Genome-wide association study of germline variants and breast cancer-specific mortality

Maria Escala-Garcia, Qi Guo, Thilo Dörk, Sander Canisius, Renske Keeman, Joe Dennis, Jonathan Beesley, Julie Lecarpentier, Manjeet K. Bolla, Qin Wang, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein & 217 others Carl Blomqvist, Bram Boeckx, Stig E. Bojesen, Bernardo Bonanni, Anne Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Adam Brentnall, Louise Brinton, Per Broberg, Ian W. Brock, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Trinidad Caldés, Daniele Campa, Federico Canzian, Angel Carracedo, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Georgia Chenevix-Trench, Ting Yuan David Cheng, Suet Feung Chin, Christine L. Clarke, NBCS Collaborators, Emilie Cordina-Duverger, Fergus J. Couch, David G. Cox, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Lorraine Durcan, Miriam Dwek, Helena M. Earl, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Jonine Figueroa, Dieter Flesch-Janys, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Eva Galle, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Vassilios Georgoulias, Graham G. Giles, Gord Glendon, David E. Goldgar, Anna González-Neira, Grethe I.Grenaker Alnæs, Mervi Grip, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan Hankinson, Elaine F. Harkness, Patricia A. Harrington, Steven N. Hart, Jaana M. Hartikainen, Alexander Hein, Peter Hillemanns, Louise Hiller, Bernd Holleczek, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Wolfgang Janni, Esther M. John, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Maria Kabisch, Katarzyna Kaczmarek, Michael J. Kerin, Sofia Khan, Elza Khusnutdinova, Johanna I. Kiiski, Cari M. Kitahara, Julia A. Knight, Yon Dschun Ko, Linetta B. Koppert, Veli Matti Kosma, Peter Kraft, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Lian Li, Annika Lindblom, Sara Lindström, Martha Linet, Jolanta Lissowska, Wing Yee Lo, Sibylle Loibl, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Melanie Maierthaler, Tom Maishman, Enes Makalic, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Pooja Middha, Nicola Miller, Roger L. Milne, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Rami Nassir, Susan L. Neuhausen, William T. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung Won Park-Simon, Jose I.A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Christos Petridis, Mila Pinchev, Karoliona Prajzendanc, Ross Prentice, Nadege Presneau, Darya Prokofieva, Katri Pylkäs, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Gadi Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Emmanouil Saloustros, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Lukas Schwentner, Rodney J. Scott, Christopher Scott, Caroline Seynaeve, Mitul Shah, Jacques Simard, Ann Smeets, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Aline Talhouk, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Maria Tengström, Mary Beth Terry, Kathrin Thöne, Rob A.E.M. Tollenaar, Ian Tomlinson, Diana Torres, Thérèse Truong, Constance Turman, Clare Turnbull, Hans Ulrich Ulmer, Michael Untch, Celine Vachon, Christi J. van Asperen, Ans M.W. van den Ouweland, Elke M. van Veen, Camilla Wendt, Alice S. Whittemore, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Yan Zhang, Douglas F. Easton, Peter A. Fasching, Heli Nevanlinna, Diana M. Eccles, Paul D.P. Pharoah, Marjanka K. Schmidt

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

Original languageEnglish
Pages (from-to)647-657
Number of pages11
JournalBritish Journal of Cancer
Volume120
DOIs
Publication statusPublished - 21 Feb 2019

Cite this

Escala-Garcia, M., Guo, Q., Dörk, T., Canisius, S., Keeman, R., Dennis, J., ... Schmidt, M. K. (2019). Genome-wide association study of germline variants and breast cancer-specific mortality. British Journal of Cancer, 120, 647-657. https://doi.org/10.1038/s41416-019-0393-x
Escala-Garcia, Maria ; Guo, Qi ; Dörk, Thilo ; Canisius, Sander ; Keeman, Renske ; Dennis, Joe ; Beesley, Jonathan ; Lecarpentier, Julie ; Bolla, Manjeet K. ; Wang, Qin ; Abraham, Jean ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Arndt, Volker ; Auer, Paul L. ; Beckmann, Matthias W. ; Behrens, Sabine ; Benitez, Javier ; Bermisheva, Marina ; Bernstein, Leslie ; Blomqvist, Carl ; Boeckx, Bram ; Bojesen, Stig E. ; Bonanni, Bernardo ; Børresen-Dale, Anne Lise ; Brauch, Hiltrud ; Brenner, Hermann ; Brentnall, Adam ; Brinton, Louise ; Broberg, Per ; Brock, Ian W. ; Brucker, Sara Y. ; Burwinkel, Barbara ; Caldas, Carlos ; Caldés, Trinidad ; Campa, Daniele ; Canzian, Federico ; Carracedo, Angel ; Carter, Brian D. ; Castelao, Jose E. ; Chang-Claude, Jenny ; Chanock, Stephen J. ; Chenevix-Trench, Georgia ; Cheng, Ting Yuan David ; Chin, Suet Feung ; Clarke, Christine L. ; NBCS Collaborators ; Cordina-Duverger, Emilie ; Couch, Fergus J. ; Cox, David G. ; Cox, Angela ; Cross, Simon S. ; Czene, Kamila ; Daly, Mary B. ; Devilee, Peter ; Dunn, Janet A. ; Dunning, Alison M. ; Durcan, Lorraine ; Dwek, Miriam ; Earl, Helena M. ; Ekici, Arif B. ; Eliassen, A. Heather ; Ellberg, Carolina ; Engel, Christoph ; Eriksson, Mikael ; Evans, D. Gareth ; Figueroa, Jonine ; Flesch-Janys, Dieter ; Flyger, Henrik ; Gabrielson, Marike ; Gago-Dominguez, Manuela ; Galle, Eva ; Gapstur, Susan M. ; García-Closas, Montserrat ; García-Sáenz, José A. ; Gaudet, Mia M. ; George, Angela ; Georgoulias, Vassilios ; Giles, Graham G. ; Glendon, Gord ; Goldgar, David E. ; González-Neira, Anna ; Alnæs, Grethe I.Grenaker ; Grip, Mervi ; Guénel, Pascal ; Haeberle, Lothar ; Hahnen, Eric ; Haiman, Christopher A. ; Håkansson, Niclas ; Hall, Per ; Hamann, Ute ; Hankinson, Susan ; Harkness, Elaine F. ; Harrington, Patricia A. ; Hart, Steven N. ; Hartikainen, Jaana M. ; Hein, Alexander ; Hillemanns, Peter ; Hiller, Louise ; Holleczek, Bernd ; Hollestelle, Antoinette ; Hooning, Maartje J. ; Hoover, Robert N. ; Hopper, John L. ; Howell, Anthony ; Huang, Guanmengqian ; Humphreys, Keith ; Hunter, David J. ; Janni, Wolfgang ; John, Esther M. ; Jones, Michael E. ; Jukkola-Vuorinen, Arja ; Jung, Audrey ; Kaaks, Rudolf ; Kabisch, Maria ; Kaczmarek, Katarzyna ; Kerin, Michael J. ; Khan, Sofia ; Khusnutdinova, Elza ; Kiiski, Johanna I. ; Kitahara, Cari M. ; Knight, Julia A. ; Ko, Yon Dschun ; Koppert, Linetta B. ; Kosma, Veli Matti ; Kraft, Peter ; Kristensen, Vessela N. ; Krüger, Ute ; Kühl, Tabea ; Lambrechts, Diether ; Le Marchand, Loic ; Lee, Eunjung ; Lejbkowicz, Flavio ; Li, Lian ; Lindblom, Annika ; Lindström, Sara ; Linet, Martha ; Lissowska, Jolanta ; Lo, Wing Yee ; Loibl, Sibylle ; Lubiński, Jan ; Lux, Michael P. ; MacInnis, Robert J. ; Maierthaler, Melanie ; Maishman, Tom ; Makalic, Enes ; Mannermaa, Arto ; Manoochehri, Mehdi ; Manoukian, Siranoush ; Margolin, Sara ; Martinez, Maria Elena ; Mavroudis, Dimitrios ; McLean, Catriona ; Meindl, Alfons ; Middha, Pooja ; Miller, Nicola ; Milne, Roger L. ; Moreno, Fernando ; Mulligan, Anna Marie ; Mulot, Claire ; Nassir, Rami ; Neuhausen, Susan L. ; Newman, William T. ; Nielsen, Sune F. ; Nordestgaard, Børge G. ; Norman, Aaron ; Olsson, Håkan ; Orr, Nick ; Pankratz, V. Shane ; Park-Simon, Tjoung Won ; Perez, Jose I.A. ; Pérez-Barrios, Clara ; Peterlongo, Paolo ; Petridis, Christos ; Pinchev, Mila ; Prajzendanc, Karoliona ; Prentice, Ross ; Presneau, Nadege ; Prokofieva, Darya ; Pylkäs, Katri ; Rack, Brigitte ; Radice, Paolo ; Ramachandran, Dhanya ; Rennert, Gadi ; Rennert, Hedy S. ; Rhenius, Valerie ; Romero, Atocha ; Roylance, Rebecca ; Saloustros, Emmanouil ; Sawyer, Elinor J. ; Schmidt, Daniel F. ; Schmutzler, Rita K. ; Schneeweiss, Andreas ; Schoemaker, Minouk J. ; Schumacher, Fredrick ; Schwentner, Lukas ; Scott, Rodney J. ; Scott, Christopher ; Seynaeve, Caroline ; Shah, Mitul ; Simard, Jacques ; Smeets, Ann ; Sohn, Christof ; Southey, Melissa C. ; Swerdlow, Anthony J. ; Talhouk, Aline ; Tamimi, Rulla M. ; Tapper, William J. ; Teixeira, Manuel R. ; Tengström, Maria ; Terry, Mary Beth ; Thöne, Kathrin ; Tollenaar, Rob A.E.M. ; Tomlinson, Ian ; Torres, Diana ; Truong, Thérèse ; Turman, Constance ; Turnbull, Clare ; Ulmer, Hans Ulrich ; Untch, Michael ; Vachon, Celine ; van Asperen, Christi J. ; van den Ouweland, Ans M.W. ; van Veen, Elke M. ; Wendt, Camilla ; Whittemore, Alice S. ; Willett, Walter ; Winqvist, Robert ; Wolk, Alicja ; Yang, Xiaohong R. ; Zhang, Yan ; Easton, Douglas F. ; Fasching, Peter A. ; Nevanlinna, Heli ; Eccles, Diana M. ; Pharoah, Paul D.P. ; Schmidt, Marjanka K. / Genome-wide association study of germline variants and breast cancer-specific mortality. In: British Journal of Cancer. 2019 ; Vol. 120. pp. 647-657.
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title = "Genome-wide association study of germline variants and breast cancer-specific mortality",
abstract = "Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7{\%}, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95{\%} confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11{\%}, P = 1.38 × 10 −7 , HR = 1.27, 95{\%} CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15{\%} close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.",
author = "Maria Escala-Garcia and Qi Guo and Thilo D{\"o}rk and Sander Canisius and Renske Keeman and Joe Dennis and Jonathan Beesley and Julie Lecarpentier and Bolla, {Manjeet K.} and Qin Wang and Jean Abraham and Andrulis, {Irene L.} and Hoda Anton-Culver and Volker Arndt and Auer, {Paul L.} and Beckmann, {Matthias W.} and Sabine Behrens and Javier Benitez and Marina Bermisheva and Leslie Bernstein and Carl Blomqvist and Bram Boeckx and Bojesen, {Stig E.} and Bernardo Bonanni and B{\o}rresen-Dale, {Anne Lise} and Hiltrud Brauch and Hermann Brenner and Adam Brentnall and Louise Brinton and Per Broberg and Brock, {Ian W.} and Brucker, {Sara Y.} and Barbara Burwinkel and Carlos Caldas and Trinidad Cald{\'e}s and Daniele Campa and Federico Canzian and Angel Carracedo and Carter, {Brian D.} and Castelao, {Jose E.} and Jenny Chang-Claude and Chanock, {Stephen J.} and Georgia Chenevix-Trench and Cheng, {Ting Yuan David} and Chin, {Suet Feung} and Clarke, {Christine L.} and {NBCS Collaborators} and Emilie Cordina-Duverger and Couch, {Fergus J.} and Cox, {David G.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Daly, {Mary B.} and Peter Devilee and Dunn, {Janet A.} and Dunning, {Alison M.} and Lorraine Durcan and Miriam Dwek and Earl, {Helena M.} and Ekici, {Arif B.} and Eliassen, {A. Heather} and Carolina Ellberg and Christoph Engel and Mikael Eriksson and Evans, {D. Gareth} and Jonine Figueroa and Dieter Flesch-Janys and Henrik Flyger and Marike Gabrielson and Manuela Gago-Dominguez and Eva Galle and Gapstur, {Susan M.} and Montserrat Garc{\'i}a-Closas and Garc{\'i}a-S{\'a}enz, {Jos{\'e} A.} and Gaudet, {Mia M.} and Angela George and Vassilios Georgoulias and Giles, {Graham G.} and Gord Glendon and Goldgar, {David E.} and Anna Gonz{\'a}lez-Neira and Aln{\ae}s, {Grethe I.Grenaker} and Mervi Grip and Pascal Gu{\'e}nel and Lothar Haeberle and Eric Hahnen and Haiman, {Christopher A.} and Niclas H{\aa}kansson and Per Hall and Ute Hamann and Susan Hankinson and Harkness, {Elaine F.} and Harrington, {Patricia A.} and Hart, {Steven N.} and Hartikainen, {Jaana M.} and Alexander Hein and Peter Hillemanns and Louise Hiller and Bernd Holleczek and Antoinette Hollestelle and Hooning, {Maartje J.} and Hoover, {Robert N.} and Hopper, {John L.} and Anthony Howell and Guanmengqian Huang and Keith Humphreys and Hunter, {David J.} and Wolfgang Janni and John, {Esther M.} and Jones, {Michael E.} and Arja Jukkola-Vuorinen and Audrey Jung and Rudolf Kaaks and Maria Kabisch and Katarzyna Kaczmarek and Kerin, {Michael J.} and Sofia Khan and Elza Khusnutdinova and Kiiski, {Johanna I.} and Kitahara, {Cari M.} and Knight, {Julia A.} and Ko, {Yon Dschun} and Koppert, {Linetta B.} and Kosma, {Veli Matti} and Peter Kraft and Kristensen, {Vessela N.} and Ute Kr{\"u}ger and Tabea K{\"u}hl and Diether Lambrechts and {Le Marchand}, Loic and Eunjung Lee and Flavio Lejbkowicz and Lian Li and Annika Lindblom and Sara Lindstr{\"o}m and Martha Linet and Jolanta Lissowska and Lo, {Wing Yee} and Sibylle Loibl and Jan Lubiński and Lux, {Michael P.} and MacInnis, {Robert J.} and Melanie Maierthaler and Tom Maishman and Enes Makalic and Arto Mannermaa and Mehdi Manoochehri and Siranoush Manoukian and Sara Margolin and Martinez, {Maria Elena} and Dimitrios Mavroudis and Catriona McLean and Alfons Meindl and Pooja Middha and Nicola Miller and Milne, {Roger L.} and Fernando Moreno and Mulligan, {Anna Marie} and Claire Mulot and Rami Nassir and Neuhausen, {Susan L.} and Newman, {William T.} and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Aaron Norman and H{\aa}kan Olsson and Nick Orr and Pankratz, {V. Shane} and Park-Simon, {Tjoung Won} and Perez, {Jose I.A.} and Clara P{\'e}rez-Barrios and Paolo Peterlongo and Christos Petridis and Mila Pinchev and Karoliona Prajzendanc and Ross Prentice and Nadege Presneau and Darya Prokofieva and Katri Pylk{\"a}s and Brigitte Rack and Paolo Radice and Dhanya Ramachandran and Gadi Rennert and Rennert, {Hedy S.} and Valerie Rhenius and Atocha Romero and Rebecca Roylance and Emmanouil Saloustros and Sawyer, {Elinor J.} and Schmidt, {Daniel F.} and Schmutzler, {Rita K.} and Andreas Schneeweiss and Schoemaker, {Minouk J.} and Fredrick Schumacher and Lukas Schwentner and Scott, {Rodney J.} and Christopher Scott and Caroline Seynaeve and Mitul Shah and Jacques Simard and Ann Smeets and Christof Sohn and Southey, {Melissa C.} and Swerdlow, {Anthony J.} and Aline Talhouk and Tamimi, {Rulla M.} and Tapper, {William J.} and Teixeira, {Manuel R.} and Maria Tengstr{\"o}m and Terry, {Mary Beth} and Kathrin Th{\"o}ne and Tollenaar, {Rob A.E.M.} and Ian Tomlinson and Diana Torres and Th{\'e}r{\`e}se Truong and Constance Turman and Clare Turnbull and Ulmer, {Hans Ulrich} and Michael Untch and Celine Vachon and {van Asperen}, {Christi J.} and {van den Ouweland}, {Ans M.W.} and {van Veen}, {Elke M.} and Camilla Wendt and Whittemore, {Alice S.} and Walter Willett and Robert Winqvist and Alicja Wolk and Yang, {Xiaohong R.} and Yan Zhang and Easton, {Douglas F.} and Fasching, {Peter A.} and Heli Nevanlinna and Eccles, {Diana M.} and Pharoah, {Paul D.P.} and Schmidt, {Marjanka K.}",
year = "2019",
month = "2",
day = "21",
doi = "10.1038/s41416-019-0393-x",
language = "English",
volume = "120",
pages = "647--657",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",

}

Escala-Garcia, M, Guo, Q, Dörk, T, Canisius, S, Keeman, R, Dennis, J, Beesley, J, Lecarpentier, J, Bolla, MK, Wang, Q, Abraham, J, Andrulis, IL, Anton-Culver, H, Arndt, V, Auer, PL, Beckmann, MW, Behrens, S, Benitez, J, Bermisheva, M, Bernstein, L, Blomqvist, C, Boeckx, B, Bojesen, SE, Bonanni, B, Børresen-Dale, AL, Brauch, H, Brenner, H, Brentnall, A, Brinton, L, Broberg, P, Brock, IW, Brucker, SY, Burwinkel, B, Caldas, C, Caldés, T, Campa, D, Canzian, F, Carracedo, A, Carter, BD, Castelao, JE, Chang-Claude, J, Chanock, SJ, Chenevix-Trench, G, Cheng, TYD, Chin, SF, Clarke, CL, NBCS Collaborators, Cordina-Duverger, E, Couch, FJ, Cox, DG, Cox, A, Cross, SS, Czene, K, Daly, MB, Devilee, P, Dunn, JA, Dunning, AM, Durcan, L, Dwek, M, Earl, HM, Ekici, AB, Eliassen, AH, Ellberg, C, Engel, C, Eriksson, M, Evans, DG, Figueroa, J, Flesch-Janys, D, Flyger, H, Gabrielson, M, Gago-Dominguez, M, Galle, E, Gapstur, SM, García-Closas, M, García-Sáenz, JA, Gaudet, MM, George, A, Georgoulias, V, Giles, GG, Glendon, G, Goldgar, DE, González-Neira, A, Alnæs, GIG, Grip, M, Guénel, P, Haeberle, L, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Hankinson, S, Harkness, EF, Harrington, PA, Hart, SN, Hartikainen, JM, Hein, A, Hillemanns, P, Hiller, L, Holleczek, B, Hollestelle, A, Hooning, MJ, Hoover, RN, Hopper, JL, Howell, A, Huang, G, Humphreys, K, Hunter, DJ, Janni, W, John, EM, Jones, ME, Jukkola-Vuorinen, A, Jung, A, Kaaks, R, Kabisch, M, Kaczmarek, K, Kerin, MJ, Khan, S, Khusnutdinova, E, Kiiski, JI, Kitahara, CM, Knight, JA, Ko, YD, Koppert, LB, Kosma, VM, Kraft, P, Kristensen, VN, Krüger, U, Kühl, T, Lambrechts, D, Le Marchand, L, Lee, E, Lejbkowicz, F, Li, L, Lindblom, A, Lindström, S, Linet, M, Lissowska, J, Lo, WY, Loibl, S, Lubiński, J, Lux, MP, MacInnis, RJ, Maierthaler, M, Maishman, T, Makalic, E, Mannermaa, A, Manoochehri, M, Manoukian, S, Margolin, S, Martinez, ME, Mavroudis, D, McLean, C, Meindl, A, Middha, P, Miller, N, Milne, RL, Moreno, F, Mulligan, AM, Mulot, C, Nassir, R, Neuhausen, SL, Newman, WT, Nielsen, SF, Nordestgaard, BG, Norman, A, Olsson, H, Orr, N, Pankratz, VS, Park-Simon, TW, Perez, JIA, Pérez-Barrios, C, Peterlongo, P, Petridis, C, Pinchev, M, Prajzendanc, K, Prentice, R, Presneau, N, Prokofieva, D, Pylkäs, K, Rack, B, Radice, P, Ramachandran, D, Rennert, G, Rennert, HS, Rhenius, V, Romero, A, Roylance, R, Saloustros, E, Sawyer, EJ, Schmidt, DF, Schmutzler, RK, Schneeweiss, A, Schoemaker, MJ, Schumacher, F, Schwentner, L, Scott, RJ, Scott, C, Seynaeve, C, Shah, M, Simard, J, Smeets, A, Sohn, C, Southey, MC, Swerdlow, AJ, Talhouk, A, Tamimi, RM, Tapper, WJ, Teixeira, MR, Tengström, M, Terry, MB, Thöne, K, Tollenaar, RAEM, Tomlinson, I, Torres, D, Truong, T, Turman, C, Turnbull, C, Ulmer, HU, Untch, M, Vachon, C, van Asperen, CJ, van den Ouweland, AMW, van Veen, EM, Wendt, C, Whittemore, AS, Willett, W, Winqvist, R, Wolk, A, Yang, XR, Zhang, Y, Easton, DF, Fasching, PA, Nevanlinna, H, Eccles, DM, Pharoah, PDP & Schmidt, MK 2019, 'Genome-wide association study of germline variants and breast cancer-specific mortality' British Journal of Cancer, vol. 120, pp. 647-657. https://doi.org/10.1038/s41416-019-0393-x

Genome-wide association study of germline variants and breast cancer-specific mortality. / Escala-Garcia, Maria; Guo, Qi; Dörk, Thilo; Canisius, Sander; Keeman, Renske; Dennis, Joe; Beesley, Jonathan; Lecarpentier, Julie; Bolla, Manjeet K.; Wang, Qin; Abraham, Jean; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Auer, Paul L.; Beckmann, Matthias W.; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Boeckx, Bram; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne Lise; Brauch, Hiltrud; Brenner, Hermann; Brentnall, Adam; Brinton, Louise; Broberg, Per; Brock, Ian W.; Brucker, Sara Y.; Burwinkel, Barbara; Caldas, Carlos; Caldés, Trinidad; Campa, Daniele; Canzian, Federico; Carracedo, Angel; Carter, Brian D.; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Cheng, Ting Yuan David; Chin, Suet Feung; Clarke, Christine L.; NBCS Collaborators; Cordina-Duverger, Emilie; Couch, Fergus J.; Cox, David G.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dunn, Janet A.; Dunning, Alison M.; Durcan, Lorraine; Dwek, Miriam; Earl, Helena M.; Ekici, Arif B.; Eliassen, A. Heather; Ellberg, Carolina; Engel, Christoph; Eriksson, Mikael; Evans, D. Gareth; Figueroa, Jonine; Flesch-Janys, Dieter; Flyger, Henrik; Gabrielson, Marike; Gago-Dominguez, Manuela; Galle, Eva; Gapstur, Susan M.; García-Closas, Montserrat; García-Sáenz, José A.; Gaudet, Mia M.; George, Angela; Georgoulias, Vassilios; Giles, Graham G.; Glendon, Gord; Goldgar, David E.; González-Neira, Anna; Alnæs, Grethe I.Grenaker; Grip, Mervi; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A.; Håkansson, Niclas; Hall, Per; Hamann, Ute; Hankinson, Susan; Harkness, Elaine F.; Harrington, Patricia A.; Hart, Steven N.; Hartikainen, Jaana M.; Hein, Alexander; Hillemanns, Peter; Hiller, Louise; Holleczek, Bernd; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Huang, Guanmengqian; Humphreys, Keith; Hunter, David J.; Janni, Wolfgang; John, Esther M.; Jones, Michael E.; Jukkola-Vuorinen, Arja; Jung, Audrey; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kerin, Michael J.; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I.; Kitahara, Cari M.; Knight, Julia A.; Ko, Yon Dschun; Koppert, Linetta B.; Kosma, Veli Matti; Kraft, Peter; Kristensen, Vessela N.; Krüger, Ute; Kühl, Tabea; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lejbkowicz, Flavio; Li, Lian; Lindblom, Annika; Lindström, Sara; Linet, Martha; Lissowska, Jolanta; Lo, Wing Yee; Loibl, Sibylle; Lubiński, Jan; Lux, Michael P.; MacInnis, Robert J.; Maierthaler, Melanie; Maishman, Tom; Makalic, Enes; Mannermaa, Arto; Manoochehri, Mehdi; Manoukian, Siranoush; Margolin, Sara; Martinez, Maria Elena; Mavroudis, Dimitrios; McLean, Catriona; Meindl, Alfons; Middha, Pooja; Miller, Nicola; Milne, Roger L.; Moreno, Fernando; Mulligan, Anna Marie; Mulot, Claire; Nassir, Rami; Neuhausen, Susan L.; Newman, William T.; Nielsen, Sune F.; Nordestgaard, Børge G.; Norman, Aaron; Olsson, Håkan; Orr, Nick; Pankratz, V. Shane; Park-Simon, Tjoung Won; Perez, Jose I.A.; Pérez-Barrios, Clara; Peterlongo, Paolo; Petridis, Christos; Pinchev, Mila; Prajzendanc, Karoliona; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Ramachandran, Dhanya; Rennert, Gadi; Rennert, Hedy S.; Rhenius, Valerie; Romero, Atocha; Roylance, Rebecca; Saloustros, Emmanouil; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmutzler, Rita K.; Schneeweiss, Andreas; Schoemaker, Minouk J.; Schumacher, Fredrick; Schwentner, Lukas; Scott, Rodney J.; Scott, Christopher; Seynaeve, Caroline; Shah, Mitul; Simard, Jacques; Smeets, Ann; Sohn, Christof; Southey, Melissa C.; Swerdlow, Anthony J.; Talhouk, Aline; Tamimi, Rulla M.; Tapper, William J.; Teixeira, Manuel R.; Tengström, Maria; Terry, Mary Beth; Thöne, Kathrin; Tollenaar, Rob A.E.M.; Tomlinson, Ian; Torres, Diana; Truong, Thérèse; Turman, Constance; Turnbull, Clare; Ulmer, Hans Ulrich; Untch, Michael; Vachon, Celine; van Asperen, Christi J.; van den Ouweland, Ans M.W.; van Veen, Elke M.; Wendt, Camilla; Whittemore, Alice S.; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Zhang, Yan; Easton, Douglas F.; Fasching, Peter A.; Nevanlinna, Heli; Eccles, Diana M.; Pharoah, Paul D.P.; Schmidt, Marjanka K.

