, SM, Adank, MA, Ahearn, TU, Andrulis, IL, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Bolla, MK, Bremer, M, Briceno, I, Camp, NJ, Campbell, A, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Collee, JM, Czene, K, Dennis, J, Dork, T, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Glendon, G, Guenel, P, Gundert, M, Hadjisavvas, A, Hahnen, E, Hall, P, Hamann, U, Harkness, EF, Hartman, M, Hogervorst, FBL, Hollestelle, A, Hoppe, R, Howell, A, Jakubowska, A, Jung, A, Khusnutdinova, E, Kim, S-W, Ko, Y-D, Kristensen, VN, Lakeman, IMM, Li, J, Lindblom, A, Loizidou, MA, Lophatananon, A, Lubinski, J, Luccarini, C, Madsen, MJ, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Milne, RL, Mohd Taib, NA, Muir, K, Nevanlinna, H, Newman, WG, Oosterwijk, JC, Park, SK, Peterlongo, P, Radice, P, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Shah, M, Sim, X, Southey, MC, Surowy, H, Suvanto, M, Tomlinson, I, Torres, D, Truong, T, van Asperen, CJ, Waltes, R, Wang, Q, Yang, XR, Pharoah, PDP, Schmidt, MK, Benitez, J, Vroling, B, Dunning, AM, Teo, SH, Kvist, A, de la Hoya, M, Devilee, P, Spurdle, AB, Vreeswijk, MPG, and Easton, DF
Abstract: BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.
Published: 2022

13. Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

Author: Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, Lynch, BM, Dixon-Suen, SC, Lewis, SJ, Martin, RM, English, DR, Boyle, T, Giles, GG, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Lush, M, Ahearn, TU, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Augustinsson, A, Auvinen, P, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Blomqvist, C, Bogdanova, N, Bojesen, SE, Bonanni, B, Brenner, H, Bruening, T, Buys, SS, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Cessna, MH, Chang-Claude, J, Chanock, SJ, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Goldberg, MS, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Haeberle, L, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Harvie, M, Hillemanns, P, Hollestelle, A, Hooning, MJ, Hoppe, R, Hopper, J, Howell, A, Hunter, DJ, Jakubowska, A, Janni, W, John, EM, Jung, A, Kaaks, R, Keeman, R, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Loibl, S, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Menon, U, Mulligan, AM, Murphy, RA, Nevanlinna, H, Nevelsteen, I, Newman, WG, Offit, K, Olshan, AF, Olsson, H, Orr, N, Patel, A, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Radice, P, Rees-Punia, E, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sandler, DP, Schmidt, MK, Schmutzler, RK, Schwentner, L, Scott, C, Shah, M, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tollenaar, RAEM, Troester, MA, Truong, T, Untch, M, Vachon, CM, Joseph, V, Wappenschmidt, B, Weinberg, CR, Wolk, A, Yannoukakos, D, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Milne, RL, and Lynch, BM
Abstract: OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics. METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity. RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger). CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer r
Published: 2022

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

Author: Ahearn, T. U. (Thomas U.), Zhang, H. (Haoyu), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Bolla, M. K. (Manjeet K.), Dennis, J. (Joe), Dunning, A. M. (Alison M.), Lush, M. (Michael), Wang, Q. (Qin), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Becher, H. (Heiko), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brooks-Wilson, A. (Angela), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Floris, G. (Giuseppe), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Jakimovska, M. (Milena), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kauppila, S. (Saila), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kyriacou, K. (Kyriacos), Lambrechts, D. (Diether), Lee, D. G. (Derrick G.), Lindblom, A. (Annika), Linet, M. (Martha), Lissowska, J. (Jolanta), Llaneza, A. (Ana), Lo, W.-Y. (Wing-Yee), MacInnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nodora, J. (Jesse), Offit, K. (Kenneth), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peto, J. (Julian), Pita, G. (Guillermo), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Punie, K. (Kevin), Pylkas, K. (Katri), Radice, P. (Paolo), Rennert, G. (Gad), Romero, A. (Atocha), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schottker, B. (Ben), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Torres, D. (Diana), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), van Deurzen, C. H. (Carolien H. M.), van Veen, E. M. (Elke M.), Wagner, P. (Philippe), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Wesseling, J. (Jelle), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Couch, F. J. (Fergus J.), Simard, J. (Jacques), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Pharoah, P. D. (Paul D. P.), Schmidt, M. K. (Marjanka K.), Garcia-Closas, M. (Montserrat), Chatterjee, N. (Nilanjan), Ahearn, T. U. (Thomas U.), Zhang, H. (Haoyu), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Bolla, M. K. (Manjeet K.), Dennis, J. (Joe), Dunning, A. M. (Alison M.), Lush, M. (Michael), Wang, Q. (Qin), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Becher, H. (Heiko), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Blomqvist, C. (Carl), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Borresen-Dale, A.-L. (Anne-Lise), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brooks-Wilson, A. (Angela), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Collee, J. M. (J. Margriet), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Floris, G. (Giuseppe), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Alnaes, G. I. (Grethe I. Grenaker), Grip, M. (Mervi), Guenel, P. (Pascal), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Jakimovska, M. (Milena), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kauppila, S. (Saila), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kruger, U. (Ute), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kyriacou, K. (Kyriacos), Lambrechts, D. (Diether), Lee, D. G. (Derrick G.), Lindblom, A. (Annika), Linet, M. (Martha), Lissowska, J. (Jolanta), Llaneza, A. (Ana), Lo, W.-Y. (Wing-Yee), MacInnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), McLean, C. (Catriona), Meindl, A. (Alfons), Menon, U. (Usha), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nodora, J. (Jesse), Offit, K. (Kenneth), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peto, J. (Julian), Pita, G. (Guillermo), Plaseska-Karanfilska, D. (Dijana), Prentice, R. (Ross), Punie, K. (Kevin), Pylkas, K. (Katri), Radice, P. (Paolo), Rennert, G. (Gad), Romero, A. (Atocha), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schottker, B. (Ben), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Torres, D. (Diana), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), van Deurzen, C. H. (Carolien H. M.), van Veen, E. M. (Elke M.), Wagner, P. (Philippe), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Wesseling, J. (Jelle), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Zheng, W. (Wei), Couch, F. J. (Fergus J.), Simard, J. (Jacques), Kraft, P. (Peter), Easton, D. F. (Douglas F.), Pharoah, P. D. (Paul D. P.), Schmidt, M. K. (Marjanka K.), Garcia-Closas, M. (Montserrat), and Chatterjee, N. (Nilanjan)
Abstract: Background: Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods: Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results: Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion: This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2022

15. Nociceptive Intra-epidermal Electric Stimulation Evokes Steady-State Responses in the Secondary Somatosensory Cortex

Author: van den Berg, Boudewijn (author), Manoochehri, M. (author), Schouten, A.C. (author), van der Helm, F.C.T. (author), Buitenweg, Jan R. (author), van den Berg, Boudewijn (author), Manoochehri, M. (author), Schouten, A.C. (author), van der Helm, F.C.T. (author), and Buitenweg, Jan R. (author)
Abstract: Recent studies have established the presence of nociceptive steady-state evoked potentials (SSEPs), generated in response to thermal or intra-epidermal electric stimuli. This study explores cortical sources and generation mechanisms of nociceptive SSEPs in response to intra-epidermal electric stimuli. Our method was to stimulate healthy volunteers (n = 22, all men) with 100 intra-epidermal pulse sequences. Each sequence had a duration of 8.5 s, and consisted of pulses with a pulse rate between 20 and 200 Hz, which was frequency modulated with a multisine waveform of 3, 7 and 13 Hz (n = 10, 1 excluded) or 3 and 7 Hz (n = 12, 1 excluded). As a result, evoked potentials in response to stimulation onset and contralateral SSEPs at 3 and 7 Hz were observed. The SSEPs at 3 and 7 Hz had an average time delay of 137 ms and 143 ms respectively. The evoked potential in response to stimulation onset had a contralateral minimum (N1) at 115 ms and a central maximum (P2) at 300 ms. Sources for the multisine SSEP at 3 and 7 Hz were found through beamforming near the primary and secondary somatosensory cortex. Sources for the N1 were found near the primary and secondary somatosensory cortex. Sources for the N2-P2 were found near the supplementary motor area. Harmonic and intermodulation frequencies in the SSEP power spectrum remained below a detectable level and no evidence for nonlinearity of nociceptive processing, i.e. processing of peripheral firing rate into cortical evoked potentials, was found., Biomechatronics & Human-Machine Control
Published: 2022
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16. Association of Mental Fatigue due to Long-term Restrictive Measures with Reasoning: A COVID-19 Study

Author: Akhoundi Z, Manoochehri M, Mehdinasab M, Šrol J, and Asl Fa
Subjects: Coronavirus disease 2019 (COVID-19), Mental fatigue, Association (psychology), Psychology, Clinical psychology, Term (time)
Abstract: Coronavirus Disease 2019 broke out in China at the end of 2019 and spread rapidly around the world. In response, many countries have adopted social distancing and lockdown measures. But restrictive measures resulted in many unwanted psychological consequences, including mental fatigue. Mental fatigue in turn is very likely to cause psychopathological disorders and cognitive malfunctions. A cognitive ability that is likely to be affected by mental fatigue is reasoning, while high reasoning ability is a prerequisite for compliance with restrictive measures. The present study aims to explore the association between mental fatigue and reasoning under the impact of long-term restrictive measures. The findings indicated that mental fatigue correlates negatively with cognitive reflection, while it has no significant association with general reasoning. The results also showed that mental fatigue correlates positively with the misperception of the preventive measures and negatively with the incomprehension of the restrictive measures. The implications of the results have been discussed.
Published: 2021

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

Author: Baxter, J.S., Johnson, N., Tomczyk, K., Gillespie, A., Maguire, S., Brough, R., Fachal, L., Michailidou, K., Bolla, M.K., Wang, Q., Dennis, J., Ahearn, T.U., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arndt, V., Aronson, K.J., Augustinsson, A., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Brenner, H., Brucker, S.Y., Cai, Q.Y., Campa, D., Canzian, F., Castelao, J.E., Chan, T.L., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Choi, J.Y., Clarke, C.L., Collaborators, N., Colonna, S., Conroy, D.M., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dork, T., Dossus, L., Dwek, M., Eccles, D.M., Ekici, A.B., Eliassen, A.H., Engel, C., Fasching, P.A., Figueroa, J., Flyger, H., Gago-Dominguez, M., Gao, C., Garcia-Closas, M., Garcia-Saenz, J.A., Ghoussaini, M., Giles, G.G., Goldberg, M.S., Gonzalez-Neira, A., Guenel, P., Gundert, M., Haeberle, L., Hahnen, E., Haiman, C.A., Hall, P., Hamann, U., Hartman, M., Hatse, S., Hauke, J., Hollestelle, A., Hoppe, R., Hopper, J.L., Hou, M.F., Ito, H., Iwasaki, M., Jager, A., Jakubowska, A., Janni, W., John, E.M., Joseph, V., Jung, A., Kaaks, R., Kang, D., Keeman, R., Khusnutdinova, E., Kim, S.W., Kosma, V.M., Kraft, P., Kristensen, V.N., Kubelka-Sabit, K., Kurian, A.W., Kwong, A., Lacey, J.V., Lambrechts, D., Larson, N.L., Larsson, S.C., Marchand, L. le, Lejbkowicz, F., Li, J.M., Long, J.R., Lophatananon, A., LubiNski, J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Matsuo, K., Mavroudis, D., Mayes, R., Menon, U., Milne, R.L., Taib, N.A.M., Muir, K., Muranen, T.A., Murphy, R.A., Nevanlinna, H., O'Brien, K.M., Offit, K., Olson, J.E., Olsson, H., Park, S.K., Park-Simon, T.W., Patel, A.V., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Rack, B., Rennert, G., Romero, A., Ruebner, M., Rudiger, T., Saloustros, E., Sandler, D.P., Sawyer, E.J., Schmidt, M.K., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Shah, M., Shen, C.Y., Shu, X.O., Simard, J., Southey, M.C., Stone, J., Surowy, H., Swerdlow, A.J., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teo, S.H., Teras, L.R., Terry, M.B., Toland, A.E., Tomlinson, I., Truong, T., Tseng, C.C., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Wang, S.S., Weinberg, C.R., Wendt, C., Winham, S.J., Winqvist, R., Wolk, A., Wu, A.H., Yamaji, T., Zheng, W., Ziogas, A., Pharoah, P.D.P., Dunning, A.M., Easton, D.F., Pettitt, S.J., Lord, C.J., Haider, S., Orr, N., Fletcher, O., kConFab Investigators, ABCTB Investigators, Medical Oncology, Clinical Genetics, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Biosciences, Dennis, Joe [0000-0003-4591-1214], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
Subjects: Basic medicine, breast cancer risk, 0302 clinical medicine, Transcription (biology), Risk Factors, WIDE ASSOCIATION, TRANSCRIPTION, Promoter Regions, Genetic, Genetics (clinical), Sequence Deletion, Genetics, Genetics & Heredity, 0303 health sciences, Chromosome Mapping, 3. Good health, 030220 oncology & carcinogenesis, Chromosomes, Human, Pair 2, Pair 2, Female, Medical Genetics, Life Sciences & Biomedicine, Human, Tumor suppressor gene, SUSCEPTIBILITY LOCI, In silico, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Chromosomes, Article, Cell Line, RNAS, Promoter Regions, 03 medical and health sciences, functional annotation, risk locus, CRISPR-Cas Systems, Genetic Association Studies, Genetic Variation, Humans, Insulin-Like Growth Factor Binding Protein 5, Molecular Sequence Annotation, 11Q13, Genetic, SDG 3 - Good Health and Well-being, Enhancer, Transcription factor, 030304 developmental biology, Medicinsk genetik, Reporter gene, Science & Technology, IDENTIFICATION, Clinical medicine, Estrogen receptor alpha
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31). ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:7 pages:1190-1203 ispartof: location:United States status: published
Published: 2021

18. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author: Park, HA, Neumeyer, S, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baten, A, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Brucker, SY, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Børresen-Dale, A-L, Grenaker Alnæs, GI, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Giles, GG, Glendon, G, Goldberg, MS, Goldgar, DE, González-Neira, A, Grip, M, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Han, S, Harkness, EF, Hart, SN, He, W, Heemskerk-Gerritsen, BAM, Hopper, JL, Hunter, DJ, Clarke, C, Marsh, D, Scott, R, Baxter, R, Yip, D, Carpenter, J, Davis, A, Pathmanathan, N, Simpson, P, Graham, D, Sachchithananthan, M, Amor, D, Andrews, L, Antill, Y, Balleine, R, Beesley, J, Bennett, I, Bogwitz, M, Botes, L, Brennan, M, Brown, M, Buckley, M, Burke, J, Butow, P, Caldon, L, Campbell, I, Chauhan, D, Chauhan, M, Christian, A, Cohen, P, Colley, A, Crook, A, Cui, J, Cummings, M, Dawson, S-J, DeFazio, A, Delatycki, M, Dickson, R, Dixon, J, Edkins, T, Edwards, S, Farshid, G, Fellows, A, Fenton, G, Field, M, Flanagan, J, Fong, P, Forrest, L, Fox, S, French, J, Friedlander, M, Gaff, C, Gattas, M, George, P, Greening, S, Harris, M, Hart, S, Hayward, N, Hopper, J, Hoskins, C, Hunt, C, James, P, Jenkins, M, Kidd, A, Kirk, J, Koehler, J, Kollias, J, Lakhani, S, Lawrence, M, Lindeman, G, Lipton, L, Lobb, L, Mann, G, McLachlan, SA, Meiser, B, Milne, R, Nightingale, S, O’Connell, S, O’Sullivan, S, Ortega, DG, Pachter, N, Patterson, B, Pearn, A, Phillips, K, Pieper, E, Rickard, E, Robinson, B, Saleh, M, Salisbury, E, Saunders, C, Saunus, J, Scott, C, Sexton, A, Shelling, A, Southey, M, Spurdle, A, Taylor, J, Taylor, R, Thorne, H, Trainer, A, Tucker, K, Visvader, J, Walker, L, Williams, R, Winship, I, Young, MA, Jager, A, Jakubowska, A, John, EM, Jung, A, Kaaks, R, Kapoor, PM, Keeman, R, Khusnutdinova, E, Kitahara, CM, Koppert, LB, Koutros, S, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lo, W-Y, Lubiński, J, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muranen, TA, Nevanlinna, H, Newman, WG, Nordestgaard, BG, Offit, K, Olshan, AF, Olsson, H, Park-Simon, T-W, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Radice, P, Rennert, G, Rennert, HS, Romero, A, Saloustros, E, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schoemaker, MJ, Schwentner, L, Shah, M, Shu, X-O, Simard, J, Smeets, A, Southey, MC, Spinelli, JJ, Stevens, V, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Vijai, J, Wang, S, Wendt, C, Winqvist, R, Wolk, A, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Zheng, W, Kraft, P, Chang-Claude, J, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, Park, Hanla A. [0000-0001-8055-3729], Dennis, Joe [0000-0003-4591-1214], Augustinsson, Annelie [0000-0003-3415-0536], Brenner, Hermann [0000-0002-6129-1572], Canzian, Federico [0000-0002-4261-4583], Cox, Angela [0000-0002-5138-1099], Devilee, Peter [0000-0002-8023-2009], Fasching, Peter A. [0000-0003-4885-8471], Harkness, Elaine F. [0000-0001-6625-7739], Hart, Steven N. [0000-0001-7714-2734], Heemskerk-Gerritsen, Bernadette A. M. [0000-0002-9724-6693], Jakubowska, Anna [0000-0002-5650-0501], Kapoor, Pooja Middha [0000-0001-5503-8215], Kurian, Allison W. [0000-0002-6175-9470], Newman, William G. [0000-0002-6382-4678], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Sawyer, Elinor J. [0000-0001-8285-4111], Scott, Christopher [0000-0003-1340-0647], Smeets, Ann [0000-0002-5091-6602], Tomlinson, Ian [0000-0003-3037-1470], Truong, Thérèse [0000-0002-2943-6786], Pharoah, Paul D. P. [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Medicin och hälsovetenskap, Cancer Research, Genotyping Techniques, Breast Neoplasms, Case-Control Studies, Cigarette Smoking, Female, Genetic Pleiotropy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Polymorphism, Single Nucleotide, ALCOHOL, Medical and Health Sciences, 0302 clinical medicine, Breast cancer, Pleiotropy, Epidemiology, Medicine, TOBACCO, Breast Neoplasms/epidemiology, Cigarette Smoking/adverse effects, WOMEN, ASSOCIATION, Single Nucleotide, 3. Good health, Substance abuse, 692/699/67/1347, 030220 oncology & carcinogenesis, Life Sciences & Biomedicine, 692/499, medicine.medical_specialty, 3122 Cancers, Single-nucleotide polymorphism, Article, 03 medical and health sciences, Internal medicine, ddc:610, Polymorphism, Genetic association, Science & Technology, business.industry, Cancer, medicine.disease, 030104 developmental biology, Clinical research, Risk factors, TISSUE, INFERENCE, CIGARETTE-SMOKING, business
Abstract: Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

19. ASH: An automatic pipeline to generate realistic and individualized chronic stroke volume conduction head models

Author: Piastra, M.C., Cruijsen, J. van der, Piai, V., Jeukens, F., Manoochehri, M., Schouten, A.C., Selles, R.W., Oostendorp, T.F., Piastra, M.C., Cruijsen, J. van der, Piai, V., Jeukens, F., Manoochehri, M., Schouten, A.C., Selles, R.W., and Oostendorp, T.F.
Abstract: Contains fulltext : 231559.pdf (Publisher’s version ) (Open Access), Objective. Large structural brain changes, such as chronic stroke lesions, alter the current pathways throughout the patients' head and therefore have to be taken into account when performing transcranial direct current stimulation simulations. Approach. We implement, test and distribute the first MATLAB pipeline that automatically generates realistic and individualized volume conduction head models of chronic stroke patients, by combining the already existing software SimNIBS, for the mesh generation, and LINDA, for the lesion identification. To highlight the impact of our pipeline, we investigated the sensitivity of the electric field distribution to the lesion location and lesion conductivity in 16 stroke patients' datasets. Main results. Our pipeline automatically generates 1 mm-resolution tetrahedral meshes including the lesion compartment in less than three hours. Moreover, for large lesions, we found a high sensitivity of the electric field distribution to the lesion conductivity value and location. Significance. This work facilitates optimizing electrode configurations with the goal to obtain more focal brain stimulations of the target volumes in rehabilitation for chronic stroke patients.
Published: 2021

20. Breast cancer risk factors and survival by tumor subtype: Pooled analyses from the breast cancer association consortium.

Author: Morra A., Jung A.Y., Behrens S., Keeman R., Ahearn T.U., Anton-Culver H., Arndt V., Augustinsson A., Auvinen P.K., Beane Freeman L.E., Becher H., Beckmann M.W., Blomqvist C., Bojesen S.E., Bolla M.K., Brenner H., Briceno I., Brucker S.Y., Camp N.J., Campa D., Canzian F., Castelao J.E., Chanock S.J., Choi J.-Y., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dork T., Dunning A.M., Dwek M., Easton D.F., Eccles D.M., Egan K.M., Evans D.G., Fasching P.A., Flyger H., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Grip M., Guenel P., Haiman C.A., Hakansson N., Hall P., Hamann U., Han S.N., Hart S.N., Hartman M., Heyworth J.S., Hoppe R., Hopper J.L., Hunter D.J., Ito H., Jager A., Jakimovska M., Jakubowska A., Janni W., Kaaks R., Kang D., Kapoor P.M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Lacey J.V., Lambrechts D., Le Marchand L., Li J., Lindblom A., Lubi-Nski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Mariapun S., Matsuo K., Mavroudis D., Milne R.L., Muranen T.A., Newman W.G., Noh D.-Y., Nordestgaard B.G., Obi N., Olshan A.F., Olsson H., Park-Simon T.-W., Petridis C., Pharoah P.D.P., Plaseska-Karanfilska D., Presneau N., Rashid M.U., Rennert G., Rennert H.S., Rhenius V., Romero A., Saloustros E., Sawyer E.J., Schneeweiss A., Schwentner L., Scott C., Shah M., Shen C.-Y., Shu X.-O., Southey M.C., Stram D.O., Tamimi R.M., Tapper W., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Therese Truong, Vachon C.M., Wang Q., Wang S.S., Williams J.A., Winqvist R., Wolk A., Wu A.H., Yoo K.-Y., Yu J.-C., Zheng W., Ziogas A., Yang X.R., Eliassen A.H., Holmes M.D., Garcia-Closas M., Teo S.H., Schmidt M.K., Chang-Claude J., Morra A., Jung A.Y., Behrens S., Keeman R., Ahearn T.U., Anton-Culver H., Arndt V., Augustinsson A., Auvinen P.K., Beane Freeman L.E., Becher H., Beckmann M.W., Blomqvist C., Bojesen S.E., Bolla M.K., Brenner H., Briceno I., Brucker S.Y., Camp N.J., Campa D., Canzian F., Castelao J.E., Chanock S.J., Choi J.-Y., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Dork T., Dunning A.M., Dwek M., Easton D.F., Eccles D.M., Egan K.M., Evans D.G., Fasching P.A., Flyger H., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Grip M., Guenel P., Haiman C.A., Hakansson N., Hall P., Hamann U., Han S.N., Hart S.N., Hartman M., Heyworth J.S., Hoppe R., Hopper J.L., Hunter D.J., Ito H., Jager A., Jakimovska M., Jakubowska A., Janni W., Kaaks R., Kang D., Kapoor P.M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Lacey J.V., Lambrechts D., Le Marchand L., Li J., Lindblom A., Lubi-Nski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Mariapun S., Matsuo K., Mavroudis D., Milne R.L., Muranen T.A., Newman W.G., Noh D.-Y., Nordestgaard B.G., Obi N., Olshan A.F., Olsson H., Park-Simon T.-W., Petridis C., Pharoah P.D.P., Plaseska-Karanfilska D., Presneau N., Rashid M.U., Rennert G., Rennert H.S., Rhenius V., Romero A., Saloustros E., Sawyer E.J., Schneeweiss A., Schwentner L., Scott C., Shah M., Shen C.-Y., Shu X.-O., Southey M.C., Stram D.O., Tamimi R.M., Tapper W., Tollenaar R.A.E.M., Tomlinson I., Torres D., Troester M.A., Therese Truong, Vachon C.M., Wang Q., Wang S.S., Williams J.A., Winqvist R., Wolk A., Wu A.H., Yoo K.-Y., Yu J.-C., Zheng W., Ziogas A., Yang X.R., Eliassen A.H., Holmes M.D., Garcia-Closas M., Teo S.H., Schmidt M.K., and Chang-Claude J.
Abstract: Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Method(s): 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. Result(s): There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 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 <20 years at first pregnancy [0.79 (0.72-0.86)]; >0.<5 years versus >=10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen.progestin therapy [0.61 (0.54.0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. Conclusion(s): We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.Copyright © 2021 American Association for Cancer Research.
Published: 2021

21. Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Author: Park H.A., Neumeyer S., Michailidou K., Bolla M.K., Wang Q., Dennis J., Ahearn T.U., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Augustinsson A., Baten A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Brauch H., Brenner H., Brucker S.Y., Burwinkel B., Campa D., Canzian F., Castelao J.E., Chanock S.J., Clarke C.L., Borresen-Dale A.-L., Grenaker Alnaes G.I., Sahlberg K.K., Ottestad L., Karesen R., Schlichting E., Holmen M.M., Sauer T., Haakensen V., Engebraten O., Naume B., Fossa A., Kiserud C.E., Reinertsen K.V., Helland A., Riis M., Geisler J., Conroy D.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Grip M., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Han S., Harkness E.F., Hart S.N., He W., Heemskerk-Gerritsen B.A.M., Hopper J.L., Hunter D.J., Clarke C., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Bennett I., Bogwitz M., Botes L., Brennan M., Brown M., Buckley M., Burke J., Butow P., Caldon L., Campbell I., Chauhan D., Chauhan M., Chenevix-Trench G., Christian A., Cohen P., Colley A., Crook A., Cui J., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Edkins T., Edwards S., Farshid G., Fellows A., Fenton G., Field M., Flanagan J., Fong P., Forrest L., Fox S., French J., Friedlander M., Gaff C., Gattas M., George P., Greening S., Harris M., Hart S., Hayward N., Hopper J., Hoskins C., Hunt C., James P., Jenkins M., Kidd A., Kirk J., Koehler J., Kollias J., Lakhani S., Lawrence M., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Milne R., Nightingale S., O'Connell S., O'Sullivan S., Ortega D.G., Pachter N., Patterson B., Pearn A., Phillips K., Pieper E., Rickard E., Robinson B., Saleh M., Salisbury E., Saunders C., Saunus J., Scott R., Sexton A., Shelling A., Simpson P., Southey M., Spurdle A., Taylor J., Taylor R., Thorne H., Trainer A., Tucker K., Visvader J., Walker L., Williams R., Winship I., Young M.A., Jager A., Jakubowska A., John E.M., Jung A., Kaaks R., Kapoor P.M., Keeman R., Khusnutdinova E., Kitahara C.M., Koppert L.B., Koutros S., Kristensen V.N., Kurian A.W., Lacey J., Lambrechts D., Le Marchand L., Lo W.-Y., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Martinez M.E., Mavroudis D., Meindl A., Menon U., Milne R.L., Muranen T.A., Nevanlinna H., Newman W.G., Nordestgaard B.G., Offit K., Olshan A.F., Olsson H., Park-Simon T.-W., Peterlongo P., Peto J., Plaseska-Karanfilska D., Presneau N., Radice P., Rennert G., Rennert H.S., Romero A., Saloustros E., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Schoemaker M.J., Schwentner L., Scott C., Shah M., Shu X.-O., Simard J., Smeets A., Southey M.C., Spinelli J.J., Stevens V., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Tomlinson I., Troester M.A., Truong T., Vachon C.M., van Veen E.M., Vijai J., Wang S., Wendt C., Winqvist R., Wolk A., Ziogas A., Dunning A.M., Pharoah P.D.P., Easton D.F., Zheng W., Kraft P., Chang-Claude J., Park H.A., Neumeyer S., Michailidou K., Bolla M.K., Wang Q., Dennis J., Ahearn T.U., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Augustinsson A., Baten A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Brauch H., Brenner H., Brucker S.Y., Burwinkel B., Campa D., Canzian F., Castelao J.E., Chanock S.J., Clarke C.L., Borresen-Dale A.-L., Grenaker Alnaes G.I., Sahlberg K.K., Ottestad L., Karesen R., Schlichting E., Holmen M.M., Sauer T., Haakensen V., Engebraten O., Naume B., Fossa A., Kiserud C.E., Reinertsen K.V., Helland A., Riis M., Geisler J., Conroy D.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., dos-Santos-Silva I., Dwek M., Eccles D.M., Eliassen A.H., Engel C., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Garcia-Closas M., Garcia-Saenz J.A., Gaudet M.M., Giles G.G., Glendon G., Goldberg M.S., Goldgar D.E., Gonzalez-Neira A., Grip M., Guenel P., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Han S., Harkness E.F., Hart S.N., He W., Heemskerk-Gerritsen B.A.M., Hopper J.L., Hunter D.J., Clarke C., Baxter R., Yip D., Carpenter J., Davis A., Pathmanathan N., Graham D., Sachchithananthan M., Amor D., Andrews L., Antill Y., Balleine R., Beesley J., Bennett I., Bogwitz M., Botes L., Brennan M., Brown M., Buckley M., Burke J., Butow P., Caldon L., Campbell I., Chauhan D., Chauhan M., Chenevix-Trench G., Christian A., Cohen P., Colley A., Crook A., Cui J., Cummings M., Dawson S.-J., DeFazio A., Delatycki M., Dickson R., Dixon J., Edkins T., Edwards S., Farshid G., Fellows A., Fenton G., Field M., Flanagan J., Fong P., Forrest L., Fox S., French J., Friedlander M., Gaff C., Gattas M., George P., Greening S., Harris M., Hart S., Hayward N., Hopper J., Hoskins C., Hunt C., James P., Jenkins M., Kidd A., Kirk J., Koehler J., Kollias J., Lakhani S., Lawrence M., Lindeman G., Lipton L., Lobb L., Mann G., Marsh D., McLachlan S.A., Meiser B., Milne R., Nightingale S., O'Connell S., O'Sullivan S., Ortega D.G., Pachter N., Patterson B., Pearn A., Phillips K., Pieper E., Rickard E., Robinson B., Saleh M., Salisbury E., Saunders C., Saunus J., Scott R., Sexton A., Shelling A., Simpson P., Southey M., Spurdle A., Taylor J., Taylor R., Thorne H., Trainer A., Tucker K., Visvader J., Walker L., Williams R., Winship I., Young M.A., Jager A., Jakubowska A., John E.M., Jung A., Kaaks R., Kapoor P.M., Keeman R., Khusnutdinova E., Kitahara C.M., Koppert L.B., Koutros S., Kristensen V.N., Kurian A.W., Lacey J., Lambrechts D., Le Marchand L., Lo W.-Y., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Martinez M.E., Mavroudis D., Meindl A., Menon U., Milne R.L., Muranen T.A., Nevanlinna H., Newman W.G., Nordestgaard B.G., Offit K., Olshan A.F., Olsson H., Park-Simon T.-W., Peterlongo P., Peto J., Plaseska-Karanfilska D., Presneau N., Radice P., Rennert G., Rennert H.S., Romero A., Saloustros E., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Schoemaker M.J., Schwentner L., Scott C., Shah M., Shu X.-O., Simard J., Smeets A., Southey M.C., Spinelli J.J., Stevens V., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Terry M.B., Tomlinson I., Troester M.A., Truong T., Vachon C.M., van Veen E.M., Vijai J., Wang S., Wendt C., Winqvist R., Wolk A., Ziogas A., Dunning A.M., Pharoah P.D.P., Easton D.F., Zheng W., Kraft P., and Chang-Claude J.
Abstract: Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Method(s): We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Result(s): Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 x 10-2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion(s): Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.Copyright © 2021, The Author(s).
Published: 2021

22. Breast cancer risk genes - Association analysis in more than 113,000 women.

Author: Cornelissen S., Michailidou K., Miller N., Taib N.A.M., Muir K., Mulligan A.M., Nevanlinna H., Newman W.G., Nordestgaard B.G., Ng P.-S., Oosterwijk J.C., Park S.K., Park-Simon T.-W., Perez J.I.A., Peterlongo P., Porteous D.J., Prajzendanc K., Prokofyeva D., Radice P., Rashid M.U., Rhenius V., Rookus M.A., Rudiger T., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Schurmann P., Shah M., Sohn C., Southey M.C., Surowy H., Suvanto M., Thanasitthichai S., Tomlinson I., Torres D., Truong T., Tzardi M., Valova Y., van Asperen C.J., van Dam R.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., Wendt C., Williams J.A., Yang X.R., Yoon S.-Y., Zamora M.P., Evans D.G., de la Hoya M., Simard J., Antoniou A.C., Borg A., Andrulis I.L., Chang-Claude J., Garcia-Closas M., Chenevix-Trench G., Milne R.L., Pharoah P.D.P., Schmidt M.K., Spurdle A.B., Vreeswijk M.P.G., Benitez J., Dunning A.M., Kvist A., Teo S.H., Devilee P., Easton D.F., Dorling L., Carvalho S., Allen J., Gonzalez-Neira A., Luccarini C., Wahlstrom C., Pooley K.A., Parsons M.T., Fortuno C., Wang Q., Bolla M.K., Dennis J., Keeman R., Alonso M.R., Alvarez N., Herraez B., Fernandez V., Nunez-Torres R., Osorio A., Valcich J., Li M., Torngren T., Harrington P.A., Baynes C., Conroy D.M., Decker B., Fachal L., Mavaddat N., Ahearn T., Aittomaki K., Antonenkova N.N., Arnold N., Arveux P., Ausems M.G.E.M., Auvinen P., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bogdanova-Markov N., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Bremer M., Briceno I., Bruning T., Burwinkel B., Cameron D.A., Camp N.J., Campbell A., Carracedo A., Castelao J.E., Cessna M.H., Chanock S.J., Christiansen H., Collee J.M., Cordina-Duverger E., Czene K., Dork T., Ekici A.B., Engel C., Eriksson M., Fasching P.A., Figueroa J., Flyger H., Forsti A., Gabrielson M., Gago-Dominguez M., Georgoulias V., Gil F., Giles G.G., Glendon G., Gomez Garcia E.B., Grenaker Alnaes G.I., Guenel P., Hadjisavvas A., Haeberle L., Hahnen E., Hall P., Hamann U., Harkness E.F., Hartikainen J.M., Hartman M., He W., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Ho W.K., Hooning M.J., Howell A., Humphreys K., Idris F., Jakubowska A., Jung A., Kapoor P.M., Kerin M.J., Khusnutdinova E., Kim S.-W., Ko Y.-D., Kosma V.-M., Kristensen V.N., Kyriacou K., Lakeman I.M.M., Lee J.W., Lee M.H., Li J., Lindblom A., Lo W.-Y., Loizidou M.A., Lophatananon A., Lubinski J., MacInnis R.J., Madsen M.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., McLean C., Meindl A., Mensenkamp A.R., Cornelissen S., Michailidou K., Miller N., Taib N.A.M., Muir K., Mulligan A.M., Nevanlinna H., Newman W.G., Nordestgaard B.G., Ng P.-S., Oosterwijk J.C., Park S.K., Park-Simon T.-W., Perez J.I.A., Peterlongo P., Porteous D.J., Prajzendanc K., Prokofyeva D., Radice P., Rashid M.U., Rhenius V., Rookus M.A., Rudiger T., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Schurmann P., Shah M., Sohn C., Southey M.C., Surowy H., Suvanto M., Thanasitthichai S., Tomlinson I., Torres D., Truong T., Tzardi M., Valova Y., van Asperen C.J., van Dam R.M., van den Ouweland A.M.W., van der Kolk L.E., van Veen E.M., Wendt C., Williams J.A., Yang X.R., Yoon S.-Y., Zamora M.P., Evans D.G., de la Hoya M., Simard J., Antoniou A.C., Borg A., Andrulis I.L., Chang-Claude J., Garcia-Closas M., Chenevix-Trench G., Milne R.L., Pharoah P.D.P., Schmidt M.K., Spurdle A.B., Vreeswijk M.P.G., Benitez J., Dunning A.M., Kvist A., Teo S.H., Devilee P., Easton D.F., Dorling L., Carvalho S., Allen J., Gonzalez-Neira A., Luccarini C., Wahlstrom C., Pooley K.A., Parsons M.T., Fortuno C., Wang Q., Bolla M.K., Dennis J., Keeman R., Alonso M.R., Alvarez N., Herraez B., Fernandez V., Nunez-Torres R., Osorio A., Valcich J., Li M., Torngren T., Harrington P.A., Baynes C., Conroy D.M., Decker B., Fachal L., Mavaddat N., Ahearn T., Aittomaki K., Antonenkova N.N., Arnold N., Arveux P., Ausems M.G.E.M., Auvinen P., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bialkowska K., Blomqvist C., Bogdanova N.V., Bogdanova-Markov N., Bojesen S.E., Bonanni B., Borresen-Dale A.-L., Brauch H., Bremer M., Briceno I., Bruning T., Burwinkel B., Cameron D.A., Camp N.J., Campbell A., Carracedo A., Castelao J.E., Cessna M.H., Chanock S.J., Christiansen H., Collee J.M., Cordina-Duverger E., Czene K., Dork T., Ekici A.B., Engel C., Eriksson M., Fasching P.A., Figueroa J., Flyger H., Forsti A., Gabrielson M., Gago-Dominguez M., Georgoulias V., Gil F., Giles G.G., Glendon G., Gomez Garcia E.B., Grenaker Alnaes G.I., Guenel P., Hadjisavvas A., Haeberle L., Hahnen E., Hall P., Hamann U., Harkness E.F., Hartikainen J.M., Hartman M., He W., Heemskerk-Gerritsen B.A.M., Hillemanns P., Hogervorst F.B.L., Hollestelle A., Ho W.K., Hooning M.J., Howell A., Humphreys K., Idris F., Jakubowska A., Jung A., Kapoor P.M., Kerin M.J., Khusnutdinova E., Kim S.-W., Ko Y.-D., Kosma V.-M., Kristensen V.N., Kyriacou K., Lakeman I.M.M., Lee J.W., Lee M.H., Li J., Lindblom A., Lo W.-Y., Loizidou M.A., Lophatananon A., Lubinski J., MacInnis R.J., Madsen M.J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., McLean C., Meindl A., and Mensenkamp A.R.
Abstract: BACKGROUND Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking. METHODS We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity. RESULTS Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants. CONCLUSIONS The results of this study define
Published: 2021

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

Author: Baxter J.S., Johnson N., Tomczyk K., Gillespie A., Maguire S., Brough R., Fachal L., Michailidou K., Bolla M.K., Wang Q., Dennis J., Ahearn T.U., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Brenner H., Brucker S.Y., Cai Q., Campa D., Canzian F., Castelao J.E., Chan T.L., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Choi J.-Y., Clarke C.L., Colonna S., Conroy D.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., Dossus L., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Engel C., Fasching P.A., Figueroa J., Flyger H., Gago-Dominguez M., Gao C., Garcia-Closas M., Garcia-Saenz J.A., Ghoussaini M., Giles G.G., Goldberg M.S., Gonzalez-Neira A., Guenel P., Gundert M., Haeberle L., Hahnen E., Haiman C.A., Hall P., Hamann U., Hartman M., Hatse S., Hauke J., Hollestelle A., Hoppe R., Hopper J.L., Hou M.-F., Ito H., Iwasaki M., Jager A., Jakubowska A., Janni W., John E.M., Joseph V., Jung A., Kaaks R., Kang D., Keeman R., Khusnutdinova E., Kim S.-W., Kosma V.-M., Kraft P., Kristensen V.N., Kubelka-Sabit K., Kurian A.W., Kwong A., Lacey J.V., Lambrechts D., Larson N.L., Larsson S.C., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., Muir K., Muranen T.A., Murphy R.A., Nevanlinna H., O'Brien K.M., Offit K., Olson J.E., Olsson H., Park S.K., Park-Simon T.-W., Patel A.V., Peterlongo P., Peto J., Plaseska-Karanfilska D., Presneau N., Pylkas K., Rack B., Rennert G., Romero A., Ruebner M., Rudiger T., Saloustros E., Sandler D.P., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Shah M., Shen C.-Y., Shu X.-O., Simard J., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Teo S.H., Teras L.R., Terry M.B., Toland A.E., Tomlinson I., Truong T., Tseng C.-C., Untch M., Vachon C.M., van den Ouweland A.M.W., Wang S.S., Weinberg C.R., Wendt C., Winham S.J., Winqvist R., Wolk A., Wu A.H., Yamaji T., Zheng W., Ziogas A., Pharoah P.D.P., Dunning A.M., Easton D.F., Pettitt S.J., Lord C.J., Haider S., Orr N., Fletcher O., Baxter J.S., Johnson N., Tomczyk K., Gillespie A., Maguire S., Brough R., Fachal L., Michailidou K., Bolla M.K., Wang Q., Dennis J., Ahearn T.U., Andrulis I.L., Anton-Culver H., Antonenkova N.N., Arndt V., Aronson K.J., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Benitez J., Bermisheva M., Bogdanova N.V., Bojesen S.E., Brenner H., Brucker S.Y., Cai Q., Campa D., Canzian F., Castelao J.E., Chan T.L., Chang-Claude J., Chanock S.J., Chenevix-Trench G., Choi J.-Y., Clarke C.L., Colonna S., Conroy D.M., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Devilee P., Dork T., Dossus L., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Engel C., Fasching P.A., Figueroa J., Flyger H., Gago-Dominguez M., Gao C., Garcia-Closas M., Garcia-Saenz J.A., Ghoussaini M., Giles G.G., Goldberg M.S., Gonzalez-Neira A., Guenel P., Gundert M., Haeberle L., Hahnen E., Haiman C.A., Hall P., Hamann U., Hartman M., Hatse S., Hauke J., Hollestelle A., Hoppe R., Hopper J.L., Hou M.-F., Ito H., Iwasaki M., Jager A., Jakubowska A., Janni W., John E.M., Joseph V., Jung A., Kaaks R., Kang D., Keeman R., Khusnutdinova E., Kim S.-W., Kosma V.-M., Kraft P., Kristensen V.N., Kubelka-Sabit K., Kurian A.W., Kwong A., Lacey J.V., Lambrechts D., Larson N.L., Larsson S.C., Le Marchand L., Lejbkowicz F., Li J., Long J., Lophatananon A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Matsuo K., Mavroudis D., Mayes R., Menon U., Milne R.L., Mohd Taib N.A., Muir K., Muranen T.A., Murphy R.A., Nevanlinna H., O'Brien K.M., Offit K., Olson J.E., Olsson H., Park S.K., Park-Simon T.-W., Patel A.V., Peterlongo P., Peto J., Plaseska-Karanfilska D., Presneau N., Pylkas K., Rack B., Rennert G., Romero A., Ruebner M., Rudiger T., Saloustros E., Sandler D.P., Sawyer E.J., Schmidt M.K., Schmutzler R.K., Schneeweiss A., Schoemaker M.J., Shah M., Shen C.-Y., Shu X.-O., Simard J., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Taylor J.A., Teo S.H., Teras L.R., Terry M.B., Toland A.E., Tomlinson I., Truong T., Tseng C.-C., Untch M., Vachon C.M., van den Ouweland A.M.W., Wang S.S., Weinberg C.R., Wendt C., Winham S.J., Winqvist R., Wolk A., Wu A.H., Yamaji T., Zheng W., Ziogas A., Pharoah P.D.P., Dunning A.M., Easton D.F., Pettitt S.J., Lord C.J., Haider S., Orr N., and Fletcher O.
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 x 10-31).Copyright © 2021 The Authors
Published: 2021

24. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Author: Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., Schmidt M.K., Morra A., Escala-Garcia M., Beesley J., Keeman R., Canisius S., Ahearn T.U., Andrulis I.L., Anton-Culver H., Arndt V., Auer P.L., Augustinsson A., Beane Freeman L.E., Becher H., Beckmann M.W., Behrens S., Bojesen S.E., Bolla M.K., Brenner H., Bruning T., Buys S.S., Caan B., Campa D., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Cheng T.-Y.D., Clarke C.L., Colonna S.V., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Dork T., Dossus L., Dunning A.M., Dwek M., Eccles D.M., Ekici A.B., Eliassen A.H., Eriksson M., Evans D.G., Fasching P.A., Flyger H., Fritschi L., Gago-Dominguez M., Garcia-Saenz J.A., Giles G.G., Grip M., Guenel P., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hart S.N., Hartikainen J.M., Hartmann A., He W., Hooning M.J., Hoppe R., Hopper J.L., Howell A., Hunter D.J., Jager A., Jakubowska A., Janni W., John E.M., Jung A.Y., Kaaks R., Keupers M., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Kurian A.W., Lacey J.V., Lambrechts D., Le Marchand L., Lindblom A., Linet M., Luben R.N., Lubinski J., Lush M., Mannermaa A., Manoochehri M., Margolin S., Martens J.W.M., Martinez M.E., Mavroudis D., Michailidou K., Milne R.L., Mulligan A.M., Muranen T.A., Nevanlinna H., Newman W.G., Nielsen S.F., Nordestgaard B.G., Olshan A.F., Olsson H., Orr N., Park-Simon T.-W., Patel A.V., Peissel B., Peterlongo P., Plaseska-Karanfilska D., Prajzendanc K., Prentice R., Presneau N., Rack B., Rennert G., Rennert H.S., Rhenius V., Romero A., Roylance R., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schneeweiss A., Scott C., Shah M., Smichkoska S., Southey M.C., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teras L.R., Terry M.B., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Vachon C.M., Wang Q., Hurson A.N., Winqvist R., Wolk A., Ziogas A., Brauch H., Garcia-Closas M., Pharoah P.D.P., Easton D.F., Chenevix-Trench G., and Schmidt M.K.
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHOD(S): We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP <0.15). RESULT(S): Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSION(S): We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on br
Published: 2021

25. Gene-environment interactions relevant to estrogen and risk of breast cancer: Can gene-environment interactions be detected only among candidate snps from genome-wide association studies?.

Author: Park J.Y., Choi J.-Y., Choi J., Chung S., Song N., Park S.K., Han W., Noh D.-Y., Ahn S.-H., Lee J.W., Kim M.K., Jee S.H., Wen W., Bolla M.K., Wang Q., Dennis J., Michailidou K., Shah M., Conroy D.M., Harrington P.A., Mayes R., Czene K., Hall P., Teras L.R., Patel A.V., Couch F.J., Olson J.E., Sawyer E.J., Roylance R., Bojesen S.E., Flyger H., Lambrechts D., Baten A., Matsuo K., Ito H., Guenel P., Truong T., Keeman R., Schmidt M.K., Wu A.H., Tseng C.-C., Cox A., Cross S.S., Investigators K., Andrulis I.L., Hopper J.L., Southey M.C., Wu P.-E., Shen C.-Y., Fasching P.A., Ekici A.B., Muir K., Lophatananon A., Brenner H., Arndt V., Jones M.E., Swerdlow A.J., Hoppe R., Ko Y.-D., Hartman M., Li J., Mannermaa A., Hartikainen J.M., Benitez J., Gonzalez-Neira A., Haiman C.A., Dork T., Bogdanova N.V., Teo S.H., Taib N.A.M., Fletcher O., Johnson N., Grip M., Winqvist R., Blomqvist C., Nevanlinna H., Lindblom A., Wendt C., Kristensen V.N., Collaborators N.B.C.S., Tollenaar R.A.E.M., Heemskerk-Gerritsen B.A.M., Radice P., Bonanni B., Hamann U., Manoochehri M., Lacey J.V., Martinez M.E., Dunning A.M., Pharoah P.D.P., Easton D.F., Yoo K.-Y., Kang D., Park J.Y., Choi J.-Y., Choi J., Chung S., Song N., Park S.K., Han W., Noh D.-Y., Ahn S.-H., Lee J.W., Kim M.K., Jee S.H., Wen W., Bolla M.K., Wang Q., Dennis J., Michailidou K., Shah M., Conroy D.M., Harrington P.A., Mayes R., Czene K., Hall P., Teras L.R., Patel A.V., Couch F.J., Olson J.E., Sawyer E.J., Roylance R., Bojesen S.E., Flyger H., Lambrechts D., Baten A., Matsuo K., Ito H., Guenel P., Truong T., Keeman R., Schmidt M.K., Wu A.H., Tseng C.-C., Cox A., Cross S.S., Investigators K., Andrulis I.L., Hopper J.L., Southey M.C., Wu P.-E., Shen C.-Y., Fasching P.A., Ekici A.B., Muir K., Lophatananon A., Brenner H., Arndt V., Jones M.E., Swerdlow A.J., Hoppe R., Ko Y.-D., Hartman M., Li J., Mannermaa A., Hartikainen J.M., Benitez J., Gonzalez-Neira A., Haiman C.A., Dork T., Bogdanova N.V., Teo S.H., Taib N.A.M., Fletcher O., Johnson N., Grip M., Winqvist R., Blomqvist C., Nevanlinna H., Lindblom A., Wendt C., Kristensen V.N., Collaborators N.B.C.S., Tollenaar R.A.E.M., Heemskerk-Gerritsen B.A.M., Radice P., Bonanni B., Hamann U., Manoochehri M., Lacey J.V., Martinez M.E., Dunning A.M., Pharoah P.D.P., Easton D.F., Yoo K.-Y., and Kang D.
Abstract: In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE2df model (p-2df = 1.2 x 10-3 ). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE2df model (p-2df = 1.1 x 10-4 ). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
Published: 2021

26. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis.

Author: Escala-Garcia M., Canisius S., Keeman R., Beesley J., Anton-Culver H., Arndt V., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bojesen S.E., Bolla M.K., Brenner H., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Couch F.J., Czene K., Daly M.B., Dennis J., Devilee P., Dork T., Dunning A.M., Easton D.F., Ekici A.B., Eliassen A.H., Fasching P.A., Flyger H., Gago-Dominguez M., Garcia-Closas M., Garcia-Saenz J.A., Geisler J., Giles G.G., Grip M., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hartikainen J.M., Heemskerk-Gerritsen B.A.M., Hollestelle A., Hoppe R., Hopper J.L., Hunter D.J., Jacot W., Jakubowska A., John E.M., Jung A.Y., Kaaks R., Khusnutdinova E., Koppert L.B., Kraft P., Kristensen V.N., Kurian A.W., Lambrechts D., Le Marchand L., Lindblom A., Luben R.N., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Mavroudis D., Muranen T.A., Nevanlinna H., Olshan A.F., Olsson H., Park-Simon T.-W., Patel A.V., Peterlongo P., Pharoah P.D.P., Punie K., Radice P., Rennert G., Rennert H.S., Romero A., Roylance R., Rudiger T., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schoemaker M.J., Scott C., Southey M.C., Surowy H., Swerdlow A.J., Tamimi R.M., Teras L.R., Thomas E., Tomlinson I., Troester M.A., Vachon C.M., Wang Q., Winqvist R., Wolk A., Ziogas A., Michailidou K., Chenevix-Trench G., Bachelot T., Schmidt M.K., Escala-Garcia M., Canisius S., Keeman R., Beesley J., Anton-Culver H., Arndt V., Augustinsson A., Becher H., Beckmann M.W., Behrens S., Bermisheva M., Bojesen S.E., Bolla M.K., Brenner H., Canzian F., Castelao J.E., Chang-Claude J., Chanock S.J., Couch F.J., Czene K., Daly M.B., Dennis J., Devilee P., Dork T., Dunning A.M., Easton D.F., Ekici A.B., Eliassen A.H., Fasching P.A., Flyger H., Gago-Dominguez M., Garcia-Closas M., Garcia-Saenz J.A., Geisler J., Giles G.G., Grip M., Gundert M., Hahnen E., Haiman C.A., Hakansson N., Hall P., Hamann U., Hartikainen J.M., Heemskerk-Gerritsen B.A.M., Hollestelle A., Hoppe R., Hopper J.L., Hunter D.J., Jacot W., Jakubowska A., John E.M., Jung A.Y., Kaaks R., Khusnutdinova E., Koppert L.B., Kraft P., Kristensen V.N., Kurian A.W., Lambrechts D., Le Marchand L., Lindblom A., Luben R.N., Lubinski J., Mannermaa A., Manoochehri M., Margolin S., Mavroudis D., Muranen T.A., Nevanlinna H., Olshan A.F., Olsson H., Park-Simon T.-W., Patel A.V., Peterlongo P., Pharoah P.D.P., Punie K., Radice P., Rennert G., Rennert H.S., Romero A., Roylance R., Rudiger T., Ruebner M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schoemaker M.J., Scott C., Southey M.C., Surowy H., Swerdlow A.J., Tamimi R.M., Teras L.R., Thomas E., Tomlinson I., Troester M.A., Vachon C.M., Wang Q., Winqvist R., Wolk A., Ziogas A., Michailidou K., Chenevix-Trench G., Bachelot T., and Schmidt M.K.
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P=3.19x10-8 and 4.42x10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.Copyright © 2021. The Author(s).
Published: 2021

27. Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration

Author: Banga, YB, Banga, YB, Lai, Y, Kim, P, Boeve, BF, Boxer, AL, Rosen, HJ, Forsberg, LK, Heuer, HW, Brushaber, D, Appleby, B, Biernacka, JM, Bordelon, YM, Botha, H, Bozoki, AC, Brannelly, P, Dickerson, BC, Dickinson, S, Dickson, DW, Domoto-Reilly, K, Faber, K, Fagan, AM, Fields, JA, Fishman, A, Foroud, TM, Galasko, DR, Gavrilova, RH, Gendron, TF, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, J, Graff-Radford, NR, Grant, I, Grossman, M, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Karydas, AM, Kaufer, D, Knopman, DS, Kramer, JH, Kremers, WK, Kornak, J, Kukull, WA, Lagone, E, Leger, GC, Litvan, I, Ljubenkov, PA, Lucente, DE, Mackenzie, IR, Manoochehri, M, Masdeu, JC, McGinnis, S, Mendez, MF, Miller, BL, Miyagawa, T, Nelson, KM, Onyike, CU, Pantelyat, A, Pascual, B, Pearlman, R, Petrucelli, L, Pottier, CP, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Rojas, JC, Sabbagh, MN, Salmon, DP, Savica, R, Seeley, WW, Staffaroni, AM, Syrjanen, JA, Tartaglia, MC, Tatton, N, Taylor, JC, Toga, AW, Weintraub, S, Wheaton, D, Wong, B, Wszolek, Z, Banga, YB, Banga, YB, Lai, Y, Kim, P, Boeve, BF, Boxer, AL, Rosen, HJ, Forsberg, LK, Heuer, HW, Brushaber, D, Appleby, B, Biernacka, JM, Bordelon, YM, Botha, H, Bozoki, AC, Brannelly, P, Dickerson, BC, Dickinson, S, Dickson, DW, Domoto-Reilly, K, Faber, K, Fagan, AM, Fields, JA, Fishman, A, Foroud, TM, Galasko, DR, Gavrilova, RH, Gendron, TF, Geschwind, DH, Ghoshal, N, Goldman, J, Graff-Radford, J, Graff-Radford, NR, Grant, I, Grossman, M, Hsiung, GYR, Huang, EJ, Huey, ED, Irwin, DJ, Jones, DT, Kantarci, K, Karydas, AM, Kaufer, D, Knopman, DS, Kramer, JH, Kremers, WK, Kornak, J, Kukull, WA, Lagone, E, Leger, GC, Litvan, I, Ljubenkov, PA, Lucente, DE, Mackenzie, IR, Manoochehri, M, Masdeu, JC, McGinnis, S, Mendez, MF, Miller, BL, Miyagawa, T, Nelson, KM, Onyike, CU, Pantelyat, A, Pascual, B, Pearlman, R, Petrucelli, L, Pottier, CP, Rademakers, R, Ramos, EM, Rankin, KP, Rascovsky, K, Rexach, JE, Ritter, A, Roberson, ED, Rojas, JC, Sabbagh, MN, Salmon, DP, Savica, R, Seeley, WW, Staffaroni, AM, Syrjanen, JA, Tartaglia, MC, Tatton, N, Taylor, JC, Toga, AW, Weintraub, S, Wheaton, D, Wong, B, and Wszolek, Z
Abstract: BACKGROUND: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. OBJECTIVE: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. METHODS: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. RESULTS: 29% of respondents self-reported as patients (63±10 years), 26% self-reported as caregivers answering on behalf of patients (65±10 years), and 45% self-reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture
Published: 2021

28. Theta but not beta power is positively associated with better explicit motor task learning

Author: van der Cruijsen, J. (author), Manoochehri, M. (author), Jonker, Z.D. (author), Andrinopoulou, Eleni Rosalina (author), Frens, Maarten A. (author), Ribbers, G.M. (author), Schouten, A.C. (author), Selles, R.W. (author), van der Cruijsen, J. (author), Manoochehri, M. (author), Jonker, Z.D. (author), Andrinopoulou, Eleni Rosalina (author), Frens, Maarten A. (author), Ribbers, G.M. (author), Schouten, A.C. (author), and Selles, R.W. (author)
Abstract: Neurophysiologic correlates of motor learning that can be monitored during neurorehabilitation interventions can facilitate the development of more effective learning methods. Previous studies have focused on the role of the beta band (14–30 Hz) because of its clear response during motor activity. However, it is difficult to discriminate between beta activity related to learning a movement and performing the movement. In this study, we analysed differences in the electroencephalography (EEG) power spectra of complex and simple explicit sequential motor tasks in healthy young subjects. The complex motor task (CMT) allowed EEG measurement related to motor learning. In contrast, the simple motor task (SMT) made it possible to control for EEG activity associated with performing the movement without significant motor learning. Source reconstruction of the EEG revealed task-related activity from 5 clusters covering both primary motor cortices (M1) and 3 clusters localised to different parts of the cingulate cortex (CC). We found no association between M1 beta power and learning, but the CMT produced stronger bilateral beta suppression compared to the SMT. However, there was a positive association between contralateral M1 theta (5–8 Hz) and alpha (8–12 Hz) power and motor learning, and theta and alpha power in the posterior mid-CC and posterior CC were positively associated with greater motor learning. These findings suggest that the theta and alpha bands are more related to motor learning than the beta band, which might merely relate to the level of perceived difficulty during learning., Biomechatronics & Human-Machine Control, Biomechanical Engineering
Published: 2021
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29. ASH: an Automatic pipeline to generate realistic and individualized chronic Stroke volume conduction Head models

Author: Piastra, Maria Carla (author), van der Cruijsen, J. (author), Piai, Vitória (author), Jeukens, Floor E.M. (author), Manoochehri, M. (author), Schouten, A.C. (author), Selles, R.W. (author), Oostendorp, Thom (author), Piastra, Maria Carla (author), van der Cruijsen, J. (author), Piai, Vitória (author), Jeukens, Floor E.M. (author), Manoochehri, M. (author), Schouten, A.C. (author), Selles, R.W. (author), and Oostendorp, Thom (author)
Abstract: Objective. Large structural brain changes, such as chronic stroke lesions, alter the current pathways throughout the patients' head and therefore have to be taken into account when performing transcranial direct current stimulation simulations. Approach. We implement, test and distribute the first MATLAB pipeline that automatically generates realistic and individualized volume conduction head models of chronic stroke patients, by combining the already existing software SimNIBS, for the mesh generation, and lesion identification with neighborhood data analysis, for the lesion identification. To highlight the impact of our pipeline, we investigated the sensitivity of the electric field distribution to the lesion location and lesion conductivity in 16 stroke patients' datasets. Main results. Our pipeline automatically generates 1 mm-resolution tetrahedral meshes including the lesion compartment in less than three hours. Moreover, for large lesions, we found a high sensitivity of the electric field distribution to the lesion conductivity value and location. Significance. This work facilitates optimizing electrode configurations with the goal to obtain more focal brain stimulations of the target volumes in rehabilitation for chronic stroke patients., Biomechatronics & Human-Machine Control
Published: 2021
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30. Multisine frequency modulation of intra-epidermal electric pulse sequences: A novel tool to study nociceptive processing

Author: van den Berg, Boudewijn (author), Manoochehri, M. (author), Kasting, Mindy (author), Schouten, A.C. (author), van der Helm, F.C.T. (author), Buitenweg, Jan R. (author), van den Berg, Boudewijn (author), Manoochehri, M. (author), Kasting, Mindy (author), Schouten, A.C. (author), van der Helm, F.C.T. (author), and Buitenweg, Jan R. (author)
Abstract: A sustained sensory stimulus with a periodic variation of intensity creates an electrophysiological brain response at associated frequencies, referred to as the steady-state evoked potential (SSEP). The SSEPs elicited by the periodic stimulation of nociceptors in the skin may represent activity of a brain network that is primarily involved in nociceptive processing. Exploring the behavior of this network could lead to valuable insights regarding the pathway from nociceptive stimulus to pain perception. We present a method to directly modulate the pulse rate of nociceptive afferents in the skin with a multisine waveform through intra-epidermal electric stimulation. The technique was demonstrated in healthy volunteers. Each subject was stimulated using a pulse sequence modulated by a multisine waveform of 3, 7 and 13 Hz. The EEG was analyzed for the presence of the base frequencies and associated (sub)harmonics. Topographies showed significant central and contralateral SSEP responses at 3, 7 and 13 Hz in respectively 7, 4 and 3 out of the 9 participants included for analysis. As such, we found that intra-epidermal stimulation with a multisine frequency modulated pulse sequence can generate nociceptive SSEPs. The possibility to stimulate the nociceptive system using multisine frequency modulated pulses offers novel opportunities to study the temporal dynamics of nociceptive processing., Biomechatronics & Human-Machine Control
Published: 2021
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31. Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium

Author: Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, Chang-Claude, J, Morra, A, Jung, AY, Behrens, S, Keeman, R, Ahearn, TU, Anton-Culver, H, Arndt, V, Augustinsson, A, Auvinen, PK, Freeman, LEB, Becher, H, Beckmann, MW, Blomqvist, C, Bojesen, SE, Bolla, MK, Brenner, H, Briceno, I, Brucker, SY, Camp, NJ, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Choi, J-Y, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dork, T, Dunning, AM, Dwek, M, Easton, DF, Eccles, DM, Egan, KM, Evans, DG, Fasching, PA, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Grip, M, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Han, SN, Hart, SN, Hartman, M, Heyworth, JS, Hoppe, R, Hopper, JL, Hunter, DJ, Ito, H, Jager, A, Jakimovska, M, Jakubowska, A, Janni, W, Kaaks, R, Kang, D, Kapoor, PM, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Lacey, J, Lambrechts, D, Le Marchand, L, Li, J, Lindblom, A, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Mariapun, S, Matsuo, K, Mavroudis, D, Milne, RL, Muranen, TA, Newman, WG, Noh, D-Y, Nordestgaard, BG, Obi, N, Olshan, AF, Olsson, H, Park-Simon, T-W, Petridis, C, Pharoah, PDP, Plaseska-Karanfilska, D, Presneau, N, Rashid, MU, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Saloustros, E, Sawyer, EJ, Schneeweiss, A, Schwentner, L, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Southey, MC, Stram, DO, Tamimi, RM, Tapper, W, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Wang, SS, Williams, JA, Winqvist, R, Wolk, A, Wu, AH, Yoo, K-Y, Yu, J-C, Zheng, W, Ziogas, A, Yang, XR, Eliassen, AH, Holmes, MD, Garcia-Closas, M, Teo, SH, Schmidt, MK, and Chang-Claude, J
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 <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
Published: 2021

32. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, M, Canisius, S, Keeman, R, Beesley, J, Anton-Culver, H, Arndt, V, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bojesen, SE, Bolla, MK, Brenner, H, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Couch, FJ, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dork, T, Dunning, AM, Easton, DF, Ekici, AB, Eliassen, AH, Fasching, PA, Flyger, H, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Geisler, J, Giles, GG, Grip, M, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartikainen, JM, Heemskerk-Gerritsen, BAM, Hollestelle, A, Hoppe, R, Hopper, JL, Hunter, DJ, Jacot, W, Jakubowska, A, John, EM, Jung, AY, Kaaks, R, Khusnutdinova, E, Koppert, LB, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Lindblom, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Muranen, TA, Nevanlinna, H, Olshan, AF, Olsson, H, Park-Simon, T-W, Patel, AV, Peterlongo, P, Pharoah, PDP, Punie, K, Radice, P, Rennert, G, Rennert, HS, Romero, A, Roylance, R, Ruediger, T, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Scott, C, Southey, MC, Surowy, H, Swerdlow, AJ, Tamimi, RM, Teras, LR, Thomas, E, Tomlinson, I, Troester, MA, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Ziogas, A, Michailidou, K, Chenevix-Trench, G, Bachelot, T, Schmidt, MK, Escala-Garcia, M, Canisius, S, Keeman, R, Beesley, J, Anton-Culver, H, Arndt, V, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bojesen, SE, Bolla, MK, Brenner, H, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Couch, FJ, Czene, K, Daly, MB, Dennis, J, Devilee, P, Dork, T, Dunning, AM, Easton, DF, Ekici, AB, Eliassen, AH, Fasching, PA, Flyger, H, Gago-Dominguez, M, Garcia-Closas, M, Garcia-Saenz, JA, Geisler, J, Giles, GG, Grip, M, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hartikainen, JM, Heemskerk-Gerritsen, BAM, Hollestelle, A, Hoppe, R, Hopper, JL, Hunter, DJ, Jacot, W, Jakubowska, A, John, EM, Jung, AY, Kaaks, R, Khusnutdinova, E, Koppert, LB, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Lindblom, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Margolin, S, Mavroudis, D, Muranen, TA, Nevanlinna, H, Olshan, AF, Olsson, H, Park-Simon, T-W, Patel, AV, Peterlongo, P, Pharoah, PDP, Punie, K, Radice, P, Rennert, G, Rennert, HS, Romero, A, Roylance, R, Ruediger, T, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Scott, C, Southey, MC, Surowy, H, Swerdlow, AJ, Tamimi, RM, Teras, LR, Thomas, E, Tomlinson, I, Troester, MA, Vachon, CM, Wang, Q, Winqvist, R, Wolk, A, Ziogas, A, Michailidou, K, Chenevix-Trench, G, Bachelot, T, and Schmidt, MK
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10-8 and 4.42 × 10-8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

33. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, Schmidt, MK, Morra, A, Escala-Garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Augustinsson, A, Freeman, LEB, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Bruening, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Cheng, T-YD, Clarke, CL, Colonna, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dork, T, Dossus, L, Dunning, AM, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fritschi, L, Gago-Dominguez, M, Garcia-Saenz, JA, Giles, GG, Grip, M, Guenel, P, Guendert, M, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, Janni, W, John, EM, Jung, AY, Kaaks, R, Keupers, M, Kitahara, CM, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lacey, J, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lush, M, Mannermaa, A, Manoochehri, M, Margolin, S, Martens, JWM, Martinez, ME, Mavroudis, D, Michailidou, K, Milne, RL, Mulligan, AM, Muranen, TA, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Olshan, AF, Olsson, H, Orr, N, Park-Simon, T-W, Patel, A, Peissel, B, Peterlongo, P, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Presneau, N, Rack, B, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Lubinski, J, Ruebner, M, Saloustros, E, Sawyer, EJ, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Smichkoska, S, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Teras, LR, Terry, MB, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wang, Q, Hurson, AN, Winqvist, R, Wolk, A, Ziogas, A, Brauch, H, Garcia-Closas, M, Pharoah, PDP, Easton, DF, Chenevix-Trench, G, and Schmidt, MK
Abstract: BACKGROUND: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. METHODS: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15). RESULTS: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. CONCLUSIONS: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast
Published: 2021

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

Author: Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, Fletcher, O, Baxter, JS, Johnson, N, Tomczyk, K, Gillespie, A, Maguire, S, Brough, R, Fachal, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Brucker, SY, Cai, Q, Campa, D, Canzian, F, Castelao, JE, Chan, TL, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Choi, J-Y, Clarke, CL, Collaborators, N, Colonna, S, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Doerk, T, Dossus, L, Dwek, M, Eccles, DM, Ekici, AB, Eliassen, AH, Engel, C, Fasching, PA, Figueroa, J, Flyger, H, Gago-Dominguez, M, Gao, C, Garcia-Closas, M, Garcia-Saenz, JA, Ghoussaini, M, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Guendert, M, Haeberle, L, Hahnen, E, Haiman, CA, Hall, P, Hamann, U, Hartman, M, Hatse, S, Hauke, J, Hollestelle, A, Hoppe, R, Hopper, JL, Hou, M-F, Ito, H, Iwasaki, M, Jager, A, Jakubowska, A, Janni, W, John, EM, Joseph, V, Jung, A, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kosma, V-M, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Kwong, A, Lacey, J, Lambrechts, D, Larson, NL, Larsson, SC, Le Marchand, L, Lejbkowicz, F, Li, J, Long, J, Lophatananon, A, LubiNski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Matsuo, K, Mavroudis, D, Mayes, R, Menon, U, Milne, RL, Taib, NAM, Muir, K, Muranen, TA, Murphy, RA, Nevanlinna, H, O'Brien, KM, Offit, K, Olson, JE, Olsson, H, Park, SK, Park-Simon, T-W, Patel, A, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Pylkas, K, Rack, B, Rennert, G, Romero, A, Ruebner, M, Ruediger, T, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Southey, MC, Stone, J, Surowy, H, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teo, SH, Teras, LR, Terry, MB, Toland, AE, Tomlinson, I, Truong, T, Tseng, C-C, Untch, M, Vachon, CM, van den Ouweland, AMW, Wang, SS, Weinberg, CR, Wendt, C, Winham, SJ, Winqvist, R, Wolk, A, Wu, AH, Yamaji, T, Zheng, W, Ziogas, A, Pharoah, PDP, Dunning, AM, Easton, DF, Pettitt, SJ, Lord, CJ, Haider, S, Orr, N, and Fletcher, O
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).
Published: 2021

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

Author: Park, J, Choi, J-Y, Choi, J, Chung, S, Song, N, Park, SK, Han, W, Noh, D-Y, Ahn, S-H, Lee, JW, Kim, MK, Jee, SH, Wen, W, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Shah, M, Conroy, DM, Harrington, PA, Mayes, R, Czene, K, Hall, P, Teras, LR, Patel, AV, Couch, FJ, Olson, JE, Sawyer, EJ, Roylance, R, Bojesen, SE, Flyger, H, Lambrechts, D, Baten, A, Matsuo, K, Ito, H, Guenel, P, Truong, T, Keeman, R, Schmidt, MK, Wu, AH, Tseng, C-C, Cox, A, Cross, SS, Andrulis, IL, Hopper, JL, Southey, MC, Wu, P-E, Shen, C-Y, Fasching, PA, Ekici, AB, Muir, K, Lophatananon, A, Brenner, H, Arndt, V, Jones, ME, Swerdlow, AJ, Hoppe, R, Ko, Y-D, Hartman, M, Li, J, Mannermaa, A, Hartikainen, JM, Benitez, J, Gonzalez-Neira, A, Haiman, CA, Doerk, T, Bogdanova, NV, Teo, SH, Mohd Taib, NA, Fletcher, O, Johnson, N, Grip, M, Winqvist, R, Blomqvist, C, Nevanlinna, H, Lindblom, A, Wendt, C, Kristensen, VN, Tollenaar, RAEM, Heemskerk-Gerritsen, BAM, Radice, P, Bonanni, B, Hamann, U, Manoochehri, M, Lacey, JV, Martinez, ME, Dunning, AM, Pharoah, PDP, Easton, DF, Yoo, K-Y, Kang, D, Park, J, Choi, J-Y, Choi, J, Chung, S, Song, N, Park, SK, Han, W, Noh, D-Y, Ahn, S-H, Lee, JW, Kim, MK, Jee, SH, Wen, W, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Shah, M, Conroy, DM, Harrington, PA, Mayes, R, Czene, K, Hall, P, Teras, LR, Patel, AV, Couch, FJ, Olson, JE, Sawyer, EJ, Roylance, R, Bojesen, SE, Flyger, H, Lambrechts, D, Baten, A, Matsuo, K, Ito, H, Guenel, P, Truong, T, Keeman, R, Schmidt, MK, Wu, AH, Tseng, C-C, Cox, A, Cross, SS, Andrulis, IL, Hopper, JL, Southey, MC, Wu, P-E, Shen, C-Y, Fasching, PA, Ekici, AB, Muir, K, Lophatananon, A, Brenner, H, Arndt, V, Jones, ME, Swerdlow, AJ, Hoppe, R, Ko, Y-D, Hartman, M, Li, J, Mannermaa, A, Hartikainen, JM, Benitez, J, Gonzalez-Neira, A, Haiman, CA, Doerk, T, Bogdanova, NV, Teo, SH, Mohd Taib, NA, Fletcher, O, Johnson, N, Grip, M, Winqvist, R, Blomqvist, C, Nevanlinna, H, Lindblom, A, Wendt, C, Kristensen, VN, Tollenaar, RAEM, Heemskerk-Gerritsen, BAM, Radice, P, Bonanni, B, Hamann, U, Manoochehri, M, Lacey, JV, Martinez, ME, Dunning, AM, Pharoah, PDP, Easton, DF, Yoo, K-Y, and Kang, D
Abstract: In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
Published: 2021

36. Gene-environment interactions relevant to estrogen and risk of breast cancer:can gene-environment interactions be detected only among candidate SNPs from genome-wide association studies?

Author: Park, J. (JooYong), Choi, J.-Y. (Ji-Yeob), Choi, J. (Jaesung), Chung, S. (Seokang), Song, N. (Nan), Park, S. K. (Sue K.), Han, W. (Wonshik), Noh, D.-Y. (Dong-Young), Ahn, S.-H. (Sei-Hyun), Lee, J. W. (Jong Won), Kim, M. K. (Mi Kyung), Jee, S. H. (Sun Ha), Wen, W. (Wanqing), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Shah, M. (Mitul), Conroy, D. M. (Don M.), Harrington, P. A. (Patricia A.), Mayes, R. (Rebecca), Czene, K. (Kamila), Hall, P. (Per), Teras, L. R. (Lauren R.), Patel, A. V. (Alpa V.), Couch, F. J. (Fergus J.), Olson, J. E. (Janet E.), Sawyer, E. J. (Elinor J.), Roylance, R. (Rebecca), Bojesen, S. E. (Stig E.), Flyger, H. (Henrik), Lambrechts, D. (Diether), Baten, A. (Adinda), Matsuo, K. (Keitaro), Ito, H. (Hidemi), Guenel, P. (Pascal), Truong, T. (Therese), Keeman, R. (Renske), Schmidt, M. K. (Marjanka K.), Wu, A. H. (Anna H.), Tseng, C.-C. (Chiu-Chen), Cox, A. (Angela), Cross, S. S. (Simon S.), Andrulis, I. L. (Irene L.), Hopper, J. L. (John L.), Southey, M. C. (Melissa C.), Wu, P.-E. (Pei-Ei), Shen, C.-Y. (Chen-Yang), Fasching, P. A. (Peter A.), Ekici, A. B. (Arif B.), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Brenner, H. (Hermann), Arndt, V. (Volker), Jones, M. E. (Michael E.), Swerdlow, A. J. (Anthony J.), Hoppe, R. (Reiner), Ko, Y.-D. (Yon-Dschun), Hartman, M. (Mikael), Li, J. (Jingmei), Mannermaa, A. (Arto), Hartikainen, J. M. (Jaana M.), Benitez, J. (Javier), Gonzalez-Neira, A. (Anna), Haiman, C. A. (Christopher A.), Doerk, T. (Thilo), Bogdanova, N. V. (Natalia V.), Teo, S. H. (Soo Hwang), Mohd Taib, N. A. (Nur Aishah), Fletcher, O. (Olivia), Johnson, N. (Nichola), Grip, M. (Mervi), Winqvist, R. (Robert), Blomqvist, C. (Carl), Nevanlinna, H. (Heli), Lindblom, A. (Annika), Wendt, C. (Camilla), Kristensen, V. N. (Vessela N.), Tollenaar, R. A. (Rob A. E. M.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Radice, P. (Paolo), Bonanni, B. (Bernardo), Hamann, U. (Ute), Manoochehri, M. (Mehdi), Lacey, J. V. (James V.), Martinez, M. E. (Maria Elena), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Yoo, K.-Y. (Keun-Young), Kang, D. (Daehee), Park, J. (JooYong), Choi, J.-Y. (Ji-Yeob), Choi, J. (Jaesung), Chung, S. (Seokang), Song, N. (Nan), Park, S. K. (Sue K.), Han, W. (Wonshik), Noh, D.-Y. (Dong-Young), Ahn, S.-H. (Sei-Hyun), Lee, J. W. (Jong Won), Kim, M. K. (Mi Kyung), Jee, S. H. (Sun Ha), Wen, W. (Wanqing), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Michailidou, K. (Kyriaki), Shah, M. (Mitul), Conroy, D. M. (Don M.), Harrington, P. A. (Patricia A.), Mayes, R. (Rebecca), Czene, K. (Kamila), Hall, P. (Per), Teras, L. R. (Lauren R.), Patel, A. V. (Alpa V.), Couch, F. J. (Fergus J.), Olson, J. E. (Janet E.), Sawyer, E. J. (Elinor J.), Roylance, R. (Rebecca), Bojesen, S. E. (Stig E.), Flyger, H. (Henrik), Lambrechts, D. (Diether), Baten, A. (Adinda), Matsuo, K. (Keitaro), Ito, H. (Hidemi), Guenel, P. (Pascal), Truong, T. (Therese), Keeman, R. (Renske), Schmidt, M. K. (Marjanka K.), Wu, A. H. (Anna H.), Tseng, C.-C. (Chiu-Chen), Cox, A. (Angela), Cross, S. S. (Simon S.), Andrulis, I. L. (Irene L.), Hopper, J. L. (John L.), Southey, M. C. (Melissa C.), Wu, P.-E. (Pei-Ei), Shen, C.-Y. (Chen-Yang), Fasching, P. A. (Peter A.), Ekici, A. B. (Arif B.), Muir, K. (Kenneth), Lophatananon, A. (Artitaya), Brenner, H. (Hermann), Arndt, V. (Volker), Jones, M. E. (Michael E.), Swerdlow, A. J. (Anthony J.), Hoppe, R. (Reiner), Ko, Y.-D. (Yon-Dschun), Hartman, M. (Mikael), Li, J. (Jingmei), Mannermaa, A. (Arto), Hartikainen, J. M. (Jaana M.), Benitez, J. (Javier), Gonzalez-Neira, A. (Anna), Haiman, C. A. (Christopher A.), Doerk, T. (Thilo), Bogdanova, N. V. (Natalia V.), Teo, S. H. (Soo Hwang), Mohd Taib, N. A. (Nur Aishah), Fletcher, O. (Olivia), Johnson, N. (Nichola), Grip, M. (Mervi), Winqvist, R. (Robert), Blomqvist, C. (Carl), Nevanlinna, H. (Heli), Lindblom, A. (Annika), Wendt, C. (Camilla), Kristensen, V. N. (Vessela N.), Tollenaar, R. A. (Rob A. E. M.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Radice, P. (Paolo), Bonanni, B. (Bernardo), Hamann, U. (Ute), Manoochehri, M. (Mehdi), Lacey, J. V. (James V.), Martinez, M. E. (Maria Elena), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Yoo, K.-Y. (Keun-Young), and Kang, D. (Daehee)
Abstract: In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
Published: 2021

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

Author: Baxter, J. S. (Joseph S.), Johnson, N. (Nichola), Tomczyk, K. (Katarzyna), Gillespie, A. (Andrea), Maguire, S. (Sarah), Brough, R. (Rachel), Fachal, L. (Laura), Michailidou, K. (Kyriaki), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Augustinsson, A. (Annelie), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brenner, H. (Hermann), Brucker, S. Y. (Sara Y.), Cai, Q. (Qiuyin), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chan, T. L. (Tsun L.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Clarke, C. L. (Christine L.), Collaborators, N. (Nbcs), Colonna, S. (Sarah), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), Dossus, L. (Laure), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Gao, C. (Chi), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Guendert, M. (Melanie), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Hartman, M. (Mikael), Hatse, S. (Sigrid), Hauke, J. (Jan), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hou, M.-F. (Ming-Feng), Ito, H. (Hidemi), Iwasaki, M. (Motoki), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Joseph, V. (Vijai), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kang, D. (Daehee), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kim, S.-W. (Sung-Won), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kwong, A. (Ava), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Larsson, S. C. (Susanna C.), Le Marchand, L. (Loic), Lejbkowicz, F. (Flavio), Li, J. (Jingmei), Long, J. (Jirong), Lophatananon, A. (Artitaya), LubiNski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Mavroudis, D. (Dimitrios), Mayes, R. (Rebecca), Menon, U. (Usha), Milne, R. L. (Roger L.), Taib, N. A. (Nur Aishah Mohd), Muir, K. (Kenneth), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), O'Brien, K. M. (Katie M.), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park, S. K. (Sue K.), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Rennert, G. (Gad), Romero, A. (Atocha), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teo, S. H. (Soo Hwang), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Toland, A. E. (Amanda E.), Tomlinson, I. (Ian), Truong, T. (Therese), Tseng, C.-C. (Chiu-Chen), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), Wang, S. S. (Sophia S.), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Winham, S. J. (Stacey J.), Winqvist, R. (Robert), Wolk, A. (Alicja), Wu, A. H. (Anna H.), Yamaji, T. (Taiki), Zheng, W. (Wei), Ziogas, A. (Argyrios), Pharoah, P. D. (Paul D. P.), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Pettitt, S. J. (Stephen J.), Lord, C. J. (Christopher J.), Haider, S. (Syed), Orr, N. (Nick), Fletcher, O. (Olivia), Baxter, J. S. (Joseph S.), Johnson, N. (Nichola), Tomczyk, K. (Katarzyna), Gillespie, A. (Andrea), Maguire, S. (Sarah), Brough, R. (Rachel), Fachal, L. (Laura), Michailidou, K. (Kyriaki), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Augustinsson, A. (Annelie), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brenner, H. (Hermann), Brucker, S. Y. (Sara Y.), Cai, Q. (Qiuyin), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chan, T. L. (Tsun L.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Choi, J.-Y. (Ji-Yeob), Clarke, C. L. (Christine L.), Collaborators, N. (Nbcs), Colonna, S. (Sarah), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Doerk, T. (Thilo), Dossus, L. (Laure), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Gao, C. (Chi), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Ghoussaini, M. (Maya), Giles, G. G. (Graham G.), Goldberg, M. S. (Mark S.), Gonzalez-Neira, A. (Anna), Guenel, P. (Pascal), Guendert, M. (Melanie), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hall, P. (Per), Hamann, U. (Ute), Hartman, M. (Mikael), Hatse, S. (Sigrid), Hauke, J. (Jan), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hou, M.-F. (Ming-Feng), Ito, H. (Hidemi), Iwasaki, M. (Motoki), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Joseph, V. (Vijai), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kang, D. (Daehee), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kim, S.-W. (Sung-Won), Kosma, V.-M. (Veli-Matti), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kubelka-Sabit, K. (Katerina), Kurian, A. W. (Allison W.), Kwong, A. (Ava), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Larson, N. L. (Nicole L.), Larsson, S. C. (Susanna C.), Le Marchand, L. (Loic), Lejbkowicz, F. (Flavio), Li, J. (Jingmei), Long, J. (Jirong), Lophatananon, A. (Artitaya), LubiNski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Matsuo, K. (Keitaro), Mavroudis, D. (Dimitrios), Mayes, R. (Rebecca), Menon, U. (Usha), Milne, R. L. (Roger L.), Taib, N. A. (Nur Aishah Mohd), Muir, K. (Kenneth), Muranen, T. A. (Taru A.), Murphy, R. A. (Rachel A.), Nevanlinna, H. (Heli), O'Brien, K. M. (Katie M.), Offit, K. (Kenneth), Olson, J. E. (Janet E.), Olsson, H. (Hakan), Park, S. K. (Sue K.), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Pylkäs, K. (Katri), Rack, B. (Brigitte), Rennert, G. (Gad), Romero, A. (Atocha), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Shah, M. (Mitul), Shen, C.-Y. (Chen-Yang), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teo, S. H. (Soo Hwang), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Toland, A. E. (Amanda E.), Tomlinson, I. (Ian), Truong, T. (Therese), Tseng, C.-C. (Chiu-Chen), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), Wang, S. S. (Sophia S.), Weinberg, C. R. (Clarice R.), Wendt, C. (Camilla), Winham, S. J. (Stacey J.), Winqvist, R. (Robert), Wolk, A. (Alicja), Wu, A. H. (Anna H.), Yamaji, T. (Taiki), Zheng, W. (Wei), Ziogas, A. (Argyrios), Pharoah, P. D. (Paul D. P.), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Pettitt, S. J. (Stephen J.), Lord, C. J. (Christopher J.), Haider, S. (Syed), Orr, N. (Nick), and Fletcher, O. (Olivia)
Abstract: A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74–0.81, p = 3.1 × 10−31).
Published: 2021

38. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Escala-Garcia, M. (Maria), Canisius, S. (Sander), Keeman, R. (Renske), Beesley, J. (Jonathan), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Augustinsson, A. (Annelie), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bermisheva, M. (Marina), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Couch, F. J. (Fergus J.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Devilee, P. (Peter), Dork, T. (Thilo), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Geisler, J. (Juergen), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hartikainen, J. M. (Jaana M.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hunter, D. J. (David J.), Jacot, W. (William), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Khusnutdinova, E. (Elza), Koppert, L. B. (Linetta B.), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Luben, R. N. (Robert N.), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa V.), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Punie, K. (Kevin), Radice, P. (Paolo), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Romero, A. (Atocha), Roylance, R. (Rebecca), Ruediger, T. (Thomas), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Scott, C. (Christopher), Southey, M. C. (Melissa C.), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Teras, L. R. (Lauren R.), Thomas, E. (Emilie), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Michailidou, K. (Kyriaki), Chenevix-Trench, G. (Georgia), Bachelot, T. (Thomas), Schmidt, M. K. (Marjanka K.), Escala-Garcia, M. (Maria), Canisius, S. (Sander), Keeman, R. (Renske), Beesley, J. (Jonathan), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Augustinsson, A. (Annelie), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bermisheva, M. (Marina), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Couch, F. J. (Fergus J.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Devilee, P. (Peter), Dork, T. (Thilo), Dunning, A. M. (Alison M.), Easton, D. F. (Douglas F.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Gago-Dominguez, M. (Manuela), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Geisler, J. (Juergen), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hartikainen, J. M. (Jaana M.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hollestelle, A. (Antoinette), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Hunter, D. J. (David J.), Jacot, W. (William), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Khusnutdinova, E. (Elza), Koppert, L. B. (Linetta B.), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Luben, R. N. (Robert N.), Lubinski, J. (Jan), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Mavroudis, D. (Dimitrios), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa V.), Peterlongo, P. (Paolo), Pharoah, P. D. (Paul D. P.), Punie, K. (Kevin), Radice, P. (Paolo), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Romero, A. (Atocha), Roylance, R. (Rebecca), Ruediger, T. (Thomas), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Scott, C. (Christopher), Southey, M. C. (Melissa C.), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Teras, L. R. (Lauren R.), Thomas, E. (Emilie), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Michailidou, K. (Kyriaki), Chenevix-Trench, G. (Georgia), Bachelot, T. (Thomas), and Schmidt, M. K. (Marjanka K.)
Abstract: Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021

39. Mendelian randomisation study of smoking exposure in relation to breast cancer risk

Author: Park, H. A. (Hanla A.), Neumeyer, S. (Sonja), Michailidou, K. (Kyriaki), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dos-Santos-Silva, I. (Isabel), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Grip, M. (Mervi), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Han, S. (Sileny), Harkness, E. F. (Elaine F.), Hart, S. N. (Steven N.), He, W. (Wei), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hopper, J. L. (John L.), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kapoor, P. M. (Pooja Middha), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Koppert, L. B. (Linetta B.), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. (James), Lambrechts, D. (Diether), LeMarchand, L. (Loic), Lo, W.-Y. (Wing-Yee), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), ElenaMartinez, M. (Maria), Mavroudis, D. (Dimitrios), Meindl, A. (Alfons), Menon, U. (Usha), Milne, R. L. (Roger L.), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nordestgaard, B. G. (Borge G.), Offit, K. (Kenneth), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Radice, P. (Paolo), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schwentner, L. (Lukas), Scott, C. (Christopher), Shah, M. (Mitul), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Smeets, A. (Ann), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stevens, V. (Victoria), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), van Veen, E. M. (Elke M.), Vijai, J. (Joseph), Wang, S. (Sophia), Wendt, C. (Camilla), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Zheng, W. (Wei), Kraft, P. (Peter), Chang-Claude, J. (Jenny), Park, H. A. (Hanla A.), Neumeyer, S. (Sonja), Michailidou, K. (Kyriaki), Bolla, M. K. (Manjeet K.), Wang, Q. (Qin), Dennis, J. (Joe), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Antonenkova, N. N. (Natalia N.), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Augustinsson, A. (Annelie), Baten, A. (Adinda), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Brucker, S. Y. (Sara Y.), Burwinkel, B. (Barbara), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chanock, S. J. (Stephen J.), Chenevix-Trench, G. (Georgia), Clarke, C. L. (Christine L.), Conroy, D. M. (Don M.), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Dork, T. (Thilo), Dos-Santos-Silva, I. (Isabel), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Eliassen, A. H. (A. Heather), Engel, C. (Christoph), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Garcia-Closas, M. (Montserrat), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Giles, G. G. (Graham G.), Glendon, G. (Gord), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Grip, M. (Mervi), Guenel, P. (Pascal), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Han, S. (Sileny), Harkness, E. F. (Elaine F.), Hart, S. N. (Steven N.), He, W. (Wei), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hopper, J. L. (John L.), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), John, E. M. (Esther M.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kapoor, P. M. (Pooja Middha), Keeman, R. (Renske), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Koppert, L. B. (Linetta B.), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. (James), Lambrechts, D. (Diether), LeMarchand, L. (Loic), Lo, W.-Y. (Wing-Yee), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), ElenaMartinez, M. (Maria), Mavroudis, D. (Dimitrios), Meindl, A. (Alfons), Menon, U. (Usha), Milne, R. L. (Roger L.), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nordestgaard, B. G. (Borge G.), Offit, K. (Kenneth), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Park-Simon, T.-W. (Tjoung-Won), Peterlongo, P. (Paolo), Peto, J. (Julian), Plaseska-Karanfilska, D. (Dijana), Presneau, N. (Nadege), Radice, P. (Paolo), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Romero, A. (Atocha), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmidt, M. K. (Marjanka K.), Schmutzler, R. K. (Rita K.), Schoemaker, M. J. (Minouk J.), Schwentner, L. (Lukas), Scott, C. (Christopher), Shah, M. (Mitul), Shu, X.-O. (Xiao-Ou), Simard, J. (Jacques), Smeets, A. (Ann), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stevens, V. (Victoria), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Terry, M. B. (Mary Beth), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), van Veen, E. M. (Elke M.), Vijai, J. (Joseph), Wang, S. (Sophia), Wendt, C. (Camilla), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Dunning, A. M. (Alison M.), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Zheng, W. (Wei), Kraft, P. (Peter), and Chang-Claude, J. (Jenny)
Abstract: Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10⁻²), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusions: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
Published: 2021

40. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), Schmidt, M. K. (Marjanka K.), Morra, A. (Anna), Escala-Garcia, M. (Maria), Beesley, J. (Jonathan), Keeman, R. (Renske), Canisius, S. (Sander), Ahearn, T. U. (Thomas U.), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Auer, P. L. (Paul L.), Augustinsson, A. (Annelie), Freeman, L. E. (Laura E. Beane), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Bojesen, S. E. (Stig E.), Bolla, M. K. (Manjeet K.), Brenner, H. (Hermann), Bruening, T. (Thomas), Buys, S. S. (Saundra S.), Caan, B. (Bette), Campa, D. (Daniele), Canzian, F. (Federico), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Cheng, T. D. (Ting-Yuan David), Clarke, C. L. (Christine L.), Colonna, S. V. (Sarah, V), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Dennis, J. (Joe), Dork, T. (Thilo), Dossus, L. (Laure), Dunning, A. M. (Alison M.), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Eliassen, A. H. (A. Heather), Eriksson, M. (Mikael), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Flyger, H. (Henrik), Fritschi, L. (Lin), Gago-Dominguez, M. (Manuela), Garcia-Saenz, J. A. (Jose A.), Giles, G. G. (Graham G.), Grip, M. (Mervi), Guenel, P. (Pascal), Guendert, M. (Melanie), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hakansson, N. (Niclas), Hall, P. (Per), Hamann, U. (Ute), Hart, S. N. (Steven N.), Hartikainen, J. M. (Jaana M.), Hartmann, A. (Arndt), He, W. (Wei), Hooning, M. J. (Maartje J.), Hoppe, R. (Reiner), Hopper, J. L. (John L.), Howell, A. (Anthony), Hunter, D. J. (David J.), Jager, A. (Agnes), Jakubowska, A. (Anna), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jung, A. Y. (Audrey Y.), Kaaks, R. (Rudolf), Keupers, M. (Machteld), Kitahara, C. M. (Cari M.), Koutros, S. (Stella), Kraft, P. (Peter), Kristensen, V. N. (Vessela N.), Kurian, A. W. (Allison W.), Lacey, J. V. (James, V), Lambrechts, D. (Diether), Le Marchand, L. (Loic), Lindblom, A. (Annika), Linet, M. (Martha), Luben, R. N. (Robert N.), Lush, M. (Michael), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Margolin, S. (Sara), Martens, J. W. (John W. M.), Martinez, M. E. (Maria Elena), Mavroudis, D. (Dimitrios), Michailidou, K. (Kyriaki), Milne, R. L. (Roger L.), Mulligan, A. M. (Anna Marie), Muranen, T. A. (Taru A.), Nevanlinna, H. (Heli), Newman, W. G. (William G.), Nielsen, S. F. (Sune F.), Nordestgaard, B. G. (Borge G.), Olshan, A. F. (Andrew F.), Olsson, H. (Hakan), Orr, N. (Nick), Park-Simon, T.-W. (Tjoung-Won), Patel, A. V. (Alpa, V), Peissel, B. (Bernard), Peterlongo, P. (Paolo), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Presneau, N. (Nadege), Rack, B. (Brigitte), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Rhenius, V. (Valerie), Romero, A. (Atocha), Roylance, R. (Rebecca), Lubinski, J. (Jan), Ruebner, M. (Matthias), Saloustros, E. (Emmanouil), Sawyer, E. J. (Elinor J.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Scott, C. (Christopher), Shah, M. (Mitul), Smichkoska, S. (Snezhana), Southey, M. C. (Melissa C.), Stone, J. (Jennifer), Surowy, H. (Harald), Swerdlow, A. J. (Anthony J.), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Teras, L. R. (Lauren R.), Terry, M. B. (Mary Beth), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Troester, M. A. (Melissa A.), Truong, T. (Therese), Vachon, C. M. (Celine M.), Wang, Q. (Qin), Hurson, A. N. (Amber N.), Winqvist, R. (Robert), Wolk, A. (Alicja), Ziogas, A. (Argyrios), Brauch, H. (Hiltrud), Garcia-Closas, M. (Montserrat), Pharoah, P. D. (Paul D. P.), Easton, D. F. (Douglas F.), Chenevix-Trench, G. (Georgia), and Schmidt, M. K. (Marjanka K.)
Abstract: Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP & 0.15). Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic varia
Published: 2021

41. Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Author: Kramer, I., Hooning, M.J., Mavaddat, N., Hauptmann, M., Keeman, R., Steyerberg, E.W., Giardiello, D., Antoniou, A.C., Pharoah, P.D.P., Canisius, S., Abu-Ful, Z., Andrulis, I.L., Anton-Culver, H., Aronson, K.J., Augustinsson, A., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Brauch, H., Bremer, M., Brucker, S.Y., Burwinkel, B., Castelao, J.E., Chan, T.L., Chang-Claude, J., Chanock, S.J., Chenevix-Trench, G., Choi, J.Y., Clarke, C.L., Collee, J.M., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Dork, T., dos-Santos-Silva, I., Dunning, A.M., Dwek, M., Eccles, D.M., Evans, D.G., Fasching, P.A., Flyger, H., Gago-Dominguez, M., Garcia-Closas, M., Garcia-Saenz, J.A., Giles, G.G., Goldgar, D.E., Gonzalez-Neira, A., Haiman, C.A., Hakansson, N., Hamann, U., Hartman, M., Heemskerk-Gerritsen, B.A.M., Hollestelle, A., Hopper, J.L., Hou, M.F., Howell, A., Ito, H., Jakimovska, M., Jakubowska, A., Janni, W., John, E.M., Jung, A., Kang, D., Kets, C.M., Khusnutdinova, E., Ko, Y.D., Kristensen, V.N., Kurian, A.W., Kwong, A., Lambrechts, D., Marchand, L. le, Li, J.M., Lindblom, A., Mannermaa, A., Manoochehri, M., Margolin, S., Matsuo, K., Mavroudis, D., Meindl, A., Milne, R.L., Mulligan, A.M., Muranen, T.A., Neuhausen, S.L., Nevanlinna, H., Newman, W.G., Olshan, A.F., Olson, J.E., Olsson, H., Park-Simon, T.W., Peto, J., Petridis, C., Plaseska-Karanfilska, D., Presneau, N., Pylkas, K., Radice, P., Rennert, G., Romero, A., Roylance, R., Saloustros, E., Sawyer, E.J., Schmutzler, R.K., Schwentner, L., Scott, C., See, M.H., Shah, M., Shen, C.Y., Shu, X.O., Siesling, S., Slager, S., Sohn, C., Southey, M.C., Spinelli, J.J., Stone, J., Tapper, W.J., Tengstrom, M., Teo, S.H., Terry, M.B., Tollenaar, R.A.E.M., Tomlinson, I., Troester, M.A., Vachon, C.M., Ongeval, C. van, Veen, E.M. van, Winqvist, R., Wolk, A., Zheng, W., Ziogas, A., Easton, D.F., Hall, P., Schmidt, M.K., NBCS Collaborators, ABCTB Investigators, and kConFab Investigators
Subjects: parasitic diseases
Abstract: Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
Published: 2020

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

Author: Ahearn, TU, Zhang, H, Michailidou, K, Milne, RL, Bolla, MK, Dennis, J, Dunning, AM, Lush, M, Wang, Q, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Augustinsson, A, Baten, A, Becher, H, Behrens, S, Benitez, J, Bermisheva, M, Blomqvist, C, Bojesen, SE, Bonanni, B, Børresen-Dale, A-L, Brauch, H, Brenner, H, Brooks-Wilson, A, Brüning, T, Burwinkel, B, Buys, SS, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Engebråten, O, Naume, B, Fosså, A, Kiserud, CE, Reinertsen, KV, Helland, Å, Riis, M, Geisler, J, Collée, JM, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dörk, T, Dwek, M, Eccles, DM, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Gago-Dominguez, M, Gapstur, SM, García-Sáenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, González-Neira, A, Alnæs, GIG, Grip, M, Guénel, P, Haiman, CA, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Clarke, C, Balleine, R, Baxter, R, Braye, S, Carpenter, J, Dahlstrom, J, Forbes, J, Lee, C, Marsh, D, Morey, A, Pathmanathan, N, Scott, R, Simpson, P, Spigelman, A, Wilcken, N, Yip, D, Zeps, N, Fox, S, Campbell, I, Bowtell, D, Spurdle, A, Webb, P, de Fazio, A, Tassell, M, Kirk, J, Lindeman, G, Price, M, Southey, M, Milne, R, Deb, S, Jakimovska, M, Jakubowska, A, John, EM, Jones, ME, Jung, A, Kaaks, R, Kauppila, S, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Koutros, S, Kristensen, VN, Krüger, U, Kubelka-Sabit, K, Kurian, AW, Kyriacou, K, Lambrechts, D, Lee, DG, Lindblom, A, Linet, M, Lissowska, J, Llaneza, A, Lo, W-Y, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Margolin, S, Martinez, ME, McLean, C, Meindl, A, Menon, U, Nevanlinna, H, Newman, WG, Nodora, J, Offit, K, Olsson, H, Orr, N, Park-Simon, T-W, Patel, AV, Peto, J, Pita, G, Plaseska-Karanfilska, D, Prentice, R, Punie, K, Pylkäs, K, Radice, P, Rennert, G, Romero, A, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Schoemaker, MJ, Schöttker, B, Sherman, ME, Shu, X-O, Smichkoska, S, Southey, MC, Spinelli, JJ, Swerdlow, AJ, Tamimi, RM, Tapper, WJ, Taylor, JA, Teras, LR, Terry, MB, Torres, D, Troester, MA, Vachon, CM, van Deurzen, CHM, van Veen, EM, Wagner, P, Weinberg, CR, Wendt, C, Wesseling, J, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Couch, FJ, Simard, J, Kraft, P, Easton, DF, Pharoah, PDP, Schmidt, MK, García-Closas, M, Chatterjee, N, Ahearn, Thomas U [0000-0003-0771-7752], Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Apollo - University of Cambridge Repository, Medicum, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Department of Obstetrics and Gynecology, Biosciences, HUS Gynecology and Obstetrics, Clinical Genetics, Medical Oncology, and Pathology
Subjects: False discovery rate, Oncology, Common breast cancer susceptibility variants, Receptor, ErbB-2, Estrogen receptor, PROGRESSION, Etiologic heterogeneity, Logistic regression, Basic medicine, Breast cancer, 0302 clinical medicine, PRIMARY THERAPY, HETEROGENEITY, RC254-282, HISTOLOGICAL GRADE, 0303 health sciences, Breast Neoplasms/epidemiology, Receptors, Estrogen/genetics, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, INTERNATIONAL EXPERT CONSENSUS, humanities, Receptor, ErbB-2/genetics, 3. Good health, Receptors, Estrogen, Receptors, Progesterone/genetics, 030220 oncology & carcinogenesis, Female, Biomarkers, Tumor/genetics, Receptors, Progesterone, Medical Genetics, Research Article, Risk, medicine.medical_specialty, SUSCEPTIBILITY LOCI, 3122 Cancers, Breast Neoplasms, Single-nucleotide polymorphism, Biology, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Progesterone receptor, Biomarkers, Tumor, medicine, Genetic predisposition, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Genetic association, Medicinsk genetik, 030304 developmental biology, Cancer och onkologi, medicine.disease, Cancer and Oncology, Clinical medicine, Genome-Wide Association Study
Abstract: Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate p Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
Published: 2020

43. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, H, Ahearn, TU, Lecarpentier, J, Barnes, D, Beesley, J, Qi, G, Jiang, X, O’Mara, TA, Zhao, N, Bolla, MK, Dunning, AM, Dennis, J, Wang, Q, Ful, ZA, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Arun, BK, Auer, PL, Azzollini, J, Barrowdale, D, Becher, H, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bialkowska, K, Blanco, A, Blomqvist, C, Bogdanova, NV, Bojesen, SE, Bonanni, B, Bondavalli, D, Borg, A, Brauch, H, Brenner, H, Briceno, I, Broeks, A, Brucker, SY, Brüning, T, Burwinkel, B, Buys, SS, Byers, H, Caldés, T, Caligo, MA, Calvello, M, Campa, D, Castelao, JE, Chang-Claude, J, Chanock, SJ, Christiaens, M, Christiansen, H, Chung, WK, Claes, KBM, Clarke, CL, Cornelissen, S, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Diez, O, Domchek, SM, Dörk, T, Dwek, M, Eccles, DM, Ekici, AB, Evans, DG, Fasching, PA, Figueroa, J, Foretova, L, Fostira, F, Friedman, E, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Gronwald, J, Guénel, P, Häberle, L, Hahnen, E, Haiman, CA, Hake, CR, Hall, P, Hamann, U, Harkness, EF, Heemskerk-Gerritsen, BAM, Hillemanns, P, Hogervorst, FBL, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huebner, H, Hulick, PJ, Imyanitov, EN, Isaacs, C, Izatt, L, Jager, A, Jakimovska, M, Jakubowska, A, James, P, Janavicius, R, Janni, W, John, EM, Jones, ME, Jung, A, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khan, S, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Konstantopoulou, I, Koppert, LB, Koutros, S, Kristensen, VN, Laenkholm, A-V, Lambrechts, D, Larsson, SC, Laurent-Puig, P, Lazaro, C, Lazarova, E, Lejbkowicz, F, Leslie, G, Lesueur, F, Lindblom, A, Lissowska, J, Lo, W-Y, Loud, JT, Lubinski, J, Lukomska, A, MacInnis, RJ, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Matricardi, L, McGuffog, L, McLean, C, Mebirouk, N, Meindl, A, Menon, U, Miller, A, Mingazheva, E, Montagna, M, Mulligan, AM, Mulot, C, Muranen, TA, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Neven, P, Newman, WG, Nielsen, FC, Nikitina-Zake, L, Nodora, J, Offit, K, Olah, E, Olopade, OI, Olsson, H, Orr, N, Papi, L, Papp, J, Park-Simon, T-W, Parsons, MT, Peissel, B, Peixoto, A, Peshkin, B, Peterlongo, P, Peto, J, Phillips, K-A, Piedmonte, M, Plaseska-Karanfilska, D, Prajzendanc, K, Prentice, R, Prokofyeva, D, Rack, B, Radice, P, Ramus, SJ, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Risch, HA, Romero, A, Rookus, MA, Rübner, M, Rüdiger, T, Saloustros, E, Sampson, S, Sandler, DP, Sawyer, EJ, Scheuner, MT, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schöttker, B, Schürmann, P, Senter, L, Sharma, P, Sherman, ME, Shu, X-O, Singer, CF, Smichkoska, S, Soucy, P, Southey, MC, Spinelli, JJ, Stone, J, Stoppa-Lyonnet, D, Swerdlow, AJ, Szabo, CI, Tamimi, RM, Tapper, WJ, Taylor, JA, Teixeira, MR, Terry, M, Thomassen, M, Thull, DL, Tischkowitz, M, Toland, AE, Tollenaar, RAEM, Tomlinson, I, Torres, D, Troester, MA, Truong, T, Tung, N, Untch, M, Vachon, CM, van den Ouweland, AMW, van der Kolk, LE, van Veen, EM, vanRensburg, EJ, Vega, A, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wildiers, H, Winqvist, R, Wolk, A, Yang, XR, Yannoukakos, D, Zheng, W, Zorn, KK, Milne, RL, Kraft, P, Simard, J, Pharoah, PDP, Michailidou, K, Antoniou, AC, Schmidt, MK, Chenevix-Trench, G, Easton, DF, Chatterjee, N, and García-Closas, M
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1,2,3. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

44. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhan, H.Y., Ahearn, T.U., Lecarpentier, J., Barnes, D., Beesley, J., Qi, G.H., Jiang, X., O'Mara, T.A., Zhao, N., Bolla, M.K., Dunning, A.M., Dennis, J., Wang, Q., Abu Ful, Z., Aittomaki, K., Andrulis, I.L., Anton-Culver, H., Arndt, V., Aronson, K.J., Arun, B.K., Auer, P.L., Azzollini, J., Barrowdale, D., Becher, H., Beckmann, M.W., Behrens, S., Benitez, J., Bermisheva, M., Bialkowska, K., Blanco, A., Blomqvist, C., Bogdanova, N.V., Bojesen, S.E., Bonanni, B., Bondavalli, D., Borg, A., Brauch, H., Brenner, H., Briceno, I., Broeks, A., Brucker, S.Y., Bruning, T., Burwinkel, B., Buys, S.S., Byers, H., Caldes, T., Caligo, M.A., Calvello, M., Campa, D., Castelao, J.E., Chang-Claude, J., Chanock, S.J., Christiaens, M., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Czene, K., Daly, M.B., Devilee, P., Diez, O., Domchek, S.M., Dork, T., Dwek, M., Eccles, D.M., Ekici, A.B., Evans, D.G., Fasching, P.A., Figueroa, J., Foretova, L., Fostira, F., Friedman, E., Frost, D., Gago-Dominguez, M., Gapstur, S.M., Garber, J., Garcia-Saenz, J.A., Gaudet, M.M., Gayther, S.A., Giles, G.G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., Gonzalez-Neira, A., Greene, M.H., Gronwald, J., Guenel, P., Haberle, L., Hahnen, E., Haiman, C.A., Hake, C.R., Hall, P., Hamann, U., Harkness, E.F., Heemskerk-Gerritsen, B.A.M., Hillemanns, P., Hogervorst, F.B.L., Holleczek, B., Hollestelle, A., Hooning, M.J., Hoover, R.N., Hopper, J.L., Howell, A., Huebner, H., Hulick, P.J., Imyanitov, E.N., Isaacs, C., Izatt, L., Jager, A., Jakimovska, M., Jakubowska, A., James, P., Janavicius, R., Janni, W., John, E.M., Jones, M.E., Jung, A., Kaaks, R., Kapoor, P.M., Karlan, B.Y., Keeman, R., Khan, S., Khusnutdinova, E., Kitahara, C.M., Ko, Y.D., Konstantopoulou, I., Koppert, L.B., Koutros, S., Kristensen, V.N., Laenkholm, A.V., Lambrechts, D., Larsson, S.C., Laurent-Puig, P., Lazaro, C., Lazarova, E., Lejbkowicz, F., Leslie, G., Lesueur, F., Lindblom, A., Lissowska, J., W.Y. lo, Loud, J.T., Lubinski, J., Lukomska, A., MacInnis, R.J., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matricardi, L., McGuffog, L., McLean, C., Mebirouk, N., Meindl, A., Menon, U., Miller, A., Mingazheva, E., Montagna, M., Mulligan, A.M., Mulot, C., Muranen, T.A., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Newman, W.G., Nielsens, F.C., Nikitina-Zake, L., Nodora, J., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Papi, L., Papp, J., Park-Simon, T.W., Parsons, M.T., Peissel, B., Peixoto, A., Peshkin, B., Peterlongo, P., Peto, J., Phillips, K.A., Piedmonte, M., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Prokofyeva, D., Rack, B., Radice, P., Ramus, S.J., Rantala, J., Rashid, M.U., Rennert, G., Rennert, H.S., Risch, H.A., Romero, A., Rookus, M.A., Rubner, M., Rudiger, T., Saloustros, E., Sampson, S., Sandler, D.P., Sawyer, E.J., Scheuner, M.T., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schottker, B., Schurmann, P., Senter, L., Sharma, P., Sherman, M.E., Shu, X.O., Singer, C.F., Smichkoska, S., Soucy, P., Southey, M.C., Spinelli, J.J., Stone, J., Stoppa-Lyonnet, D., Swerdlow, A.J., Szabo, C.I., Tamimi, R.M., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Terry, M., Thomassen, M., Thull, D.L., Tischkowitz, M., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Troester, M.A., Truong, T., Tung, N., Untch, M., Vachon, C.M., Ouweland, A.M.W. van den, Kolk, L.E. van der, Veen, E.M. van, vanRensburg, E.J., Vega, A., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wildiers, H., Winqvist, R., Wolk, A., Yang, X.H.R., Yannoukakos, D., Zheng, W., Zorn, K.K., Milne, R.L., Kraft, P., Simard, J., Pharoah, P.D.P., Michailidou, K., Antoniou, A.C., Schmidt, M.K., Chenevix-Trench, G., Easton, D.F., Chatterjee, N., Garcia-Closas, M., kConFab Investigators, ABCTB Investigators, EMBRACE Study, and GEMO Study Collaborators
Abstract: Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade.Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
Published: 2020

45. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes

Author: Fachal, L., Aschard, H., Beesley, J., Barnes, D.R., Allen, J., Kar, S., Pooley, K.A., Dennis, J., Michailidou, K., Turman, C., Soucy, P., Lemaçon, A., Lush, M., Tyrer, J.P., Ghoussaini, M., Marjaneh, M.M., Jiang, X., Agata, S., Aittomäki, K., Alonso, M.R., Andrulis, I.L., Anton-Culver, H., Antonenkova, N.N., Arason, A., Arndt, V., Aronson, K.J., Arun, B.K., Auber, B., Auer, P.L., Azzollini, J., Balmaña, J., Barkardottir, R.B., Barrowdale, D., Beeghly-Fadiel, A., Benitez, J., Bermisheva, M., Białkowska, K., Blanco, A.M., Blomqvist, C., Blot, W., Bogdanova, N.V., Bojesen, S.E., Bolla, M.K., Bonanni, B., Borg, A., Bosse, K., Brauch, H., Brenner, H., Briceno, I., Brock, I.W., Brooks-Wilson, A., Brüning, T., Burwinkel, B., Buys, S.S., Cai, Q., Caldés, T., Caligo, M.A., Camp, N.J., Campbell, I., Canzian, F., Carroll, J.S., Carter, B.D., Castelao, J.E., Chiquette, J., Christiansen, H., Chung, W.K., Claes, K.B.M., Clarke, C.L., Mari, V., Berthet, P., Castera, L., Vaur, D., Lallaoui, H., Bignon, Y.-J., Uhrhammer, N., Bonadona, V., Lasset, C., Révillion, F., Vennin, P., Muller, D., Gomes, D.M., Ingster, O., Coupier, I., Pujol, P., Collonge-Rame, M.-A., Mortemousque, I., Bera, O., Rose, M., Baurand, A., Bertolone, G., Faivre, L., Dreyfus, H., Leroux, D., Venat-Bouvet, L., Bézieau, S., Delnatte, C., Chiesa, J., Gilbert-Dussardier, B., Gesta, P., Prieur, F.P., Bronner, M., Sokolowska, J., Coulet, F., Boutry-Kryza, N., Calender, A., Giraud, S., Leone, M., Fert-Ferrer, S., Stoppa-Lyonnet, D., Jiao, Y., Lesueur, F.L., Mebirouk, N., Barouk-Simonet, E., Bubien, V., Longy, M., Sevenet, N., Gladieff, L., Toulas, C., Reimineras, A., Sobol, H., Paillerets, B.B.-D., Cabaret, O., Caron, O., Guillaud-Bataille, M., Rouleau, E., Belotti, M., Buecher, B., Caputo, S., Colas, C., Pauw, A.D., Fourme, E., Gauthier-Villars, M., Golmard, L., Moncoutier, V., Saule, C., Donaldson, A., Murray, A., Brady, A., Brewer, C., Pottinger, C., Miller, C., Gallagher, D., Gregory, H., Cook, J., Eason, J., Adlard, J., Barwell, J., Ong, K.-R., Snape, K., Walker, L., Izatt, L., Side, L., Tischkowitz, M., Rogers, M.T., Porteous, M.E., Ahmed, M., Morrison, P.J., Brennan, P., Eeles, R., Davidson, R., Collée, M., Cornelissen, S., Couch, F.J., Cox, A., Cross, S.S., Cybulski, C., Czene, K., Daly, M.B., de la Hoya, M., Devilee, P., Diez, O., Ding, Y.C., Dite, G.S., Domchek, S.M., Dörk, T., dos-Santos-Silva, I., Droit, A., Dubois, S., Dumont, M., Duran, M., Durcan, L., Dwek, M., Eccles, D.M., Engel, C., Eriksson, M., Evans, D.G., Fasching, P.A., Fletcher, O., Floris, G., Flyger, H., Foretova, L., Foulkes, W.D., Friedman, E., Fritschi, L., Frost, D., Gabrielson, M., Gago-Dominguez, M., Gambino, G., Ganz, P.A., Gapstur, S.M., Garber, J., García-Sáenz, J.A., Gaudet, M.M., Georgoulias, V., Giles, G., Glendon, G., Godwin, A.K., Goldberg, M.S., Goldgar, D.E., González-Neira, A., Tibiletti, M.G., Greene, M.H., Grip, M., Gronwald, J., Grundy, A., Guénel, P., Hahnen, E., Haiman, C.A., Håkansson, N., Hall, P., Hamann, U., Harrington, P.A., Hartikainen, J.M., Hartman, M., He, W., Healey, C.S., Heemskerk-Gerritsen, B.A.M., Heyworth, J., Hillemanns, P., Hogervorst, F.B.L., Hollestelle, A., Hooning, M., Hopper, J., Howell, A., Huang, G., Hulick, P.J., Imyanitov, E.N., Sexton, A., Christian, A., Trainer, A., Spigelman, A., Fellows, A., Shelling, A., Fazio, A.D., Blackburn, A., Crook, A., Meiser, B., Patterson, B., Clarke, C., Saunders, C., Hunt, C., Scott, C., Amor, D., Marsh, D., Edkins, E., Salisbury, E., Haan, E., Neidermayr, E., Macrea, F., Farshid, G., Lindeman, G., Chenevix-Trench, G., Mann, G., Gill, G., Thorne, H., Hickie, I., Winship, I., Flanagan, J., Kollias, J., Visvader, J., Stone, J., Taylor, J., Burke, J., Saunus, J., Forbes, J., Kirk, J., French, J., Tucker, K., Wu, K., Phillips, K., Lipton, L., Andrews, L., Lobb, L., Kentwell, M., Spurdle, M., Cummings, M., Gleeson, M., Harris, M., Jenkins, M., Young, M.A., Delatycki, M., Wallis, M., Burgess, M., Price, M., Brown, M., Southey, M., Bogwitz, M., Field, M., Friedlander, M., Gattas, M., Saleh, M., Hayward, N., Pachter, N., Cohen, P., Duijf, P., James, P., Simpson, P., Fong, P., Butow, P., Williams, R., Kefford, R., Scott, R., Milne, R.L., Balleine, R., Dawson, S.–J., Lok, S., O’Connell, S., Greening, S., Nightingale, S., Edwards, S., Fox, S., McLachlan, S.-A., Lakhani, S., Antill, Y., Aalfs, C., Meijers-Heijboer, H., van Engelen, K., Gille, H., Boere, I., van Deurzen, C., Obdeijn, I.-M., van den Ouweland, A., Seynaeve, C., Siesling, S., Verloop, J., van Asperen, C.J., van Cronenburg, T., Blok, R., de Boer, M., Garcia, E.G., Adank, M., Hogervorst, F., Jenner, D., van Leeuwen, F., Rookus, M., Russell, N., Schmidt, M., van den Belt-Dusebout, S., Kets, C., Mensenkamp, A., de Bock, T., van der Hout, A., Mourits, M., Oosterwijk, J., Ausems, M., Koudijs, M., Baxter, R., Yip, D., Carpenter, J., Davis, A., Pathmanathan, N., Graham, D., Sachchithananthan, M., Isaacs, C., Iwasaki, M., Jager, A., Jakimovska, M., Jakubowska, A., James, P.A., Janavicius, R., Jankowitz, R.C., John, E.M., Johnson, N., Jones, M.E., Jukkola-Vuorinen, A., Jung, A., Kaaks, R., Kang, D., Kapoor, P.M., Karlan, B.Y., Keeman, R., Kerin, M.J., Khusnutdinova, E., Kiiski, J.I., Kitahara, C.M., Ko, Y.-D., Konstantopoulou, I., Kosma, V.-M., Koutros, S., Kubelka-Sabit, K., Kwong, A., Kyriacou, K., Laitman, Y., Lambrechts, D., Lee, E., Leslie, G., Lester, J., Lesueur, F., Lindblom, A., Lo, W.-Y., Long, J., Lophatananon, A., Loud, J.T., Lubiński, J., MacInnis, R.J., Maishman, T., Makalic, E., Mannermaa, A., Manoochehri, M., Manoukian, S., Margolin, S., Martinez, M.E., Matsuo, K., Maurer, T., Mavroudis, D., Mayes, R., McGuffog, L., McLean, C., Meindl, A., Miller, A., Miller, N., Montagna, M., Moreno, F., Muir, K., Mulligan, A.M., Muñoz-Garzon, V.M., Muranen, T.A., Narod, S.A., Nassir, R., Nathanson, K.L., Neuhausen, S.L., Nevanlinna, H., Neven, P., Nielsen, F.C., Nikitina-Zake, L., Norman, A., Offit, K., Olah, E., Olopade, O.I., Olsson, H., Orr, N., Osorio, A., Pankratz, V.S., Papp, J., Park, S.K., Park-Simon, T.-W., Parsons, M.T., Paul, J., Pedersen, I.S., Peissel, B., Peshkin, B., Peterlongo, P., Peto, J., Plaseska-Karanfilska, D., Prajzendanc, K., Prentice, R., Presneau, N., Prokofyeva, D., Pujana, M.A., Pylkäs, K., Radice, P., Ramus, S.J., Rantala, J., Rau-Murthy, R., Rennert, G., Risch, H.A., Robson, M., Romero, A., Rossing, M., Saloustros, E., Sánchez-Herrero, E., Sandler, D.P., Santamariña, M., Sawyer, E.J., Scheuner, M.T., Schmidt, D.F., Schmutzler, R.K., Schneeweiss, A., Schoemaker, M.J., Schöttker, B., Schürmann, P., Scott, R.J., Senter, L., Seynaeve, C.M., Shah, M., Sharma, P., Shen, C.-Y., Shu, X.-O., Singer, C.F., Slavin, T.P., Smichkoska, S., Southey, M.C., Spinelli, J.J., Spurdle, A.B., Sutter, C., Swerdlow, A.J., Tamimi, R.M., Tan, Y.Y., Tapper, W.J., Taylor, J.A., Teixeira, M.R., Tengström, M., Teo, S.H., Terry, M.B., Teulé, A., Thomassen, M., Thull, D.L., Toland, A.E., Tollenaar, R.A.E.M., Tomlinson, I., Torres, D., Torres-Mejía, G., Troester, M.A., Truong, T., Tung, N., Tzardi, M., Ulmer, H.-U., Vachon, C.M., van der Kolk, L.E., van Rensburg, E.J., Vega, A., Viel, A., Vijai, J., Vogel, M.J., Wang, Q., Wappenschmidt, B., Weinberg, C.R., Weitzel, J.N., Wendt, C., Wildiers, H., Winqvist, R., Wolk, A., Wu, A.H., Yannoukakos, D., Zhang, Y., Zheng, W., Hunter, D., Pharoah, P.D.P., Chang-Claude, J., García-Closas, M., Schmidt, M.K., Kristensen, V.N., French, J.D., Edwards, S.L., Antoniou, A.C., Simard, J., Easton, D.F., Kraft, P., Dunning, A.M., Collaborators, GEMO Study, Collaborators, EMBRACE, Investigators, KConFab, Investigators, HEBON, Investigators, ABCTB, Fachal, Laura, Aschard, Hugues, Beesley, Jonathan, Barnes, Daniel R, Duijf, Pascal, Dunning, Alison M, GEMO Study Collaborators, EMBRACE Collaborators, KConFab Investigators, HEBON Investigators, ABCTB Investigators, MUMC+: MA Medische Oncologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Klinische Genetica, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), European Commission, Government of Canada, Canadian Institutes of Health Research, National Institutes of Health (US), Cancer Research UK, Département de Biologie Computationnelle - Department of Computational Biology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, University of Cambridge [UK] (CAM), NSCAD, University of Cyprus [Nicosia], Harvard T.H. Chan School of Public Health, This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded 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 Genome Québec) and the Quebec Breast Cancer Foundation), the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492), and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE, part of the GAME-ON initiative). For a full description of funding and acknowledgments, see the Supplementary Note., We thank all of the individuals who took part in these studies, as well as all of the researchers, clinicians, technicians and administrative staff who enabled this work to be carried out, European Project: 656144,H2020,H2020-MSCA-IF-2014,RADIOGENFF(2016), European Project: 223175,EC:FP7:HEALTH,FP7-HEALTH-2007-B,COGS(2009), European Project: 633784,H2020,H2020-PHC-2014-two-stage,B-CAST(2015), European Project: 634935,H2020,H2020-PHC-2014-two-stage,BRIDGES(2015), Clinical Genetics, Medical Oncology, Pathology, Radiology & Nuclear Medicine, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), University of Cyprus [Nicosia] (UCY), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Life Course Epidemiology (LCE), Targeted Gynaecologic Oncology (TARGON), Basic and Translational Research and Imaging Methodology Development in Groningen (BRIDGE), Aschard, Hugues [0000-0002-7554-6783], Barnes, Daniel R [0000-0002-3781-7570], Dennis, Joe [0000-0003-4591-1214], Michailidou, Kyriaki [0000-0001-7065-1237], Lemaçon, Audrey [0000-0002-1817-7029], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arndt, Volker [0000-0001-9320-8684], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Bojesen, Stig E [0000-0002-4061-4133], Bonanni, Bernardo [0000-0003-3589-2128], Brauch, Hiltrud [0000-0001-7531-2736], Campbell, Ian [0000-0002-7773-4155], Carroll, Jason S [0000-0003-3643-0080], Claes, Kathleen BM [0000-0003-0841-7372], Collée, J Margriet [0000-0002-9272-9346], Devilee, Peter [0000-0002-8023-2009], Dörk, Thilo [0000-0002-9458-0282], Dwek, Miriam [0000-0001-7184-2932], Fletcher, Olivia [0000-0001-9387-7116], Floris, Giuseppe [0000-0003-2391-5425], Foulkes, William D [0000-0001-7427-4651], García-Sáenz, José A [0000-0001-6880-0301], Greene, Mark H [0000-0003-1852-9239], Guénel, Pascal [0000-0002-8359-518X], Heemskerk-Gerritsen, Bernadette AM [0000-0002-9724-6693], Hollestelle, Antoinette [0000-0003-1166-1966], Hulick, Peter J [0000-0001-8397-4078], Jakimovska, Milena [0000-0002-1506-0669], Jakubowska, Anna [0000-0002-5650-0501], James, Paul A [0000-0002-4361-4657], Jones, Michael E [0000-0001-7479-3451], Kapoor, Pooja Middha [0000-0001-5503-8215], Keeman, Renske [0000-0002-5452-9933], Konstantopoulou, Irene [0000-0002-0470-0309], Leslie, Goska [0000-0001-5756-6222], Lesueur, Fabienne [0000-0001-7404-4549], Matsuo, Keitaro [0000-0003-1761-6314], McLean, Catriona [0000-0002-0302-5727], Miller, Austin [0000-0001-9739-8462], Muir, Kenneth [0000-0001-6429-988X], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Nevanlinna, Heli [0000-0002-0916-2976], Olopade, Olufunmilayo I [0000-0002-9936-1599], Orr, Nick [0000-0003-2866-942X], Pankratz, V Shane [0000-0002-3742-040X], Parsons, Michael T [0000-0003-3242-8477], Paul, James [0000-0001-7367-5816], Peshkin, Beth [0000-0002-2997-4701], Peterlongo, Paolo [0000-0001-6951-6855], Peto, Julian [0000-0002-1685-8912], Plaseska-Karanfilska, Dijana [0000-0001-8877-2416], Pylkäs, Katri [0000-0002-2449-0521], Radice, Paolo [0000-0001-6298-4111], Rennert, Gad [0000-0002-8512-068X], Robson, Mark [0000-0002-3109-1692], Romero, Atocha [0000-0002-1634-7397], Saloustros, Emmanouil [0000-0002-0485-0120], Scott, Christopher [0000-0003-1340-0647], Scott, Rodney J [0000-0001-7724-3404], Spurdle, Amanda B [0000-0003-1337-7897], Stone, Jennifer [0000-0001-5077-0124], Sutter, Christian [0000-0003-4051-5888], Tan, Yen Yen [0000-0003-1063-5352], Teixeira, Manuel R [0000-0002-4896-5982], Toland, Amanda E [0000-0002-0271-1792], Tomlinson, Ian [0000-0003-3037-1470], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Wolk, Alicja [0000-0001-7387-6845], Yannoukakos, Drakoulis [0000-0001-7509-3510], Pharoah, Paul DP [0000-0001-8494-732X], Schmidt, Marjanka K [0000-0002-2228-429X], Milne, Roger L [0000-0001-5764-7268], Edwards, Stacey L [0000-0001-7428-4139], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Kraft, Peter [0000-0002-4472-8103], Dunning, Alison M [0000-0001-6651-7166], Apollo - University of Cambridge Repository, Academic Medical Center, ARD - Amsterdam Reproduction and Development, Human genetics, CCA - Cancer biology and immunology, Molecular cell biology and Immunology, Medicum, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, University of Helsinki, HUS Comprehensive Cancer Center, Department of Oncology, Clinicum, Doctoral Programme in Clinical Research, Staff Services, INDIVIDRUG - Individualized Drug Therapy, HUS Gynecology and Obstetrics, and Department of Obstetrics and Gynecology
Subjects: CHROMATIN, Linkage disequilibrium, Genome-wide association study, Regulatory Sequences, Nucleic Acid, Genome-wide association studies, Linkage Disequilibrium, Basic medicine, 0302 clinical medicine, Breast cancer, MESH: Risk Factors, Risk Factors, COMPREHENSIVE MOLECULAR PORTRAITS, 11 Medical and Health Sciences, HEBON Investigators, Genetics & Heredity, 0303 health sciences, [STAT.AP]Statistics [stat]/Applications [stat.AP], PROTEIN FUNCTION, Tumor, breast tumor, MESH: Polymorphism, Single Nucleotide, 1184 Genetics, developmental biology, physiology, MESH: Genetic Predisposition to Disease, apoptosis, Chromosome Mapping, Single Nucleotide, 3. Good health, MESH: Linkage Disequilibrium, Female, MESH: Biomarkers, Tumor, Biomarkers, Tumor/genetics, [STAT.ME]Statistics [stat]/Methodology [stat.ME], Life Sciences & Biomedicine, SUSCEPTIBILITY LOCI, MESH: Bayes Theorem, Quantitative Trait Loci, ABCTB Investigators, INTEGRATIVE ANALYSIS, Breast Neoplasms, Computational biology, Biology, Quantitative trait locus, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, Article, ENHANCER, GEMO Study Collaborators, 03 medical and health sciences, breast cancer, SDG 3 - Good Health and Well-being, REVEALS, Genetics, Biomarkers, Tumor, MESH: Regulatory Sequences, Nucleic Acid, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, EMBRACE Collaborators, Gene, 030304 developmental biology, Genetic association, Bayes Theorem, Genome-Wide Association Study, MESH: Humans, Science & Technology, Nucleic Acid, gene mapping, 06 Biological Sciences, MESH: Quantitative Trait Loci, DNA binding site, ESTROGEN-RECEPTOR, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Clinical medicine, Expression quantitative trait loci, MESH: Genome-Wide Association Study, Human genome, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, KConFab Investigators, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Chromosome Mapping, Chromosome Mapping/methods, Regulatory Sequences, MESH: Female, Biomarkers, 030217 neurology & neurosurgery, MESH: Breast Neoplasms, Developmental Biology
Abstract: Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes., This work was supported by the European Union’s Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement number 656144. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project (funded 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 Genome Québec) and the Quebec Breast Cancer Foundation); the NCI Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project (NIH grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118, C8197/A16565 and C1287/A16563). BCAC is funded by Cancer Research UK (C1287/A16563), by the European Community’s Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS) and by the European Union’s Horizon 2020 Research and Innovation Programme under grant agreements 633784 (B-CAST) and 634935 (BRIDGES). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program, and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combining of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA 148065 (DRIVE; part of the GAME-ON initiative).
Published: 2020

46. Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

Author: Zhang, H. (Haoyu), Ahearn, T. U. (Thomas U.), Lecarpentier, J. (Julie), Barnes, D. (Daniel), Beesley, J. (Jonathan), Qi, G. (Guanghao), Hang, X. (Xia), O'Mara, T. A. (Tracy A.), Zhao, N. (Ni), Bolla, M. K. (Manjeet K.), Dunning, A. M. (Alison M.), Dennis, J. (Joe), Wang, Q. (Qin), Abu Ful, Z. (Zumuruda), Aittomaki, K. (Kristiina), Andrulis, I. L. (Irene L.), Anton-Culver, H. (Hoda), Arndt, V. (Volker), Aronson, K. J. (Kristan J.), Arun, B. K. (Banu K.), Auer, P. L. (Paul L.), Azzollini, J. (Jacopo), Barrowdale, D. (Daniel), Becher, H. (Heiko), Beckmann, M. W. (Matthias W.), Behrens, S. (Sabine), Benitez, J. (Javier), Bermisheva, M. (Marina), Bialkowska, K. (Katarzyna), Blanco, A. (Ana), Blomqvist, C. (Carl), Bogdanova, N. V. (Natalia, V), Bojesen, S. E. (Stig E.), Bonanni, B. (Bernardo), Bondavalli, D. (Davide), Borg, A. (Ake), Brauch, H. (Hiltrud), Brenner, H. (Hermann), Briceno, I. (Ignacio), Broeks, A. (Annegien), Brucker, S. Y. (Sara Y.), Bruening, T. (Thomas), Burwinkel, B. (Barbara), Buys, S. S. (Saundra S.), Byers, H. (Helen), Caldes, T. (Trinidad), Caligo, M. A. (Maria A.), Calvello, M. (Mariarosaria), Campa, D. (Daniele), Castelao, J. E. (Jose E.), Chang-Claude, J. (Jenny), Chanock, S. J. (Stephen J.), Christiaens, M. (Melissa), Christiansen, H. (Hans), Chung, W. K. (Wendy K.), Claes, K. B. (Kathleen B. M.), Clarke, C. L. (Christine L.), Cornelissen, S. (Sten), Couch, F. J. (Fergus J.), Cox, A. (Angela), Cross, S. S. (Simon S.), Czene, K. (Kamila), Daly, M. B. (Mary B.), Devilee, P. (Peter), Diez, O. (Orland), Domchek, S. M. (Susan M.), Doerk, T. (Thilo), Dwek, M. (Miriam), Eccles, D. M. (Diana M.), Ekici, A. B. (Arif B.), Evans, D. G. (D. Gareth), Fasching, P. A. (Peter A.), Figueroa, J. (Jonine), Foretova, L. (Lenka), Fostira, F. (Florentia), Friedman, E. (Eitan), Frost, D. (Debra), Gago-Dominguez, M. (Manuela), Gapstur, S. M. (Susan M.), Garber, J. (Judy), Garcia-Saenz, J. A. (Jose A.), Gaudet, M. M. (Mia M.), Gayther, S. A. (Simon A.), Giles, G. G. (Graham G.), Godwin, A. K. (Andrew K.), Goldberg, M. S. (Mark S.), Goldgar, D. E. (David E.), Gonzalez-Neira, A. (Anna), Greene, M. H. (Mark H.), Gronwald, J. (Jacek), Guenel, P. (Pascal), Haeberle, L. (Lothar), Hahnen, E. (Eric), Haiman, C. A. (Christopher A.), Hake, C. R. (Christopher R.), Hall, P. (Per), Hamann, U. (Ute), Harkness, E. F. (Elaine F.), Heemskerk-Gerritsen, B. A. (Bernadette A. M.), Hillemanns, P. (Peter), Hogervorst, F. B. (Frans B. L.), Holleczek, B. (Bernd), Hollestelle, A. (Antoinette), Hooning, M. J. (Maartje J.), Hoover, R. N. (Robert N.), Hopper, J. L. (John L.), Howell, A. (Anthony), Huebner, H. (Hanna), Hulick, P. J. (Peter J.), Imyanitov, E. N. (Evgeny N.), Isaacs, C. (Claudine), Izatt, L. (Louise), Jager, A. (Agnes), Jakimovska, M. (Milena), Jakubowska, A. (Anna), James, P. (Paul), Janavicius, R. (Ramunas), Janni, W. (Wolfgang), John, E. M. (Esther M.), Jones, M. E. (Michael E.), Jung, A. (Audrey), Kaaks, R. (Rudolf), Kapoor, P. M. (Pooja Middha), Karlan, B. Y. (Beth Y.), Keeman, R. (Renske), Khan, S. (Sofia), Khusnutdinova, E. (Elza), Kitahara, C. M. (Cari M.), Ko, Y.-D. (Yon-Dschun), Konstantopoulou, I. (Irene), Koppert, L. B. (Linetta B.), Koutros, S. (Stella), Kristensen, V. N. (Vessela N.), Laenkholm, A.-V. (Anne-Vibeke), Lambrechts, D. (Diether), Larsson, S. C. (Susanna C.), Laurent-Puig, P. (Pierre), Lazaro, C. (Conxi), Lazarova, E. (Emilija), Lejbkowicz, F. (Flavio), Leslie, G. (Goska), Lesueur, F. (Fabienne), Lindblom, A. (Annika), Lissowska, J. (Jolanta), Lo, W.-Y. (Wing-Yee), Loud, J. T. (Jennifer T.), Lubinski, J. (Jan), Lukomska, A. (Alicja), Maclnnis, R. J. (Robert J.), Mannermaa, A. (Arto), Manoochehri, M. (Mehdi), Manoukian, S. (Siranoush), Margolin, S. (Sara), Martinez, M. E. (Maria Elena), Matricardi, L. (Laura), McGuffog, L. (Lesley), McLean, C. (Catriona), Mebirouk, N. (Noura), Meindl, A. (Alfons), Menon, U. (Usha), Miller, A. (Austin), Mingazheva, E. (Elvira), Montagna, M. (Marco), Mulligan, A. M. (Anna Marie), Mulot, C. (Claire), Muranen, T. A. (Taru A.), Nathanson, K. L. (Katherine L.), Neuhausen, S. L. (Susan L.), Nevanlinna, H. (Heli), Neven, P. (Patrick), Newman, W. G. (William G.), Nielsens, F. C. (Finn C.), Nikitina-Zake, L. (Liene), Nodora, J. (Jesse), Offit, K. (Kenneth), Olah, E. (Edith), Olopade, O. I. (Olufunmilayo, I), Olsson, H. (Hakan), Orr, N. (Nick), Papi, L. (Laura), Papp, J. (Janos), Park-Simon, T.-W. (Tjoung-Won), Parsons, M. T. (Michael T.), Peissel, B. (Bernard), Peixoto, A. (Ana), Peshkin, B. (Beth), Peterlongo, P. (Paolo), Peto, J. (Julian), Phillips, K.-A. (Kelly-Anne), Piedmonte, M. (Marion), Plaseska-Karanfilska, D. (Dijana), Prajzendanc, K. (Karolina), Prentice, R. (Ross), Prokofyeva, D. (Darya), Rack, B. (Brigitte), Radice, P. (Paolo), Ramus, S. J. (Susan J.), Rantala, J. (Johanna), Rashid, M. U. (Muhammad U.), Rennert, G. (Gad), Rennert, H. S. (Hedy S.), Risch, H. A. (Harvey A.), Romero, A. (Atocha), Rookus, M. A. (Matti A.), Ruebner, M. (Matthias), Ruediger, T. (Thomas), Saloustros, E. (Emmanouil), Sampson, S. (Sarah), Sandler, D. P. (Dale P.), Sawyer, E. J. (Elinor J.), Scheuner, M. T. (Maren T.), Schmutzler, R. K. (Rita K.), Schneeweiss, A. (Andreas), Schoemaker, M. J. (Minouk J.), Schoettker, B. (Ben), Schuermann, P. (Peter), Senter, L. (Leigha), Sharma, P. (Priyanka), Sherman, M. E. (Mark E.), Shu, X.-O. (Xiao-Ou), Singer, C. F. (Christian F.), Smichkoska, S. (Snezhana), Soucy, P. (Penny), Southey, M. C. (Melissa C.), Spinelli, J. J. (John J.), Stone, J. (Jennifer), Stoppa-Lyonnet, D. (Dominique), Swerdlow, A. J. (Anthony J.), Szabo, C. I. (Csilla, I), Tamimi, R. M. (Rulla M.), Tapper, W. J. (William J.), Taylor, J. A. (Jack A.), Teixeira, M. R. (Manuel R.), Terry, M. (MaryBeth), Thomassen, M. (Mads), Thull, D. L. (Darcy L.), Tischkowitz, M. (Marc), Toland, A. E. (Amanda E.), Tollenaar, R. A. (Rob A. E. M.), Tomlinson, I. (Ian), Torres, D. (Diana), Troester, M. A. (Melissa A.), Truong, T. (Therese), Tung, N. (Nadine), Untch, M. (Michael), Vachon, C. M. (Celine M.), van den Ouweland, A. M. (Ans M. W.), van der Kolk, L. E. (Lizet E.), van Veen, E. M. (Elke M.), vanRensburg, E. J. (Elizabeth J.), Vega, A. (Ana), Wappenschmidt, B. (Barbara), Weinberg, C. R. (Clarice R.), Weitzel, J. N. (Jeffrey N.), Wildiers, H. (Hans), Winqvist, R. (Robert), Wolk, A. (Alicja), Yang, X. R. (Xiaohong R.), Yannoukakos, D. (Drakoulis), Zheng, W. (Wei), Zorn, K. K. (Kristin K.), Milne, R. L. (Roger L.), Kraft, P. (Peter), Simard, J. (Jacques), Pharoah, P. D. (Paul D. P.), Michailidou, K. (Kyriaki), Antoniou, A. C. (Antonis C.), Schmidt, M. K. (Marjanka K.), Chenevix-Trench, G. (Georgia), Easton, D. F. (Douglas F.), Chatterjee, N. (Nilanjan), and Garcia-Closas, M. (Montserrat)
Abstract: Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P
Published: 2020

