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

Anna Morra; Maria Escala-garcia; Jonathan Beesley; Renske Keeman; Sander Canisius; Thomas U. Ahearn; Irene L. Andrulis; Hoda Anton-culver; Volker Arndt; Paul L. Auer; Annelie Augustinsson; Laura E. Beane Freeman; Heiko Becher; Matthias W. Beckmann; Sabine Behrens; Stig E. Bojesen; Manjeet K. Bolla; Hermann Brenner; Thomas Brüning; Saundra S. Buys; Bette Caan; Daniele Campa; Federico Canzian; Jose E. Castelao; Jenny Chang-claude; Stephen J. Chanock; Ting-yuan David Cheng; Christine L. Clarke; Anne-lise Børresen-dale; Kristine K. Sahlberg; Lars Ottestad; Rolf Kåresen; Ellen Schlichting; Marit Muri Holmen; Toril Sauer; Vilde Haakensen; Olav Engebråten; Bjørn Naume; Alexander Fosså; Cecile E. Kiserud; Kristin V. Reinertsen; Åslaug Helland; Margit Riis; Jürgen Geisler; Grethe I. Grenaker Alnæs; Sarah V. Colonna; Fergus J. Couch; Angela Cox; Simon S. Cross; Kamila Czene; Mary B. Daly; Joe Dennis; Thilo Dörk; Laure Dossus; Alison M. Dunning; Miriam Dwek; Diana M. Eccles; Arif B. Ekici; A. Heather Eliassen; Mikael Eriksson; D. Gareth Evans; Peter A. Fasching; Henrik Flyger; Lin Fritschi; Manuela Gago-dominguez; José A. García-sáenz; Graham G. Giles; Mervi Grip; Pascal Guénel; Melanie Gündert; Eric Hahnen; Christopher A. Haiman; Niclas Håkansson; Per Hall; Ute Hamann; Steven N. Hart; Jaana M. Hartikainen; Arndt Hartmann; Wei He; Maartje J. Hooning; Reiner Hoppe; John L. Hopper; Anthony Howell; David J. Hunter; Christine Clarke; Deborah Marsh; Rodney Scott; Robert Baxter; Desmond Yip; Jane Carpenter; Alison Davis; Nirmala Pathmanathan; Peter Simpson; J. Dinny Graham; Mythily Sachchithananthan; Agnes Jager; Anna Jakubowska; Wolfgang Janni; Esther M. John; Audrey Y. Jung; Rudolf Kaaks; Machteld Keupers; Cari M. Kitahara; Stella Koutros; Peter Kraft; Vessela N. Kristensen; Allison W. Kurian; James V. Lacey; Diether Lambrechts; Loic Le Marchand; Annika Lindblom; Martha Linet; Robert N. Luben; Jan Lubiński; Michael Lush; Arto Mannermaa; Mehdi Manoochehri; Sara Margolin; John W. M. Martens; Maria Elena Martinez; Dimitrios Mavroudis; Kyriaki Michailidou; Roger L. Milne; Anna Marie Mulligan; Taru A. Muranen; Heli Nevanlinna; William G. Newman; Sune F. Nielsen; Børge G. