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329 results on '"Kurian, AW"'

1. 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

2. Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmaña, J, Bandera, EV, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, NV, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, GEMO Study Collaborators, GC-HBOC Study Collaborators, EMBRACE Collaborators, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dörk, T, du Bois, A, Dürst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, RT, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, OPAL Study Group, AOCS Group, Hahnen, E, Haiman, CA, Håkansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Høgdall, E, Høgdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, KConFab Investigators, HEBON Investigators, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Lubiński, J, Mai, PL, Manoukian, S, Marks, JR, Matsuno, RK, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, OI, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamariña, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, Terry, MB, OCAC Consortium, CIMBA Consortium, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Van Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Published: 2022

3. Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Author: Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, Pharoah, PDP, Dareng, EO, Tyrer, JP, Barnes, DR, Jones, MR, Yang, X, Aben, KKH, Adank, MA, Agata, S, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Aravantinos, G, Arun, BK, Augustinsson, A, Balmana, J, Bandera, E, Barkardottir, RB, Barrowdale, D, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bermisheva, M, Bernardini, MQ, Bjorge, L, Black, A, Bogdanova, N, Bonanni, B, Borg, A, Brenton, JD, Budzilowska, A, Butzow, R, Buys, SS, Cai, H, Caligo, MA, Campbell, I, Cannioto, R, Cassingham, H, Chang-Claude, J, Chanock, SJ, Chen, K, Chiew, Y-E, Chung, WK, Claes, KBM, Colonna, S, Cook, LS, Couch, FJ, Daly, MB, Dao, F, Davies, E, de la Hoya, M, de Putter, R, Dennis, J, DePersia, A, Devilee, P, Diez, O, Ding, YC, Doherty, JA, Domchek, SM, Dork, T, du Bois, A, Durst, M, Eccles, DM, Eliassen, HA, Engel, C, Evans, GD, Fasching, PA, Flanagan, JM, Fortner, R, Machackova, E, Friedman, E, Ganz, PA, Garber, J, Gensini, F, Giles, GG, Glendon, G, Godwin, AK, Goodman, MT, Greene, MH, Gronwald, J, Group, OS, AOCSGroup, Hahnen, E, Haiman, CA, Hakansson, N, Hamann, U, Hansen, TVO, Harris, HR, Hartman, M, Heitz, F, Hildebrandt, MAT, Hogdall, E, Hogdall, CK, Hopper, JL, Huang, R-Y, Huff, C, Hulick, PJ, Huntsman, DG, Imyanitov, EN, Isaacs, C, Jakubowska, A, James, PA, Janavicius, R, Jensen, A, Johannsson, OT, John, EM, Jones, ME, Kang, D, Karlan, BY, Karnezis, A, Kelemen, LE, Khusnutdinova, E, Kiemeney, LA, Kim, B-G, Kjaer, SK, Komenaka, I, Kupryjanczyk, J, Kurian, AW, Kwong, A, Lambrechts, D, Larson, MC, Lazaro, C, Le, ND, Leslie, G, Lester, J, Lesueur, F, Levine, DA, Li, L, Li, J, Loud, JT, Lu, KH, Mai, PL, Manoukian, S, Marks, JR, KimMatsuno, R, Matsuo, K, May, T, McGuffog, L, McLaughlin, JR, McNeish, IA, Mebirouk, N, Menon, U, Miller, A, Milne, RL, Minlikeeva, A, Modugno, F, Montagna, M, Moysich, KB, Munro, E, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Yie, JNY, Nielsen, HR, Nielsen, FC, Nikitina-Zake, L, Odunsi, K, Offit, K, Olah, E, Olbrecht, S, Olopade, O, Olson, SH, Olsson, H, Osorio, A, Papi, L, Park, SK, Parsons, MT, Pathak, H, Pedersen, IS, Peixoto, A, Pejovic, T, Perez-Segura, P, Permuth, JB, Peshkin, B, Peterlongo, P, Piskorz, A, Prokofyeva, D, Radice, P, Rantala, J, Riggan, MJ, Risch, HA, Rodriguez-Antona, C, Ross, E, Rossing, MA, Runnebaum, I, Sandler, DP, Santamarina, M, Soucy, P, Schmutzler, RK, Setiawan, VW, Shan, K, Sieh, W, Simard, J, Singer, CF, Sokolenko, AP, Song, H, Southey, MC, Steed, H, Stoppa-Lyonnet, D, Sutphen, R, Swerdlow, AJ, Tan, YY, Teixeira, MR, Teo, SH, Terry, KL, BethTerry, M, Thomassen, M, Thompson, PJ, Thomsen, LCV, Thull, DL, Tischkowitz, M, Titus, L, Toland, AE, Torres, D, Trabert, B, Travis, R, Tung, N, Tworoger, SS, Valen, E, van Altena, AM, van der Hout, AH, Nieuwenhuysen, E, van Rensburg, EJ, Vega, A, Edwards, DV, Vierkant, RA, Wang, F, Wappenschmidt, B, Webb, PM, Weinberg, CR, Weitzel, JN, Wentzensen, N, White, E, Whittemore, AS, Winham, SJ, Wolk, A, Woo, Y-L, Wu, AH, Yan, L, Yannoukakos, D, Zavaglia, KM, Zheng, W, Ziogas, A, Zorn, KK, Kleibl, Z, Easton, D, Lawrenson, K, DeFazio, A, Sellers, TA, Ramus, SJ, Pearce, CL, Monteiro, AN, Cunningham, J, Goode, EL, Schildkraut, JM, Berchuck, A, Chenevix-Trench, G, Gayther, SA, Antoniou, AC, and Pharoah, PDP
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Published: 2022

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

Author: Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, Easton, DF, Dennis, J, Tyrer, JP, Walker, LC, Michailidou, K, Dorling, L, Bolla, MK, Wang, Q, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Freeman, LEB, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bogdanova, N, Bojesen, SE, Brenner, H, Castelao, JE, Chang-Claude, J, Chenevix-Trench, G, Clarke, CL, Collee, JM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Devilee, P, Dork, T, Dossus, L, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fletcher, O, Flyger, H, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Garcia-Closas, M, Giles, GG, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hall, P, Hollestelle, A, Hoppe, R, Hopper, JL, Howell, A, Jager, A, Jakubowska, A, John, EM, Johnson, N, Jones, ME, Jung, A, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Ko, Y-D, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kubelka-Sabit, K, Kurian, AW, Lacey, J, Lambrechts, D, Larson, NL, Linet, M, Ogrodniczak, A, Mannermaa, A, Manoukian, S, Margolin, S, Mavroudis, D, Milne, RL, Muranen, TA, Murphy, RA, Nevanlinna, H, Olson, JE, Olsson, H, Park-Simon, T-W, Perou, CM, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmidt, MK, Schmutzler, RK, Shibli, R, Smeets, A, Soucy, P, Southey, MC, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Teras, LR, Terry, MB, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, Wendt, C, Winqvist, R, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Simard, J, Dunning, AM, Pharoah, PDP, and Easton, DF
Abstract: Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.
Published: 2022

5. 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

6. Abstract ES3-2: Clinical management of moderate penetrance genes

Author: Kurian, AW, primary
Published: 2022
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7. 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

8. Genetic insights into biological mechanisms governing human ovarian ageing

Author: Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, Perry, JRB, Ruth, KS, Day, FR, Hussain, J, Martinez-Marchal, A, Aiken, CE, Azad, A, Thompson, DJ, Knoblochova, L, Abe, H, Tarry-Adkins, JL, Gonzalez, JM, Fontanillas, P, Claringbould, A, Bakker, OB, Sulem, P, Walters, RG, Terao, C, Turon, S, Horikoshi, M, Lin, K, Onland-Moret, NC, Sankar, A, Hertz, EPT, Timshel, PN, Shukla, V, Borup, R, Olsen, KW, Aguilera, P, Ferrer-Roda, M, Huang, Y, Stankovic, S, Timmers, PRHJ, Ahearn, TU, Alizadeh, BZ, Naderi, E, Andrulis, IL, Arnold, AM, Aronson, KJ, Augustinsson, A, Bandinelli, S, Barbieri, CM, Beaumont, RN, Becher, H, Beckmann, MW, Benonisdottir, S, Bergmann, S, Bochud, M, Boerwinkle, E, Bojesen, SE, Bolla, MK, Boomsma, DI, Bowker, N, Brody, JA, Broer, L, Buring, JE, Campbell, A, Campbell, H, Castelao, JE, Catamo, E, Chanock, SJ, Chenevix-Trench, G, Ciullo, M, Corre, T, Couch, FJ, Cox, A, Crisponi, L, Cross, SS, Cucca, F, Czene, K, Smith, GD, de Geus, EJCN, de Mutsert, R, De Vivo, I, Demerath, EW, Dennis, J, Dunning, AM, Dwek, M, Eriksson, M, Esko, T, Fasching, PA, Faul, JD, Ferrucci, L, Franceschini, N, Frayling, TM, Gago-Dominguez, M, Mezzavilla, M, Garcia-Closas, M, Gieger, C, Giles, GG, Grallert, H, Gudbjartsson, DF, Gudnason, V, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Hayward, C, He, C, He, W, Heiss, G, Hoffding, MK, Hopper, JL, Hottenga, JJ, Hu, F, Hunter, D, Ikram, MA, Jackson, RD, Joaquim, MDR, John, EM, Joshi, PK, Karasik, D, Kardia, SLR, Kartsonaki, C, Karlsson, R, Kitahara, CM, Kolcic, I, Kooperberg, C, Kraft, P, Kurian, AW, Kutalik, Z, La Bianca, M, LaChance, G, Langenberg, C, Launer, LJ, Laven, JSE, Lawlor, DA, Le Marchand, L, Li, J, Lindblom, A, Lindstrom, S, Lindstrom, T, Linet, M, Liu, Y, Liu, S, Luan, J, Magi, R, Magnusson, PKE, Mangino, M, Mannermaa, A, Marco, B, Marten, J, Martin, NG, Mbarek, H, McKnight, B, Medland, SE, Meisinger, C, Meitinger, T, Menni, C, Metspalu, A, Milani, L, Milne, RL, Montgomery, GW, Mook-Kanamori, DO, Mulas, A, Mulligan, AM, Murray, A, Nalls, MA, Newman, A, Noordam, R, Nutile, T, Nyholt, DR, Olshan, AF, Olsson, H, Painter, JN, Patel, AV, Pedersen, NL, Perjakova, N, Peters, A, Peters, U, Pharoah, PDP, Polasek, O, Porcu, E, Psaty, BM, Rahman, I, Rennert, G, Rennert, HS, Ridker, PM, Ring, SM, Robino, A, Rose, LM, Rosendaal, FR, Rossouw, J, Rudan, I, Rueedi, R, Ruggiero, D, Sala, CF, Saloustros, E, Sandler, DP, Sanna, S, Sawyer, EJ, Sarnowski, C, Schlessinger, D, Schmidt, MK, Schoemaker, MJ, Schraut, KE, Scott, C, Shekari, S, Shrikhande, A, Smith, AV, Smith, BH, Smith, JA, Sorice, R, Southey, MC, Spector, TD, Spinelli, JJ, Stampfer, M, Stoeckl, D, van Meurs, JBJ, Strauch, K, Styrkarsdottir, U, Swerdlow, AJ, Tanaka, T, Teras, LR, Teumer, A, thorsteinsdottir, U, Timpson, NJ, Toniolo, D, Traglia, M, Troester, MA, Truong, T, Tyrrell, J, Uitterlinden, AG, Ulivi, S, Vachon, CM, Vitart, V, Voelker, U, Vollenweider, P, Voelzke, H, Wang, Q, Wareham, NJ, Weinberg, CR, Weir, DR, Wilcox, AN, van Dijk, KW, Willemsen, G, Wilson, JF, Wolffenbuttel, BHR, Wolk, A, Wood, AR, Zhao, W, Zygmunt, M, Chen, Z, Li, L, Franke, L, Burgess, S, Deelen, P, Pers, TH, Grondahl, ML, Andersen, CY, Pujol, A, Lopez-Contreras, AJ, Daniel, JA, Stefansson, K, Chang-Claude, J, van der Schouw, YT, Lunetta, KL, Chasman, DI, Easton, DF, Visser, JA, Ozanne, SE, Namekawa, SH, Solc, P, Murabito, JM, Ong, KK, Hoffmann, ER, Roig, I, and Perry, JRB
Abstract: Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
Published: 2021

9. Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Author: Yadav, S, Hu, C, Nathanson, KL, Weitzel, JN, Goldgar, DE, Kraft, P, Gnanaolivu, RD, Na, J, Huang, H, Boddicker, NJ, Larson, N, Gao, C, Yao, S, Weinberg, C, Vachon, CM, Trentham-Dietz, A, Taylor, JA, Sandler, DR, Patel, A, Palmer, JR, Olson, JE, Neuhausen, S, Martinez, E, Lindstrom, S, Lacey, JV, Kurian, AW, John, EM, Haiman, C, Bernstein, L, Auer, PW, Anton-Culver, H, Ambrosone, CB, Karam, R, Chao, E, Yussuf, A, Pesaran, T, Dolinsky, JS, Hart, SN, LaDuca, H, Polley, EC, Domchek, SM, Couch, FJ, Yadav, S, Hu, C, Nathanson, KL, Weitzel, JN, Goldgar, DE, Kraft, P, Gnanaolivu, RD, Na, J, Huang, H, Boddicker, NJ, Larson, N, Gao, C, Yao, S, Weinberg, C, Vachon, CM, Trentham-Dietz, A, Taylor, JA, Sandler, DR, Patel, A, Palmer, JR, Olson, JE, Neuhausen, S, Martinez, E, Lindstrom, S, Lacey, JV, Kurian, AW, John, EM, Haiman, C, Bernstein, L, Auer, PW, Anton-Culver, H, Ambrosone, CB, Karam, R, Chao, E, Yussuf, A, Pesaran, T, Dolinsky, JS, Hart, SN, LaDuca, H, Polley, EC, Domchek, SM, and Couch, FJ
Abstract: PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.
Published: 2021

10. Recreational Physical Activity and Outcomes After Breast Cancer in Women at High Familial Risk

Author: Kehm, RD, MacInnis, RJ, John, EM, Liao, Y, Kurian, AW, Genkinger, JM, Knight, JA, Colonna, S, Chung, WK, Milne, R, Zeinomar, N, Dite, GS, Southey, MC, Giles, GG, Mclachlan, S-A, Whitaker, KD, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Investigators, K, Phillips, K-A, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, Terry, MB, Kehm, RD, MacInnis, RJ, John, EM, Liao, Y, Kurian, AW, Genkinger, JM, Knight, JA, Colonna, S, Chung, WK, Milne, R, Zeinomar, N, Dite, GS, Southey, MC, Giles, GG, Mclachlan, S-A, Whitaker, KD, Friedlander, ML, Weideman, PC, Glendon, G, Nesci, S, Investigators, K, Phillips, K-A, Andrulis, IL, Buys, SS, Daly, MB, Hopper, JL, and Terry, MB
Abstract: BACKGROUND: Recreational physical activity (RPA) is associated with improved survival after breast cancer (BC) in average-risk women, but evidence is limited for women who are at increased familial risk because of a BC family history or BRCA1 and BRCA2 pathogenic variants (BRCA1/2 PVs). METHODS: We estimated associations of RPA (self-reported average hours per week within 3 years of BC diagnosis) with all-cause mortality and second BC events (recurrence or new primary) after first invasive BC in women in the Prospective Family Study Cohort (n = 4610, diagnosed 1993-2011, aged 22-79 years at diagnosis). We fitted Cox proportional hazards regression models adjusted for age at diagnosis, demographics, and lifestyle factors. We tested for multiplicative interactions (Wald test statistic for cross-product terms) and additive interactions (relative excess risk due to interaction) by age at diagnosis, body mass index, estrogen receptor status, stage at diagnosis, BRCA1/2 PVs, and familial risk score estimated from multigenerational pedigree data. Statistical tests were 2-sided. RESULTS: We observed 1212 deaths and 473 second BC events over a median follow-up from study enrollment of 11.0 and 10.5 years, respectively. After adjusting for covariates, RPA (any vs none) was associated with lower all-cause mortality of 16.1% (95% confidence interval [CI] = 2.4% to 27.9%) overall, 11.8% (95% CI = -3.6% to 24.9%) in women without BRCA1/2 PVs, and 47.5% (95% CI = 17.4% to 66.6%) in women with BRCA1/2 PVs (RPA*BRCA1/2 multiplicative interaction P = .005; relative excess risk due to interaction = 0.87, 95% CI = 0.01 to 1.74). RPA was not associated with risk of second BC events. CONCLUSION: Findings support that RPA is associated with lower all-cause mortality in women with BC, particularly in women with BRCA1/2 PVs.
Published: 2021

11. 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

12. Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk

Author: Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, Chang-Claude, J, Kapoor, PM, Mavaddat, N, Choudhury, PP, Wilcox, AN, Lindstrom, S, Behrens, S, Michailidou, K, Dennis, J, Bolla, MK, Wang, Q, Jung, A, Abu-Ful, Z, Ahearn, T, Andrulis, IL, Anton-Culver, H, Arndt, V, Aronson, KJ, Auer, PL, Freeman, LEB, Becher, H, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bojesen, SE, Brauch, H, Brenner, H, Bruening, T, Cai, Q, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chanock, SJ, Chatterjee, N, Chenevix-Trench, G, Clarke, CL, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dai, JY, Earp, HS, Ekici, AB, Eliassen, AH, Eriksson, M, Evans, DG, Fasching, PA, Figueroa, J, Fritschi, L, Gabrielson, M, Gago-Dominguez, M, Gao, C, Gapstur, SM, Gaudet, MM, Giles, GG, Gonzalez-Neira, A, Guenel, P, Haeberle, L, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Hatse, S, Heyworth, J, Holleczek, B, Hoover, RN, Hopper, JL, Howell, A, Hunter, DJ, John, EM, Jones, ME, Kaaks, R, Keeman, R, Kitahara, CM, Ko, Y-D, Koutros, S, Kurian, AW, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Linet, M, Lissowska, J, Llaneza, A, MacInnis, RJ, Martinez, ME, Maurer, T, McLean, C, Neuhausen, SL, Newman, WG, Norman, A, O'Brien, KM, Olshan, AF, Olson, JE, Olsson, H, Orr, N, Perou, CM, Pita, G, Polley, EC, Prentice, RL, Rennert, G, Rennert, HS, Ruddy, KJ, Sandler, DP, Saunders, C, Schoemaker, MJ, Schoettker, B, Schumacher, F, Scott, C, Scott, RJ, Shu, X-O, Smeets, A, Southey, MC, Spinelli, JJ, Stone, J, Swerdlow, AJ, Tamimi, RM, Taylor, JA, Troester, MA, Vachon, CM, van Veen, EM, Wang, X, Weinberg, CR, Weltens, C, Willett, W, Winham, SJ, Wolk, A, Yang, XR, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Schmidt, MK, Kraft, P, Easton, DF, Milne, RL, Garcia-Closas, M, and Chang-Claude, J
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Published: 2021

13. 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

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

Author: Johnson, N, Maguire, S, Morra, A, Kapoor, PM, Tomczyk, K, Jones, ME, Schoemaker, MJ, Gilham, C, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baynes, C, Freeman, LEB, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Doerk, T, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, Hooning, MJ, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, John, EM, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Linet, M, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mavroudis, D, Mayes, R, Meindl, A, Milne, RL, Neuhausen, SL, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Obi, N, Olshan, AF, Olson, JE, Olsson, H, Orban, E, Park-Simon, T-W, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Rennert, HS, Ruddy, KJ, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Scott, C, Shu, X-O, Simard, J, Smichkoska, S, Sohn, C, Southey, MC, Spinelli, JJ, Stone, J, Tamimi, RM, Taylor, JA, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Wang, SS, Weinberg, CR, Wendt, C, Wildiers, H, Winqvist, R, Wolk, A, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Howie, AF, Peto, J, dos-Santos-Silva, I, Swerdlow, AJ, Chang-Claude, J, Schmidt, MK, Orr, N, Fletcher, O, Johnson, N, Maguire, S, Morra, A, Kapoor, PM, Tomczyk, K, Jones, ME, Schoemaker, MJ, Gilham, C, Bolla, MK, Wang, Q, Dennis, J, Ahearn, TU, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Aronson, KJ, Augustinsson, A, Baynes, C, Freeman, LEB, Beckmann, MW, Benitez, J, Bermisheva, M, Blomqvist, C, Boeckx, B, Bogdanova, NV, Bojesen, SE, Brauch, H, Brenner, H, Burwinkel, B, Campa, D, Canzian, F, Castelao, JE, Chanock, SJ, Chenevix-Trench, G, Clarke, CL, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Doerk, T, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Figueroa, J, Floris, G, Flyger, H, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Gaudet, MM, Giles, GG, Goldberg, MS, Gonzalez-Neira, A, Guenel, P, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, Hooning, MJ, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, John, EM, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Kosma, V-M, Koutros, S, Kraft, P, Kristensen, VN, Kurian, AW, Lambrechts, D, Le Marchand, L, Linet, M, Lubinski, J, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mavroudis, D, Mayes, R, Meindl, A, Milne, RL, Neuhausen, SL, Nevanlinna, H, Newman, WG, Nielsen, SF, Nordestgaard, BG, Obi, N, Olshan, AF, Olson, JE, Olsson, H, Orban, E, Park-Simon, T-W, Peterlongo, P, Plaseska-Karanfilska, D, Pylkas, K, Rennert, G, Rennert, HS, Ruddy, KJ, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Scott, C, Shu, X-O, Simard, J, Smichkoska, S, Sohn, C, Southey, MC, Spinelli, JJ, Stone, J, Tamimi, RM, Taylor, JA, Tollenaar, RAEM, Tomlinson, I, Troester, MA, Truong, T, Vachon, CM, van Veen, EM, Wang, SS, Weinberg, CR, Wendt, C, Wildiers, H, Winqvist, R, Wolk, A, Zheng, W, Ziogas, A, Dunning, AM, Pharoah, PDP, Easton, DF, Howie, AF, Peto, J, dos-Santos-Silva, I, Swerdlow, AJ, Chang-Claude, J, Schmidt, MK, Orr, N, and Fletcher, O
Abstract: BACKGROUND: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. METHODS: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. RESULTS: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10-18); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10-8). CONCLUSIONS: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
Published: 2021

15. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers (vol 12, 1078, 2021)

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomaki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Bialkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldes, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, Collee, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Doerk, T, dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, Gonzalez-Neira, A, Greene, MH, Guenel, P, Haeberle, L, Hahnen, E, Haiman, CA, Hakansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, Fox, S, van der Hout, AH, Clarke, C, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernandez, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teule, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

16. 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

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

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
Published: 2021

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

Author: Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, Antoniou, AC, Coignard, J, Lush, M, Beesley, J, O'Mara, TA, Dennis, J, Tyrer, JP, Barnes, DR, McGuffog, L, Leslie, G, Bolla, MK, Adank, MA, Agata, S, Ahearn, T, Aittomäki, K, Andrulis, IL, Anton-Culver, H, Arndt, V, Arnold, N, Aronson, KJ, Arun, BK, Augustinsson, A, Azzollini, J, Barrowdale, D, Baynes, C, Becher, H, Bermisheva, M, Bernstein, L, Białkowska, K, Blomqvist, C, Bojesen, SE, Bonanni, B, Borg, A, Brauch, H, Brenner, H, Burwinkel, B, Buys, SS, Caldés, T, Caligo, MA, Campa, D, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chung, WK, Claes, KBM, Clarke, CL, GEMO Study Collaborators, EMBRACE Collaborators, Collée, JM, Conroy, DM, Czene, K, Daly, MB, Devilee, P, Diez, O, Ding, YC, Domchek, SM, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Dwek, M, Eccles, DM, Eliassen, AH, Engel, C, Eriksson, M, Evans, DG, Fasching, PA, Flyger, H, Fostira, F, Friedman, E, Fritschi, L, Frost, D, Gago-Dominguez, M, Gapstur, SM, Garber, J, Garcia-Barberan, V, García-Closas, M, García-Sáenz, JA, Gaudet, MM, Gayther, SA, Gehrig, A, Georgoulias, V, Giles, GG, Godwin, AK, Goldberg, MS, Goldgar, DE, González-Neira, A, Greene, MH, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, He, W, Hogervorst, FBL, Hollestelle, A, Hopper, JL, Horcasitas, DJ, Hulick, PJ, Hunter, DJ, Imyanitov, EN, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Jager, A, Jakubowska, A, James, PA, Jensen, UB, John, EM, Jones, ME, Kaaks, R, Kapoor, PM, Karlan, BY, Keeman, R, Khusnutdinova, E, Kiiski, JI, Ko, Y-D, Kosma, V-M, Kraft, P, Kurian, AW, Laitman, Y, Lambrechts, D, Le Marchand, L, Lester, J, Lesueur, F, Lindstrom, T, Lopez-Fernández, A, Loud, JT, Luccarini, C, Mannermaa, A, Manoukian, S, Margolin, S, Martens, JWM, Mebirouk, N, Meindl, A, Miller, A, Milne, RL, Montagna, M, Nathanson, KL, Neuhausen, SL, Nevanlinna, H, Nielsen, FC, O'Brien, KM, Olopade, OI, Olson, JE, Olsson, H, Osorio, A, Ottini, L, Park-Simon, T-W, Parsons, MT, Pedersen, IS, Peshkin, B, Peterlongo, P, Peto, J, Pharoah, PDP, Phillips, K-A, Polley, EC, Poppe, B, Presneau, N, Pujana, MA, Punie, K, Radice, P, Rantala, J, Rashid, MU, Rennert, G, Rennert, HS, Robson, M, Romero, A, Rossing, M, Saloustros, E, Sandler, DP, Santella, R, Scheuner, MT, Schmidt, MK, Schmidt, G, Scott, C, Sharma, P, Soucy, P, Southey, MC, Spinelli, JJ, Steinsnyder, Z, Stone, J, Stoppa-Lyonnet, D, Swerdlow, A, Tamimi, RM, Tapper, WJ, Taylor, JA, Terry, MB, Teulé, A, Thull, DL, Tischkowitz, M, Toland, AE, Torres, D, Trainer, AH, Truong, T, Tung, N, Vachon, CM, Vega, A, Vijai, J, Wang, Q, Wappenschmidt, B, Weinberg, CR, Weitzel, JN, Wendt, C, Wolk, A, Yadav, S, Yang, XR, Yannoukakos, D, Zheng, W, Ziogas, A, Zorn, KK, Park, SK, Thomassen, M, Offit, K, Schmutzler, RK, Couch, FJ, Simard, J, Chenevix-Trench, G, Easton, DF, Andrieu, N, and Antoniou, AC
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.
Published: 2021

19. 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

20. Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk

Author: Liu, J, van der Smissen, WJCP, Collee, JM, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Ahearn, TU, Aittomaki, K, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Augustinsson, A, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bernstein, L, Bogdanova, N, Bogdanova-Markov, N, Bojesen, SE, Brauch, H, Brenner, H, Briceno, I, Brucker, SY, Bruening, T, Burwinkel, B, Cai, Q, Cai, H, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiaens, M, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, Devilee, P, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Fasching, PA, Figueroa, J, Flyger, H, Fritschi, L, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Harrington, PA, Hart, SN, Hartman, M, Hillemanns, P, Hopper, JL, Hou, M-F, Hunter, DJ, Huo, D, Ito, H, Iwasaki, M, Jakimovska, M, Jakubowska, A, John, EM, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kraft, P, Kristensen, VN, Kurian, AW, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Mariapun, S, Matsuo, K, Maurer, T, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Offit, K, Olopade, O, Olson, JE, Olsson, H, Orr, N, Park, SK, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Ruebner, M, Saloustros, E, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Sohn, C, Southey, MC, Spinelli, JJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Torres, D, Truong, T, Untch, M, Vachon, CM, van Asperen, CJ, Wolk, A, Yamaji, T, Zheng, W, Ziogas, A, Ziv, E, Torres-Mejia, G, Doerk, T, Swerdlow, AJ, Hamann, U, Schmidt, MK, Dunning, AM, Pharoah, PDP, Easton, DF, Hooning, MJ, Martens, JWM, Hollestelle, A, Liu, J, van der Smissen, WJCP, Collee, JM, Bolla, MK, Wang, Q, Michailidou, K, Dennis, J, Ahearn, TU, Aittomaki, K, Ambrosone, CB, Andrulis, IL, Anton-Culver, H, Antonenkova, NN, Arndt, V, Arnold, N, Aronson, KJ, Augustinsson, A, Auvinen, P, Becher, H, Beckmann, MW, Behrens, S, Bermisheva, M, Bernstein, L, Bogdanova, N, Bogdanova-Markov, N, Bojesen, SE, Brauch, H, Brenner, H, Briceno, I, Brucker, SY, Bruening, T, Burwinkel, B, Cai, Q, Cai, H, Campa, D, Canzian, F, Castelao, JE, Chang-Claude, J, Chanock, SJ, Choi, J-Y, Christiaens, M, Clarke, CL, Couch, FJ, Czene, K, Daly, MB, Devilee, P, dos-Santos-Silva, I, Dwek, M, Eccles, DM, Eliassen, AH, Fasching, PA, Figueroa, J, Flyger, H, Fritschi, L, Gago-Dominguez, M, Gapstur, SM, Garcia-Closas, M, Garcia-Saenz, JA, Gaudet, MM, Giles, GG, Goldberg, MS, Goldgar, DE, Guenel, P, Haiman, CA, Hakansson, N, Hall, P, Harrington, PA, Hart, SN, Hartman, M, Hillemanns, P, Hopper, JL, Hou, M-F, Hunter, DJ, Huo, D, Ito, H, Iwasaki, M, Jakimovska, M, Jakubowska, A, John, EM, Kaaks, R, Kang, D, Keeman, R, Khusnutdinova, E, Kim, S-W, Kraft, P, Kristensen, VN, Kurian, AW, Le Marchand, L, Li, J, Lindblom, A, Lophatananon, A, Luben, RN, Lubinski, J, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Mariapun, S, Matsuo, K, Maurer, T, Mavroudis, D, Meindl, A, Menon, U, Milne, RL, Muir, K, Mulligan, AM, Neuhausen, SL, Nevanlinna, H, Offit, K, Olopade, O, Olson, JE, Olsson, H, Orr, N, Park, SK, Peterlongo, P, Peto, J, Plaseska-Karanfilska, D, Presneau, N, Rack, B, Rau-Murthy, R, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Ruebner, M, Saloustros, E, Schmutzler, RK, Schneeweiss, A, Scott, C, Shah, M, Shen, C-Y, Shu, X-O, Simard, J, Sohn, C, Southey, MC, Spinelli, JJ, Tamimi, RM, Tapper, WJ, Teo, SH, Terry, MB, Torres, D, Truong, T, Untch, M, Vachon, CM, van Asperen, CJ, Wolk, A, Yamaji, T, Zheng, W, Ziogas, A, Ziv, E, Torres-Mejia, G, Doerk, T, Swerdlow, AJ, Hamann, U, Schmidt, MK, Dunning, AM, Pharoah, PDP, Easton, DF, Hooning, MJ, Martens, JWM, and Hollestelle, A
Abstract: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
Published: 2020

21. Identification of novel breast cancer susceptibility loci in meta-analyses conducted among Asian and European descendants

Author: Shu, X, Long, J, Cai, Q, Kweon, S-S, Choi, J-Y, Kubo, M, Park, SK, Bolla, MK, Dennis, J, Wang, Q, Yang, Y, Shi, J, Guo, X, Li, B, Tao, R, Aronson, KJ, Chan, KYK, Chan, TL, Gao, Y-T, Hartman, M, Ho, WK, Ito, H, Iwasaki, M, Iwata, H, John, EM, Kasuga, Y, Khoo, US, Kim, M-K, Kong, S-Y, Kurian, AW, Kwong, A, Lee, E-S, Li, J, Lophatananon, A, Low, S-K, Mariapun, S, Matsuda, K, Matsuo, K, Muir, K, Noh, D-Y, Park, B, Park, M-H, Shen, C-Y, Shin, M-H, Spinelli, JJ, Takahashi, A, Tseng, C, Tsugane, S, Wu, AH, Xiang, Y-B, Yamaji, T, Zheng, Y, Milne, RL, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Teo, S-H, Shu, X-O, Kang, D, Easton, DF, Simard, J, Zheng, W, Shu, X, Long, J, Cai, Q, Kweon, S-S, Choi, J-Y, Kubo, M, Park, SK, Bolla, MK, Dennis, J, Wang, Q, Yang, Y, Shi, J, Guo, X, Li, B, Tao, R, Aronson, KJ, Chan, KYK, Chan, TL, Gao, Y-T, Hartman, M, Ho, WK, Ito, H, Iwasaki, M, Iwata, H, John, EM, Kasuga, Y, Khoo, US, Kim, M-K, Kong, S-Y, Kurian, AW, Kwong, A, Lee, E-S, Li, J, Lophatananon, A, Low, S-K, Mariapun, S, Matsuda, K, Matsuo, K, Muir, K, Noh, D-Y, Park, B, Park, M-H, Shen, C-Y, Shin, M-H, Spinelli, JJ, Takahashi, A, Tseng, C, Tsugane, S, Wu, AH, Xiang, Y-B, Yamaji, T, Zheng, Y, Milne, RL, Dunning, AM, Pharoah, PDP, Garcia-Closas, M, Teo, S-H, Shu, X-O, Kang, D, Easton, DF, Simard, J, and Zheng, W
Abstract: Known risk variants explain only a small proportion of breast cancer heritability, particularly in Asian women. To search for additional genetic susceptibility loci for breast cancer, here we perform a meta-analysis of data from genome-wide association studies (GWAS) conducted in Asians (24,206 cases and 24,775 controls) and European descendants (122,977 cases and 105,974 controls). We identified 31 potential novel loci with the lead variant showing an association with breast cancer risk at P < 5 × 10-8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). In addition, we replicated the associations for 78 of the 166 known risk variants at P < 0.05 in Asians. These findings improve our understanding of breast cancer genetics and etiology and extend previous findings from studies of European descendants to Asian women.
Published: 2020

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

Author: Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, Schmidt MK, Kramer I, Hooning MJ, Mavaddat N, Hauptmann M, Keeman R, Steyerberg EW, Giardiello D, Antoniou AC, Pharoah PDP, Canisius S, Abu-Ful Z, Andrulis IL, Anton-Culver H, Aronson KJ, Augustinsson A, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bogdanova NV, Bojesen SE, Bolla MK, Bonanni B, Brauch H, Bremer M, Brucker SY, Burwinkel B, Castelao JE, Chan TL, Chang-Claude J, Chanock SJ, Chenevix-Trench G, Choi J-Y, Clarke CL, NBCS Collaborators, Collée JM, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Evans DG, Fasching PA, Flyger H, Gago-Dominguez M, García-Closas M, García-Sáenz JA, Giles GG, Goldgar DE, González-Neira A, Haiman CA, Håkansson N, Hamann U, Hartman M, Heemskerk-Gerritsen BAM, Hollestelle A, Hopper JL, Hou M-F, Howell A, ABCTB Investigators, kConFab Investigators, Ito H, Jakimovska M, Jakubowska A, Janni W, John EM, Jung A, Kang D, Kets CM, Khusnutdinova E, Ko Y-D, Kristensen VN, Kurian AW, Kwong A, Lambrechts D, Le Marchand L, Li J, Lindblom A, Lubiński J, Mannermaa A, Manoochehri M, Margolin S, Matsuo K, Mavroudis D, Meindl A, Milne RL, Mulligan AM, Muranen TA, Neuhausen SL, Nevanlinna H, Newman WG, Olshan AF, Olson JE, Olsson H, Park-Simon T-W, Peto J, Petridis C, Plaseska-Karanfilska D, Presneau N, Pylkäs K, Radice P, Rennert G, Romero A, Roylance R, Saloustros E, Sawyer EJ, Schmutzler RK, Schwentner L, Scott C, See M-H, Shah M, Shen C-Y, Shu X-O, Siesling S, Slager S, Sohn C, Southey MC, Spinelli JJ, Stone J, Tapper WJ, Tengström M, Teo SH, Terry MB, Tollenaar RAEM, Tomlinson I, Troester MA, Vachon CM, van Ongeval C, van Veen EM, Winqvist R, Wolk A, Zheng W, Ziogas A, Easton DF, Hall P, and Schmidt MK
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

23. EE458 Economic Burden of Disease Recurrence in Elderly Patients With Human Epidermal Growth Factor Receptor 2-Negative (HER2–) Early Breast Cancer (eBC).

Author: Earla, JR, Kurian, AW, Kponee-Shovein, K., Song, Y, Mahendran, M, Hua, Q, Hilts, A, Hirshfield, KM, and Mejia, JA
Published: 2024
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24. Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry

Author: Yang, Y, Shu, X, Shu, X-O, Bolla, MK, Kweon, S-S, Cai, Q, Michailidou, K, Wang, Q, Dennis, J, Park, B, Matsuo, K, Kwong, A, Park, SK, Wu, AH, Teo, SH, Iwasaki, M, Choi, J-Y, Li, J, Hartman, M, Shen, C-Y, Muir, K, Lophatananon, A, Li, B, Wen, W, Gao, Y-T, Xiang, Y-B, Aronson, KJ, Spinell, JJ, Gago-Dominguez, M, John, EM, Kurian, AW, Chang-Claude, J, Chen, S-T, Dork, T, Evans, DGR, Schmidt, MK, Shin, M-H, Giles, GG, Milne, RL, Simard, J, Kubo, M, Kraft, P, Kang, D, Easton, DF, Zheng, W, Long, J, Yang, Y, Shu, X, Shu, X-O, Bolla, MK, Kweon, S-S, Cai, Q, Michailidou, K, Wang, Q, Dennis, J, Park, B, Matsuo, K, Kwong, A, Park, SK, Wu, AH, Teo, SH, Iwasaki, M, Choi, J-Y, Li, J, Hartman, M, Shen, C-Y, Muir, K, Lophatananon, A, Li, B, Wen, W, Gao, Y-T, Xiang, Y-B, Aronson, KJ, Spinell, JJ, Gago-Dominguez, M, John, EM, Kurian, AW, Chang-Claude, J, Chen, S-T, Dork, T, Evans, DGR, Schmidt, MK, Shin, M-H, Giles, GG, Milne, RL, Simard, J, Kubo, M, Kraft, P, Kang, D, Easton, DF, Zheng, W, and Long, J
Abstract: BACKGROUND: We previously conducted a systematic field synopsis of 1059 breast cancer candidate gene studies and investigated 279 genetic variants, 51 of which showed associations. The major limitation of this work was the small sample size, even pooling data from all 1059 studies. Thereafter, genome-wide association studies (GWAS) have accumulated data for hundreds of thousands of subjects. It's necessary to re-evaluate these variants in large GWAS datasets. METHODS: Of these 279 variants, data were obtained for 228 from GWAS conducted within the Asian Breast Cancer Consortium (24,206 cases and 24,775 controls) and the Breast Cancer Association Consortium (122,977 cases and 105,974 controls of European ancestry). Meta-analyses were conducted to combine the results from these two datasets. FINDINGS: Of those 228 variants, an association was observed for 12 variants in 10 genes at a Bonferroni-corrected threshold of P < 2·19 × 10-4. The associations for four variants reached P < 5 × 10-8 and have been reported by previous GWAS, including rs6435074 and rs6723097 (CASP8), rs17879961 (CHEK2) and rs2853669 (TERT). The remaining eight variants were rs676387 (HSD17B1), rs762551 (CYP1A2), rs1045485 (CASP8), rs9340799 (ESR1), rs7931342 (CHR11), rs1050450 (GPX1), rs13010627 (CASP10) and rs9344 (CCND1). Further investigating these 10 genes identified associations for two additional variants at P < 5 × 10-8, including rs4793090 (near HSD17B1), and rs9210 (near CYP1A2), which have not been identified by previous GWAS. INTERPRETATION: Though most candidate gene variants were not associated with breast cancer risk, we found 14 variants showing an association. Our findings warrant further functional investigation of these variants. FUND: National Institutes of Health.
Published: 2019

25. From the Past to the Present: Insurer Coverage Frameworks for Next-Generation Tumor Sequencing

Author: Trosman, JR, Weldon, CB, Gradishar, WJ, III, BAB, Cristofanilli, M, Kurian, AW, Ford, JM, Balch, A, Watkins, J, and Phillips, KA
Subjects: tumor sequencing, History, precision medicine, Decision Making, Human Genome, Insurance Carriers, High-Throughput Nucleotide Sequencing, insurance coverage, 21st Century, reimbursement, Basic Behavioral and Social Science, Good Health and Well Being, Clinical Research, Neoplasms, precision oncology, Applied Economics, Behavioral and Social Science, Genetics, Public Health and Health Services, Health Policy & Services, Humans, next-generation sequencing, Generic health relevance, Cancer
Abstract: Next-generation sequencing promises major advancements in precision medicine but faces considerable challenges with insurance coverage. These challenges are especially important to address in oncology in which next-generation tumor sequencing (NGTS) holds a particular promise, guiding the use of life-saving or life-prolonging therapies. Payers' coverage decision making on NGTS is challenging because this revolutionary technology pushes the very boundaries of the underlying framework used in coverage decisions. Some experts have called for the adaptation of the coverage framework to make it better equipped for assessing NGTS. Medicare's recent decision to cover NGTS makes this topic particularly urgent to examine. In this article, we discussed the previously proposed approaches for adaptation of the NGTS coverage framework, highlighted their innovations, and outlined remaining gaps in their ability to assess the features of NGTS. We then compared the three approaches with Medicare's national coverage determination for NGTS and discussed its implications for US private payers as well as for other technologies and clinical areas. We focused on US payers because analyses of coverage approaches and policies in the large and complex US health care system may inform similar efforts in other countries. We concluded that further adaptation of the coverage framework will facilitate a better suited assessment of NGTS and future genomics innovations.
Published: 2018

26. Abstract P4-06-07: Trends and results of BRCA1/2 and multigene panel testing in newly diagnosed breast cancer patients

Author: Kurian, AW, primary and Katz, SJ, additional
Published: 2018
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27. Abstract P4-20-02: Value of cancer care for metastatic breast cancer patients and providers

Author: May, SG, primary, Chung, AH, additional, Vania, DK, additional, Hou, N, additional, MacEwan, J, additional, Batt, K, additional, Kurian, AW, additional, Zacker, C, additional, Globe, D, additional, and Goldman, DP, additional
Published: 2017
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28. Abstract PD8-06: Multiple-gene panel testing for hereditary cancer risk reveals a racial/ethnic disparity in genetic information