47. Two truncating variants in FANCC and breast cancer risk.

Author: Gaudet M.M., Kaaks R., Kang D., Kwong A., Lambrechts D., Marchand L.L., Li J., Lindstrom S., Linet M., Lo W.-Y., Long J., Lophatananon A., Lubinski J., Manoochehri M., Manoukian S., Margolin S., Martinez E., Matsuo K., Mavroudis D., Meindl A., Menon U., Milne R.L., Mohd Taib N.A., Muir K., Mulligan A.M., Neuhausen S.L., Nevanlinna H., Neven P., Newman W.G., Offit K., Olopade O.I., Olshan A.F., Olson J.E., Olsson H., Park S.K., Park-Simon T.-W., Peto J., Plaseska-Karanfilska D., Pohl-Rescigno E., Presneau N., Rack B., Radice P., Rashid M.U., Rennert G., Rennert H.S., Romero A., Ruebner M., Saloustros E., Schmidt M.K., Schmutzler R.K., Schneider M.O., Schoemaker M.J., Scott C., Shen C.-Y., Shu X.-O., Simard J., Slager S., Smichkoska S., Southey M.C., Spinelli J.J., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teo S.H., Terry M.B., Toland A.E., Tollenaar R.A.E.M., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tsugane S., Untch M., Vachon C.M., Ouweland A.M.W.V.D., Veen E.M.V., Vijai J., Wendt C., Wolk A., Yu J.-C., Zheng W., Ziogas A., Ziv E., Dunning A.M., Pharoah P.D.P., Schindler D., Devilee P., Easton D.F., Hopper J.L., Howell T., Huo D., Ito H., Iwasaki M., Jakubowska A., Janni W., John E.M., Dork T., Peterlongo P., Mannermaa A., Bolla M.K., Wang Q., Dennis J., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Augustinsson A., Freeman L.E.B., Beckmann M.W., Beeghly-Fadiel A., Behrens S., Bermisheva M., Blomqvist C., Bogdanova N.V., Bojesen S.E., Brauch H., Brenner H., Burwinkel B., Canzian F., Chan T.L., Chang-Claude J., Chanock S.J., Choi J.-Y., Christiansen H., Clarke C.L., Couch F.J., Czene K., Daly M.B., Dos-Santos-Silva I., Dwek M., Eccles D.M., Ekici A.B., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Flyger H., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Garcia-Closas M., Garcia-Saenz J.A., Jung A., Giles G.G., Goldberg M.S., Goldgar D.E., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hartman M., Hauke J., Hein A., Hillemanns P., Hogervorst F.B.L., Hooning M.J., Kapoor P.M., Khusnutdinova E., Kim S.-W., Kitahara C.M., Koutros S., Kraft P., Kristensen V.N., Gaudet M.M., Kaaks R., Kang D., Kwong A., Lambrechts D., Marchand L.L., Li J., Lindstrom S., Linet M., Lo W.-Y., Long J., Lophatananon A., Lubinski J., Manoochehri M., Manoukian S., Margolin S., Martinez E., Matsuo K., Mavroudis D., Meindl A., Menon U., Milne R.L., Mohd Taib N.A., Muir K., Mulligan A.M., Neuhausen S.L., Nevanlinna H., Neven P., Newman W.G., Offit K., Olopade O.I., Olshan A.F., Olson J.E., Olsson H., Park S.K., Park-Simon T.-W., Peto J., Plaseska-Karanfilska D., Pohl-Rescigno E., Presneau N., Rack B., Radice P., Rashid M.U., Rennert G., Rennert H.S., Romero A., Ruebner M., Saloustros E., Schmidt M.K., Schmutzler R.K., Schneider M.O., Schoemaker M.J., Scott C., Shen C.-Y., Shu X.-O., Simard J., Slager S., Smichkoska S., Southey M.C., Spinelli J.J., Stone J., Surowy H., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teo S.H., Terry M.B., Toland A.E., Tollenaar R.A.E.M., Torres D., Torres-Mejia G., Troester M.A., Truong T., Tsugane S., Untch M., Vachon C.M., Ouweland A.M.W.V.D., Veen E.M.V., Vijai J., Wendt C., Wolk A., Yu J.-C., Zheng W., Ziogas A., Ziv E., Dunning A.M., Pharoah P.D.P., Schindler D., Devilee P., Easton D.F., Hopper J.L., Howell T., Huo D., Ito H., Iwasaki M., Jakubowska A., Janni W., John E.M., Dork T., Peterlongo P., Mannermaa A., Bolla M.K., Wang Q., Dennis J., Ahearn T., Andrulis I.L., Anton-Culver H., Arndt V., Aronson K.J., Augustinsson A., Freeman L.E.B., Beckmann M.W., Beeghly-Fadiel A., Behrens S., Bermisheva M., Blomqvist C., Bogdanova N.V., Bojesen S.E., Brauch H., Brenner H., Burwinkel B., Canzian F., Chan T.L., Chang-Claude J., Chanock S.J., Choi J.-Y., Christiansen H., Clarke C.L., Couch F.J., Czene K., Daly M.B., Dos-Santos-Silva I., Dwek M., Eccles D.M., Ekici A.B., Eriksson M., Evans D.G., Fasching P.A., Figueroa J., Flyger H., Fritschi L., Gabrielson M., Gago-Dominguez M., Gao C., Gapstur S.M., Garcia-Closas M., Garcia-Saenz J.A., Jung A., Giles G.G., Goldberg M.S., Goldgar D.E., Guenel P., Haeberle L., Haiman C.A., Hakansson N., Hall P., Hamann U., Hartman M., Hauke J., Hein A., Hillemanns P., Hogervorst F.B.L., Hooning M.J., Kapoor P.M., Khusnutdinova E., Kim S.-W., Kitahara C.M., Koutros S., Kraft P., and Kristensen V.N.
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p=0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Published: 2020

48. Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts.

Author: Smit V.T.H.B.M., Pharoah P.D.P., Shah M., Siesling S., Southey M.C., Schmidt M.K., Hooning M.J., Westenend P.J., Wendt C., Wang Q., Van't Veer L.J., van Ongeval C., van Leeuwen F.E., van Deurzen C.H.M., van den Broek A.J., Tollenaar R.A.E.M., Tapper W.J., Giardiello D., Hauptmann M., Steyerberg E.W., Adank M.A., Akdeniz D., Blom J.C., Blomqvist C., Bojesen S.E., Bolla M.K., Brinkhuis M., Chang-Claude J., Czene K., Devilee P., Dunning A.M., Easton D.F., Eccles D.M., Fasching P.A., Figueroa J., Flyger H., Garcia-Closas M., Haeberle L., Haiman C.A., Hall P., Hamann U., Hopper J.L., Jager A., Jakubowska A., Jung A., Keeman R., Koppert L.B., Kramer I., Lambrechts D., Le Marchand L., Lindblom A., Lubinski J., Manoochehri M., Mariani L., Nevanlinna H., Oldenburg H.S.A., Pelders S., Smit V.T.H.B.M., Pharoah P.D.P., Shah M., Siesling S., Southey M.C., Schmidt M.K., Hooning M.J., Westenend P.J., Wendt C., Wang Q., Van't Veer L.J., van Ongeval C., van Leeuwen F.E., van Deurzen C.H.M., van den Broek A.J., Tollenaar R.A.E.M., Tapper W.J., Giardiello D., Hauptmann M., Steyerberg E.W., Adank M.A., Akdeniz D., Blom J.C., Blomqvist C., Bojesen S.E., Bolla M.K., Brinkhuis M., Chang-Claude J., Czene K., Devilee P., Dunning A.M., Easton D.F., Eccles D.M., Fasching P.A., Figueroa J., Flyger H., Garcia-Closas M., Haeberle L., Haiman C.A., Hall P., Hamann U., Hopper J.L., Jager A., Jakubowska A., Jung A., Keeman R., Koppert L.B., Kramer I., Lambrechts D., Le Marchand L., Lindblom A., Lubinski J., Manoochehri M., Mariani L., Nevanlinna H., Oldenburg H.S.A., and Pelders S.
Abstract: Background: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). Method(s): We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. Result(s): The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. Conclusion(s): Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.Copyright © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
Published: 2020

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

Author: Wendt C., Van Leeuwen F.E., Van Ongeval C., Van't Veer L.J., Wang Q., Westenend P.J., Schmidt M.K., Hooning M.J., Giardiello D., Steyerberg E.W., Hauptmann M., Adank M.A., Akdeniz D., Blomqvist C., Bojesen S.E., Bolla M.K., Brinkhuis M., Chang-Claude J., Czene K., Devilee P., Dunning A.M., Easton D.F., Eccles D.M., Fasching P.A., Figueroa J., Flyger H., Garcia-Closas M., Haeberle L., Haiman C.A., Hall P., Hamann U., Hopper J.L., Jager A., Jakubowska A., Jung A., Keeman R., Kramer I., Lambrechts D., Le Marchand L., Lindblom A., Lubinski J., Manoochehri M., Mariani L., Nevanlinna H., Oldenburg H.S.A., Pelders S., Pharoah P.D.P., Shah M., Siesling S., Smit V.T.H.B.M., Southey M.C., Tapper W.J., Tollenaar R.A.E.M., Van Den Broek A.J., Van Deurzen C.H.M., Wendt C., Van Leeuwen F.E., Van Ongeval C., Van't Veer L.J., Wang Q., Westenend P.J., Schmidt M.K., Hooning M.J., Giardiello D., Steyerberg E.W., Hauptmann M., Adank M.A., Akdeniz D., Blomqvist C., Bojesen S.E., Bolla M.K., Brinkhuis M., Chang-Claude J., Czene K., Devilee P., Dunning A.M., Easton D.F., Eccles D.M., Fasching P.A., Figueroa J., Flyger H., Garcia-Closas M., Haeberle L., Haiman C.A., Hall P., Hamann U., Hopper J.L., Jager A., Jakubowska A., Jung A., Keeman R., Kramer I., Lambrechts D., Le Marchand L., Lindblom A., Lubinski J., Manoochehri M., Mariani L., Nevanlinna H., Oldenburg H.S.A., Pelders S., Pharoah P.D.P., Shah M., Siesling S., Smit V.T.H.B.M., Southey M.C., Tapper W.J., Tollenaar R.A.E.M., Van Den Broek A.J., and Van Deurzen C.H.M.
Abstract: Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Method(s): We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Result(s): In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was-0.13 (95% PI:-1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusion(s): We developed a reasonab
Published: 2020

50. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Author: Garcia-Closas M., John E.M., Kaaks R., Kapoor P.M., Keeman R., Kitahara C.M., Koppert L.B., Kraft P., Kristensen V.N., Lambrechts D., Le Marchand L., Lejbkowicz F., Lindblom A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., Meindl A., Milne R.L., Mulligan A.M., Neuhausen S.L., Nevanlinna H., Newman W.G., Olshan A.F., Olson J.E., Olsson H., Orr N., Peterlongo P., Petridis C., Prentice R.L., Presneau N., Punie K., Ramachandran D., Rennert G., Romero A., Sachchithananthan M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schwentner L., Scott C., Simard J., Sohn C., Southey M.C., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teixeira M.R., Terry M.B., Thorne H., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Turnbull C., Vachon C.M., van der Kolk L.E., Wang Q., Winqvist R., Wolk A., Yang X.R., Ziogas A., Pharoah P.D.P., Hall P., Wessels L.F.A., Chenevix-Trench G., Bader G.D., Dork T., Easton D.F., Canisius S., Schmidt M.K., Escala-Garcia M., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Ashworth A., Auer P.L., Auvinen P., Beckmann M.W., Beesley J., Behrens S., Benitez J., Bermisheva M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borresen-Dale A.-L., Brauch H., Brenner H., Brucker S.Y., Burwinkel B., Caldas C., Canzian F., Chang-Claude J., Chanock S.J., Chin S.-F., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Devilee P., Dunn J.A., Dunning A.M., Dwek M., Earl H.M., Eccles D.M., Eliassen A.H., Ellberg C., Evans D.G., Fasching P.A., Figueroa J., Flyger H., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Giles G.G., Goldgar D.E., Gonzalez-Neira A., Grip M., Guenel P., Guo Q., Haiman C.A., Hakansson N., Hamann U., Harrington P.A., Hiller L., Hooning M.J., Hopper J.L., Howell A., Huang C.-S., Huang G., Hunter D.J., Jakubowska A., Garcia-Closas M., John E.M., Kaaks R., Kapoor P.M., Keeman R., Kitahara C.M., Koppert L.B., Kraft P., Kristensen V.N., Lambrechts D., Le Marchand L., Lejbkowicz F., Lindblom A., Lubinski J., Mannermaa A., Manoochehri M., Manoukian S., Margolin S., Martinez M.E., Maurer T., Mavroudis D., Meindl A., Milne R.L., Mulligan A.M., Neuhausen S.L., Nevanlinna H., Newman W.G., Olshan A.F., Olson J.E., Olsson H., Orr N., Peterlongo P., Petridis C., Prentice R.L., Presneau N., Punie K., Ramachandran D., Rennert G., Romero A., Sachchithananthan M., Saloustros E., Sawyer E.J., Schmutzler R.K., Schwentner L., Scott C., Simard J., Sohn C., Southey M.C., Swerdlow A.J., Tamimi R.M., Tapper W.J., Teixeira M.R., Terry M.B., Thorne H., Tollenaar R.A.E.M., Tomlinson I., Troester M.A., Truong T., Turnbull C., Vachon C.M., van der Kolk L.E., Wang Q., Winqvist R., Wolk A., Yang X.R., Ziogas A., Pharoah P.D.P., Hall P., Wessels L.F.A., Chenevix-Trench G., Bader G.D., Dork T., Easton D.F., Canisius S., Schmidt M.K., Escala-Garcia M., Abraham J., Andrulis I.L., Anton-Culver H., Arndt V., Ashworth A., Auer P.L., Auvinen P., Beckmann M.W., Beesley J., Behrens S., Benitez J., Bermisheva M., Blomqvist C., Blot W., Bogdanova N.V., Bojesen S.E., Bolla M.K., Borresen-Dale A.-L., Brauch H., Brenner H., Brucker S.Y., Burwinkel B., Caldas C., Canzian F., Chang-Claude J., Chanock S.J., Chin S.-F., Clarke C.L., Couch F.J., Cox A., Cross S.S., Czene K., Daly M.B., Dennis J., Devilee P., Dunn J.A., Dunning A.M., Dwek M., Earl H.M., Eccles D.M., Eliassen A.H., Ellberg C., Evans D.G., Fasching P.A., Figueroa J., Flyger H., Gago-Dominguez M., Gapstur S.M., Garcia-Saenz J.A., Gaudet M.M., George A., Giles G.G., Goldgar D.E., Gonzalez-Neira A., Grip M., Guenel P., Guo Q., Haiman C.A., Hakansson N., Hamann U., Harrington P.A., Hiller L., Hooning M.J., Hopper J.L., Howell A., Huang C.-S., Huang G., Hunter D.J., and Jakubowska A.
Abstract: Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.Copyright © 2020, The Author(s).
Published: 2020

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