In: British Journal of Cancer, Vol. 120, 21.02.2019, p. 647-657.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Genome-wide association study of germline variants and breast cancer-specific mortality

AU - Escala-Garcia, Maria

AU - Guo, Qi

AU - Dörk, Thilo

AU - Canisius, Sander

AU - Keeman, Renske

AU - Dennis, Joe

AU - Beesley, Jonathan

AU - Lecarpentier, Julie

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Abraham, Jean

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Arndt, Volker

AU - Auer, Paul L.

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Bernstein, Leslie

AU - Blomqvist, Carl

AU - Boeckx, Bram

AU - Bojesen, Stig E.

AU - Bonanni, Bernardo

AU - Børresen-Dale, Anne Lise

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brentnall, Adam

AU - Brinton, Louise

AU - Broberg, Per

AU - Brock, Ian W.

AU - Brucker, Sara Y.

AU - Burwinkel, Barbara

AU - Caldas, Carlos

AU - Caldés, Trinidad

AU - Campa, Daniele

AU - Canzian, Federico

AU - Carracedo, Angel

AU - Carter, Brian D.

AU - Castelao, Jose E.

AU - Chang-Claude, Jenny

AU - Chanock, Stephen J.

AU - Chenevix-Trench, Georgia

AU - Cheng, Ting Yuan David

AU - Chin, Suet Feung

AU - Clarke, Christine L.

AU - NBCS Collaborators

AU - Cordina-Duverger, Emilie

AU - Couch, Fergus J.

AU - Cox, David G.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Devilee, Peter

AU - Dunn, Janet A.

AU - Dunning, Alison M.

AU - Durcan, Lorraine

AU - Dwek, Miriam

AU - Earl, Helena M.

AU - Ekici, Arif B.

AU - Eliassen, A. Heather

AU - Ellberg, Carolina

AU - Engel, Christoph

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Figueroa, Jonine

AU - Flesch-Janys, Dieter

AU - Flyger, Henrik

AU - Gabrielson, Marike

AU - Gago-Dominguez, Manuela

AU - Galle, Eva

AU - Gapstur, Susan M.

AU - García-Closas, Montserrat

AU - García-Sáenz, José A.

AU - Gaudet, Mia M.

AU - George, Angela

AU - Georgoulias, Vassilios

AU - Giles, Graham G.

AU - Glendon, Gord

AU - Goldgar, David E.

AU - González-Neira, Anna

AU - Alnæs, Grethe I.Grenaker

AU - Grip, Mervi

AU - Guénel, Pascal

AU - Haeberle, Lothar

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Hankinson, Susan

AU - Harkness, Elaine F.

AU - Harrington, Patricia A.

AU - Hart, Steven N.

AU - Hartikainen, Jaana M.

AU - Hein, Alexander

AU - Hillemanns, Peter

AU - Hiller, Louise

AU - Holleczek, Bernd

AU - Hollestelle, Antoinette

AU - Hooning, Maartje J.

AU - Hoover, Robert N.

AU - Hopper, John L.

AU - Howell, Anthony

AU - Huang, Guanmengqian

AU - Humphreys, Keith

AU - Hunter, David J.

AU - Janni, Wolfgang

AU - John, Esther M.

AU - Jones, Michael E.

AU - Jukkola-Vuorinen, Arja

AU - Jung, Audrey

AU - Kaaks, Rudolf

AU - Kabisch, Maria

AU - Kaczmarek, Katarzyna

AU - Kerin, Michael J.

AU - Khan, Sofia

AU - Khusnutdinova, Elza

AU - Kiiski, Johanna I.

AU - Kitahara, Cari M.

AU - Knight, Julia A.

AU - Ko, Yon Dschun

AU - Koppert, Linetta B.

AU - Kosma, Veli Matti

AU - Kraft, Peter

AU - Kristensen, Vessela N.

AU - Krüger, Ute

AU - Kühl, Tabea

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Lee, Eunjung

AU - Lejbkowicz, Flavio

AU - Li, Lian

AU - Lindblom, Annika

AU - Lindström, Sara

AU - Linet, Martha

AU - Lissowska, Jolanta

AU - Lo, Wing Yee

AU - Loibl, Sibylle

AU - Lubiński, Jan

AU - Lux, Michael P.

AU - MacInnis, Robert J.

AU - Maierthaler, Melanie

AU - Maishman, Tom

AU - Makalic, Enes

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Martinez, Maria Elena

AU - Mavroudis, Dimitrios

AU - McLean, Catriona

AU - Meindl, Alfons

AU - Middha, Pooja

AU - Miller, Nicola

AU - Milne, Roger L.

AU - Moreno, Fernando

AU - Mulligan, Anna Marie

AU - Mulot, Claire

AU - Nassir, Rami

AU - Neuhausen, Susan L.

AU - Newman, William T.

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Norman, Aaron

AU - Olsson, Håkan

AU - Orr, Nick

AU - Pankratz, V. Shane

AU - Park-Simon, Tjoung Won

AU - Perez, Jose I.A.

AU - Pérez-Barrios, Clara

AU - Peterlongo, Paolo

AU - Petridis, Christos

AU - Pinchev, Mila

AU - Prajzendanc, Karoliona

AU - Prentice, Ross

AU - Presneau, Nadege

AU - Prokofieva, Darya

AU - Pylkäs, Katri

AU - Rack, Brigitte

AU - Radice, Paolo

AU - Ramachandran, Dhanya

AU - Rennert, Gadi

AU - Rennert, Hedy S.

AU - Rhenius, Valerie

AU - Romero, Atocha

AU - Roylance, Rebecca

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J.

AU - Schmidt, Daniel F.

AU - Schmutzler, Rita K.

AU - Schneeweiss, Andreas

AU - Schoemaker, Minouk J.

AU - Schumacher, Fredrick

AU - Schwentner, Lukas

AU - Scott, Rodney J.

AU - Scott, Christopher

AU - Seynaeve, Caroline

AU - Shah, Mitul

AU - Simard, Jacques

AU - Smeets, Ann

AU - Sohn, Christof

AU - Southey, Melissa C.

AU - Swerdlow, Anthony J.

AU - Talhouk, Aline

AU - Tamimi, Rulla M.

AU - Tapper, William J.

AU - Teixeira, Manuel R.

AU - Tengström, Maria

AU - Terry, Mary Beth

AU - Thöne, Kathrin

AU - Tollenaar, Rob A.E.M.

AU - Tomlinson, Ian

AU - Torres, Diana

AU - Truong, Thérèse

AU - Turman, Constance

AU - Turnbull, Clare

AU - Ulmer, Hans Ulrich

AU - Untch, Michael

AU - Vachon, Celine

AU - van Asperen, Christi J.

AU - van den Ouweland, Ans M.W.

AU - van Veen, Elke M.

AU - Wendt, Camilla

AU - Whittemore, Alice S.

AU - Willett, Walter

AU - Winqvist, Robert

AU - Wolk, Alicja

AU - Yang, Xiaohong R.

AU - Zhang, Yan

AU - Easton, Douglas F.

AU - Fasching, Peter A.

AU - Nevanlinna, Heli

AU - Eccles, Diana M.

AU - Pharoah, Paul D.P.

AU - Schmidt, Marjanka K.

PY - 2019/2/21

Y1 - 2019/2/21

N2 - Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

AB - Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10 −8 . For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10 −7 , hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84–0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10 −7 , HR = 1.27, 95% CI = 1.16–1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

UR - http://www.scopus.com/inward/record.url?scp=85061925826&partnerID=8YFLogxK

U2 - 10.1038/s41416-019-0393-x

DO - 10.1038/s41416-019-0393-x

M3 - Article

VL - 120

SP - 647

EP - 657

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

ER -