Author: Caswell-Jin, JL*, primary, Gupta, T*, additional, Hall, E, additional, Petrovchich, IM, additional, Mills, MA, additional, Kingham, KE, additional, Koff, R, additional, Chun, NM, additional, Levonian, P, additional, Lebensohn, AP, additional, Ford, JM, additional, and Kurian, AW, additional
Published: 2017
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29. Abstract PD7-01: Interim analysis of multiplex gene panel testing for inherited susceptibility to breast cancer

Author: Idos, GE, primary, Kurian, AW, additional, Mcdonnell, KJ, additional, Ricker, CN, additional, Sturgeon, DY, additional, Culver, JO, additional, Lowstuter, K, additional, Hartman, A-R, additional, Allen, B, additional, Teeter, C-R, additional, Kingham, KE, additional, Koff, R, additional, Lebensohn, A, additional, Chun, NM, additional, Mills, MA, additional, Petrovchich, I, additional, Hong, C, additional, Ladabaum, U, additional, Ford, JM, additional, and Gruber, SB, additional
Published: 2016
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30. Abstract P2-09-07: The patient experience in a prospective trial of multiplex gene panel testing for cancer risk

Author: Kurian, AW, primary, Idos, G, additional, McDonnell, K, additional, Ricker, C, additional, Sturgeon, D, additional, Culver, J, additional, Lowstuter, K, additional, Hartman, A-R, additional, Allen, B, additional, Rowe-Teeter, C, additional, Kingham, KE, additional, Koff, RB, additional, Lebensohn, A, additional, Chun, NM, additional, Petrovchich, IM, additional, Mills, MA, additional, Hong, C, additional, Ladabaum, U, additional, Ford, JM, additional, and Gruber, SB, additional
Published: 2016
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31. Abstract P1-02-10: Variation in HER2 positive rates in California by geographic region: Implications for setting pathology laboratory benchmarks

Author: Allison, KH, primary, Jensen, KC, additional, West, RB, additional, Clarke, CA, additional, Gomez, SL, additional, and Kurian, AW, additional
Published: 2013
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32. Abstract P2-01-01: Impact of California breast density notification law SB 1538 on California women and their health care providers

Author: Ikeda, DM, primary, Thomas, WR, additional, Joe, BN, additional, Lindfors, K, additional, Brenner, RJ, additional, Feig, S, additional, Bassett, LW, additional, Leung, JW, additional, Ojeda-Fournier, H, additional, Hargreaves, J, additional, Price, E, additional, Lipson, J, additional, Kurian, AW, additional, Love, E, additional, Walgenbach, DD, additional, Ryan, L, additional, Durbin, M, additional, Daniel, BL, additional, Nayak, L, additional, and Sickles, EA, additional
Published: 2013
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33. Abstract P4-11-02: NovelBRCA1andBRCA2genomic rearrangements in Southern Chinese breast/ovarian cancer patients

Author: Kwong, A, primary, Ng, EKO, additional, Law, FBF, additional, Wa, A, additional, Wong, CLP, additional, Wong, CHN, additional, Kurian, AW, additional, West, DW, additional, Ford, JM, additional, and Ma, ESK, additional
Published: 2012
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34. Abstract P3-11-02: Male breast cancer: A comparison between BRCA mutation carriers and non-carriers in Hong Kong, Southern China

Author: Kwong, A, primary, Chau, WW, additional, Wong, CHN, additional, Law, FBF, additional, Ng, EKO, additional, Suen, DTK, additional, Kurian, AW, additional, West, DW, additional, Ford, JM, additional, and Ma, ESK, additional
Published: 2012
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35. P4-10-10: Breast Cancer Risk Factors among Asian Versus Caucasian Women with BRCA1/2 Mutations.

Author: de, Bruin MA, primary, Kwong, A, additional, Goldstein, BA, additional, Lipson, JA, additional, Ikeda, DM, additional, McPherson, LA, additional, Sharma, B, additional, Kardashian, A, additional, Schackmann, EA, additional, Kingham, KE, additional, Mills, MA, additional, West, DW, additional, Ford, JM, additional, and Kurian, AW, additional
Published: 2011
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36. P3-14-08: A Phase II Study of Gemcitabine and Carboplatin (GC) Plus Iniparib (BSI-201) as Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer.

Author: Telli, ML, primary, Kurian, AW, additional, Jensen, KC, additional, Vinayak, S, additional, Flaherty, P, additional, Lipson, JA, additional, Wapnir, I, additional, Daniel, B, additional, Carlson, RW, additional, Mills, MA, additional, Chang, P-J, additional, Schackmann, E, additional, Rocha, C, additional, Sherman, B, additional, Blackwood-Chirchir, A, additional, Bradley, C, additional, and Ford, JM, additional
Published: 2011
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37. Differences in breast cancer subtype distribution exist among ethnic subgroups of Asian women in California.

Author: Telli, ML, primary, Kurian, AW, additional, Chang, ET, additional, Keegan, TH, additional, McClure, LA, additional, Ford, JM, additional, and Gomez, SL, additional
Published: 2009
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38. Age-specific incidence of breast cancer subtypes: understanding the black-white crossover.

Author: Clarke CA, Keegan TH, Yang J, Press DJ, Kurian AW, Patel AH, Lacey JV Jr, Clarke, Christina A, Keegan, Theresa H M, Yang, Juan, Press, David J, Kurian, Allison W, Patel, Anish H, and Lacey, James V Jr
Abstract: Background: Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black-white crossover). We used newly available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity.Methods: We classified 91908 invasive breast cancers diagnosed in California between January 1, 2006, and December 31, 2009, by subtype based on tumor expression of estrogen receptor (ER) and progesterone receptor (PR)-together referred to as hormone receptor (HR)-and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes were classified as ER or PR positive and HER2 negative (HR(+)/HER2(-)), ER or PR positive and HER2 positive (HR(+)/HER2(+)), ER and PR negative and HER2 positive (HR(-)/HER2(+)), and ER, PR, and HER2 negative (triple-negative). We calculated and compared age-specific incidence rates, incidence rate ratios, and 95% confidence intervals by subtype and race (black, white, Hispanic, and Asian). All P values are two-sided.Results: We did not observe an age-related black-white crossover in incidence for any molecular subtype of breast cancer. Compared with white women, black women had statistically significantly higher rates of triple-negative breast cancer at all ages but statistically significantly lower rates of HR(+)/HER2(-) breast cancers after age 35 years (all P < .05). The age-specific incidence of HR(+)/HER2(+) and HR(-)/HER2(+) subtypes did not vary markedly between white and black women.Conclusions: The black-white crossover in breast cancer incidence occurs only when all breast cancer subtypes are combined and relates largely to higher rates of triple-negative breast cancers and lower rates of HR(+)/HER2(-) breast cancers in black vs white women. [ABSTRACT FROM AUTHOR]
Published: 2012
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39. Online tool to guide decisions for BRCA1/2 mutation carriers.

Author: Kurian AW, Munoz DF, Rust P, Schackmann EA, Smith M, Clarke L, Mills MA, Plevritis SK, Kurian, Allison W, Munoz, Diego F, Rust, Peter, Schackmann, Elizabeth A, Smith, Michael, Clarke, Lauren, Mills, Meredith A, and Plevritis, Sylvia K
Published: 2012
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40. BRCA1 and BRCA2 mutations across race and ethnicity: distribution and clinical implications.

Author: Kurian AW
Published: 2010
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41. Performance of BRCA1/2 mutation prediction models in Asian Americans.

Author: Kurian AW, Gong GD, Chun NM, Mills MA, Staton AD, Kingham KE, Crawford BB, Lee R, Chan S, Donlon SS, Ridge Y, Panabaker K, West DW, Whittemore AS, Ford JM, Kurian, Allison W, Gong, Gail D, Chun, Nicolette M, Mills, Meredith A, and Staton, Ashley D
Published: 2008
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42. Development of a breast cancer risk prediction model integrating monogenic, polygenic, and epidemiologic risk.

Author: Kalia SS, Boddicker NJ, Yadav S, Huang H, Na J, Hu C, Ambrosone CB, Yao S, Haiman CA, Chen F, John EM, Kurian AW, Guo B, Lindström S, Auer P, Lacey JV, Neuhausen SL, Martinez ME, Sandler DP, O'Brien KM, Taylor JA, Teras LR, Hodge JM, Lori A, Bodelon C, Trentham-Dietz A, Burnside ES, Vachon CM, Winham SJ, Goldgar DE, Domchek SM, Nathanson KL, Weitzel JN, Couch FJ, and Kraft P
Abstract: Background: Breast cancer has been associated with monogenic, polygenic, and epidemiologic (clinical, reproductive and lifestyle) risk factors, but studies evaluating the combined effects of these factors have been limited., Methods: We extended previous work in breast cancer risk modeling, incorporating pathogenic variants (PV) in six breast cancer predisposition genes and a 105-SNP polygenic risk score (PRS), to include an epidemiologic risk score (ERS) in a sample of non-Hispanic White women drawn from prospective cohorts and population-based case-control studies, with 23,518 cases and 22,832 controls, from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium., Results: The model predicts 4.4-fold higher risk of breast cancer for postmenopausal women with no predisposition PV and median PRS, but with the highest versus lowest ERS. Overall, women with CHEK2 PVs had >20% lifetime risk of breast cancer. However, 15.6% of women with CHEK2 PVs and a family history of breast cancer, and 45.1% of women with CHEK2 PVs but without a family history of breast cancer, had low (<20%) predicted lifetime risk and thus were below the threshold for MRI screening. CHEK2 PV carriers at the 10th percentile of the joint distribution of ERS and PRS, without a family history of breast cancer, had a predicted lifetime risk similar to the general population., Conclusions: These results illustrate that an ERS, alone and combined with the PRS, can contribute to clinically relevant risk stratification., Impact: Integrating monogenic, polygenic, and epidemiologic risk factors in breast cancer risk prediction models may inform personalized screening and prevention efforts.
Published: 2024
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43. Genetic Counseling, Testing, and Family Communication Into Survivorship After Diagnosis of Breast Cancer.

Author: Katz SJ, Abrahamse P, Furgal A, Hodan R, Tocco RS, Ward KC, Hamilton AS, Wallner LP, and Kurian AW
Subjects: Humans, Female, Middle Aged, Adult, Aged, Young Adult, Cancer Survivors, Survivorship, Family, Georgia, SEER Program, Breast Neoplasms genetics, Breast Neoplasms diagnosis, Genetic Counseling, Genetic Testing, Communication
Abstract: Purpose: To examine receipt of genetic testing and communication with relatives about results into survivorship after diagnosis of breast cancer., Methods: Women age 20-79 years diagnosed with early-stage breast cancer in 2014-2015 and reported to the Georgia and Los Angeles County SEER registries were surveyed approximately 7 months and 6 years after diagnosis (n = 1,412). We asked about genetic counseling, testing, and communication with relatives about results. We categorized women into indications for testing on the basis of clinical guidelines at the time of diagnosis and at the time of the follow-up survey (FUPs)., Results: A total of 47.4% had indications for genetic testing at any time: 28.0% at baseline and an additional 19.4% at the time of the FUPs (only); 71.9% (95% CI, 67.4 to 76.4) of those with a baseline indication reported genetic testing versus 53.3% (95% CI, 47.3 to 59.2) with an indication at FUPs only and 35.0% (95% CI, 31.6 to 38.4) with no indication ( P < .001). There were no significant racial or ethnic differences in receipt of testing, controlling for age and clinical indications ( P = .239); results for genetic counseling were similar. Only 3.4% of survivors had direct-to-consumer genetic testing (DTCt) for cancer. Testers who reported a pathogenic variant (n = 62) were much more likely to have talked to most or all their first-degree adult relatives about genetic testing than those with a variant of unknown significance (n = 49) or a negative finding (n = 419): 62.7% versus 38.8% and 38.0%, respectively ( P < .001)., Conclusion: Many women with indications for genetic counseling and testing into survivorship do not receive it. But those tested reach out to family members on the basis of the clinical relevance of their results. Very few patients obtained DTCt, which suggests that these tests do not substitute for clinical testing in breast cancer survivors.
Published: 2024
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44. Smoking and the Risk of Second Primary Lung Cancer Among Breast Cancer Survivors from the Population-Based UK Biobank Study.

Author: Graber-Naidich A, Choi E, Wu JT, Ellis-Caleo TJ, Neal J, Wakelee HA, Kurian AW, and Han SS
Abstract: Objective: Long-term breast cancer (BC) survivors are known to develop second malignancies, with second primary lung cancer (SPLC) one common type. Smoking was identified as a main risk factor for SPLC among BC survivors. These findings were limited to the U.S. and focused on smoking status, not incorporating cumulative smoking exposures (eg, pack-years). We examine SPLC incidence and evaluate the associations between SPLC risk and cumulative cigarette smoking exposures and other potential factors among BC survivors in a prospective European cohort., Methods: Of 502,505 participants enrolled in the UK Biobank in 2006 to 2010, we identified 8429 patients diagnosed with BC between 2006 and 2016 and followed for second malignancies through 2016. Smoking information was collected at enrollment, and treatment data were collected using electronic health records. Multivariable cause-specific Cox regression (CSC) evaluated the association between each factor and SPLC risk., Results: Of 8429 BC patients, 40 (0.47%) developed SPLC over 45,376 person-years. The 10-year cumulative SPLC incidence was 0.48% (95% CI = 0.33%-0.62%). The CSC analysis confirmed the association between SPLC and ever-smoking status (adjusted hazard-ratio (aHR) = 3.46 (P < .001). The analysis showed a 24% increment in SPLC risk per 10 smoking pack-years among BC survivors (aHR = 1.24 per-10 pack-years, P = .01). The associations between SPLC and other variables remained statistically insignificant. We applied the USPSTF lung cancer screening eligibility criteria and found that 80% of the 40 BC survivors who developed SPLC would have been ineligible for lung cancer screening., Conclusion: In a large, European cohort, cumulative smoking exposure is significantly associated with SPLC risk among BC survivors., Competing Interests: Disclosure The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Published: 2024
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45. Surgery and Suicide Deaths Among Patients With Cancer.

Author: Chen ML, Gomez SL, O'Hara R, John EM, Morris AM, Kurian AW, and Linos E
Subjects: Humans, Male, Female, Middle Aged, Aged, Adult, United States epidemiology, Surgical Procedures, Operative mortality, Surgical Procedures, Operative psychology, Surgical Procedures, Operative statistics & numerical data, Neoplasms mortality, Neoplasms psychology, Suicide statistics & numerical data, Suicide psychology
Published: 2024
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46. Real-world treatment patterns and outcomes in patients with HR+/HER2- metastatic breast cancer treated with chemotherapy in the United States.

Author: Tolaney SM, Punie K, Carey LA, Kurian AW, Ntalla I, Sjekloca N, Shah A, Rehnquist MK, Stokes M, Fraeman K, Verret W, and Jhaveri K
Subjects: Humans, Female, Middle Aged, Retrospective Studies, Aged, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Treatment Outcome, Receptors, Estrogen metabolism, Receptors, Progesterone metabolism, Neoplasm Metastasis, Progression-Free Survival, Capecitabine therapeutic use, Capecitabine pharmacology, Polyether Polyketides, Furans, Ketones, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms mortality, Receptor, ErbB-2 metabolism
Abstract: Background: Until recently, treatment options for patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) and resistance to endocrine therapy were limited to chemotherapy. This real-world study describes treatment patterns and outcomes in patients treated with chemotherapy in the United States before approval of antibody-drug conjugates., Patients and Methods: This retrospective, observational study included adults with HR+/HER2- mBC from the ConcertAI Patient360™ Breast Cancer dataset who initiated their first chemotherapy in the metastatic setting between January 2011 and June 2021. Treatment patterns were described; real-world overall survival, time to next treatment or death, and real-world progression-free survival were evaluated for all eligible patients and patients treated with subsequent chemotherapy. Index dates were the start date of each chemotherapy treatment., Results: Among 1545 eligible patients, 76% were white, 12% had Eastern Cooperative Oncology Group performance status ≥2, 38% had de novo mBC, and median age was 61 years (range, 52-69 years). Within the index period, capecitabine was used the most as the first chemotherapy agent and decreased in later treatments, while the use of eribulin increased between first and fourth chemotherapies. Median (95% confidence interval) real-world overall survival was 23.3 months (21.3-25.4 months) from start of first chemotherapy, time to next treatment or death was 6.5 months (5.9-7.1 months), and real-world progression-free survival was 6.9 months (6.4-7.6 months); median times from second, third, and fourth chemotherapies decreased with each additional chemotherapy treatment., Conclusions: This real-world study demonstrates that for patients with HR+/HER2- mBC, chemotherapy provides relatively limited survival benefit which decreases with each additional chemotherapy line, and highlights the need for improved treatment options., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Published: 2024
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47. The population-level effects of omitting chemotherapy guided by a 21-gene expression assay in node-positive breast cancer: a simulation modeling study.

Author: Wojcik KM, Caswell-Jin JL, Wilson OWA, Schechter C, Kamil D, Kurian AW, and Jayasekera J
Subjects: Humans, Female, Middle Aged, Adult, Aged, Computer Simulation, Premenopause, Postmenopause, Quality-Adjusted Life Years, Lymphatic Metastasis, Gene Expression Profiling methods, Neoplasm Recurrence, Local genetics, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism, Disease-Free Survival, Breast Neoplasms drug therapy, Breast Neoplasms genetics, Breast Neoplasms pathology, Breast Neoplasms mortality
Abstract: Background: A recent trial showed that postmenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor-2 (HER2)-negative, lymph node-positive (1-3 nodes) breast cancer with a 21-gene recurrence score of ≤ 25 could safely omit chemotherapy. However, there are limited data on population-level long-term outcomes associated with omitting chemotherapy among diverse women seen in real-world practice., Methods: We adapted an established, validated simulation model to generate the joint distributions of population-level characteristics of women diagnosed with early-stage breast cancer in the U.S. Input parameters were derived from cancer registry, meta-analyses, and clinical trial data. The effects of omitting chemotherapy on 10-year distant recurrence-free survival, life-years, and quality adjusted life-years (QALYs) were modeled for premenopausal and postmenopausal women. QALYs were discounted at 3%. Results were evaluated for subgroups stratified by race and ethnicity. Sensitivity analyses included testing results across a range of inputs. The model was validated using the published RxPONDER trial data., Results: In premenopausal women, the 10-year distant recurrence-free survival rates were 85.3% with chemo-endocrine and 80.1% with endocrine therapy. The estimated life-years and QALYs gained with chemotherapy in premenopausal women were 2.1 and 0.6, respectively. There was no chemotherapy benefit in postmenopausal women. There was no variation in the absolute benefit of chemotherapy across racial or ethnic subgroups. However, there were differences in distant recurrence-free survival rates, life-years, and QALYs across groups. Sensitivity analysis showed similar results. The model closely replicated the RxPONDER trial., Conclusions: Modeled population-level outcomes show a small chemotherapy benefit in premenopausal women, but no benefit among postmenopausal women. Simulation modeling provides a useful tool to extend trial data and evaluate population-level outcomes., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
Published: 2024
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48. Pregnancy-Related Factors and Breast Cancer Risk for Women Across a Range of Familial Risk.

Author: McDonald JA, Liao Y, Knight JA, John EM, Kurian AW, Daly M, Buys SS, Huang Y, Frost CJ, Andrulis IL, Colonna SV, Friedlander ML, Hopper JL, Chung WK, Genkinger JM, MacInnis RJ, and Terry MB
Subjects: Humans, Female, Pregnancy, Adult, Middle Aged, Prospective Studies, Risk Factors, Australia epidemiology, Canada epidemiology, Parity, United States epidemiology, Registries, Genetic Predisposition to Disease, Cohort Studies, Breast Feeding statistics & numerical data, Breast Neoplasms genetics, Breast Neoplasms epidemiology
Abstract: Importance: Few studies have investigated whether the associations between pregnancy-related factors and breast cancer (BC) risk differ by underlying BC susceptibility. Evidence regarding variation in BC risk is critical to understanding BC causes and for developing effective risk-based screening guidelines., Objective: To examine the association between pregnancy-related factors and BC risk, including modification by a of BC where scores are based on age and BC family history., Design, Setting, and Participants: This cohort study included participants from the prospective Family Study Cohort (ProF-SC), which includes the 6 sites of the Breast Cancer Family Registry (US, Canada, and Australia) and the Kathleen Cuningham Foundation Consortium (Australia). Analyses were performed in a cohort of women enrolled from 1992 to 2011 without any personal history of BC who were followed up through 2017 with a median (range) follow-up of 10 (1-23) years. Data were analyzed from March 1992 to March 2017., Exposures: Parity, number of full-term pregnancies (FTP), age at first FTP, years since last FTP, and breastfeeding., Main Outcomes and Measures: BC diagnoses were obtained through self-report or report by a first-degree relative and confirmed through pathology and data linkages. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% CIs for each exposure, examining modification by PARS of BC. Differences were assessed by estrogen receptor (ER) subtype., Results: The study included 17 274 women (mean [SD] age, 46.7 [15.1] years; 791 African American or Black participants [4.6%], 1399 Hispanic or Latinx participants [8.2%], and 13 790 White participants [80.7%]) with 943 prospectively ascertained BC cases. Compared with nulliparous women, BC risk was higher after a recent pregnancy for those women with higher PARS (last FTP 0-5 years HR for interaction, 1.53; 95% CI, 1.13-2.07; P for interaction < .001). Associations between other exposures were limited to ER-negative disease. ER-negative BC was positively associated with increasing PARS and increasing years since last FTP (P for interaction < .001) with higher risk for recent pregnancy vs nulliparous women (last FTP 0-5 years HR for interaction, 1.54; 95% CI, 1.03-2.31). ER-negative BC was positively associated with increasing PARS and being aged 20 years or older vs less than 20 years at first FTP (P for interaction = .002) and inversely associated with multiparity vs nulliparity (P for interaction = .01)., Conclusions and Relevance: In this cohort study of women with no prior BC diagnoses, associations between pregnancy-related factors and BC risk were modified by PARS, with greater associations observed for ER-negative BC.
Published: 2024
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49. Automated Extraction of Patient-Centered Outcomes After Breast Cancer Treatment: An Open-Source Large Language Model-Based Toolkit.

Author: Luo M, Trivedi S, Kurian AW, Ward K, Keegan THM, Rubin D, and Banerjee I
Subjects: Humans, Female, Patient-Centered Care, Electronic Health Records, Quality of Life, Patient Outcome Assessment, Breast Neoplasms psychology, Natural Language Processing
Abstract: Purpose: Patient-centered outcomes (PCOs) are pivotal in cancer treatment, as they directly reflect patients' quality of life. Although multiple studies suggest that factors affecting breast cancer-related morbidity and survival are influenced by treatment side effects and adherence to long-term treatment, such data are generally only available on a smaller scale or from a single center. The primary challenge with collecting these data is that the outcomes are captured as free text in clinical narratives written by clinicians., Materials and Methods: Given the complexity of PCO documentation in these narratives, computerized methods are necessary to unlock the wealth of information buried in unstructured text notes that often document PCOs. Inspired by the success of large language models (LLMs), we examined the adaptability of three LLMs, GPT-2, BioGPT, and PMC-LLaMA, on PCO tasks across three institutions, Mayo Clinic, Emory University Hospital, and Stanford University. We developed an open-source framework for fine-tuning LLM that can directly extract the five different categories of PCO from the clinic notes., Results: We found that these LLMs without fine-tuning (zero-shot) struggle with challenging PCO extraction tasks, displaying almost random performance, even with some task-specific examples (few-shot learning). The performance of our fine-tuned, task-specific models is notably superior compared with their non-fine-tuned LLM models. Moreover, the fine-tuned GPT-2 model has demonstrated a significantly better performance than the other two larger LLMs., Conclusion: Our discovery indicates that although LLMs serve as effective general-purpose models for tasks across various domains, they require fine-tuning when applied to the clinician domain. Our proposed approach has the potential to lead more efficient, adaptable models for PCO information extraction, reducing reliance on extensive computational resources while still delivering superior performance for specific tasks.
Published: 2024
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50. Family communication of cancer genetic test results in an ethnically diverse population: a qualitative exploration of more than 200 patients.

Author: Hodan R, Picus M, Stanclift C, Ormond KE, Pichardo JM, Kurian AW, Ricker C, and Idos GE
Abstract: Previous research on family communication of cancer genetic test results has primarily focused on non-Hispanic White patients with high-risk pathogenic variants (PV). There are limited data on patient communication of moderate-risk PVs, variants of uncertain significance (VUS), and negative results. This qualitative study examined communication of positive, negative, and VUS hereditary cancer multi-gene panel (MGP) results in an ethnically and socioeconomically diverse population. As part of a multicenter, prospective cohort study of 2000 patients who underwent MGP testing at three hospitals in California, USA, free-text written survey responses to the question: "Feel free to share any thoughts or experiences with discussing genetic test results with others" were collected from participant questionnaires administered at 3 and 12-months post results disclosure. Content and thematic analyses were performed using a theory-driven analysis, Theory of Planned Behavior (TPB), on 256 responses from 214 respondents. Respondents with high perceived utility of sharing genetic test results often reported positive attitudes towards sharing test results and direct encouragement for genetic testing of others. Respondents with high self-efficacy in the sharing process were likely to report high perceived utility of sharing, whereas patients with low self-efficacy more often had VUS results and were more likely to report uncertainty about sharing. Consistent with TPB, our findings suggest that clinician reinforcement of the utility of genetic testing may increase intent for patients to communicate genetic information. Our findings suggest that clinicians should focus on strategies to improve patient understanding of VUS results., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Published: 2024
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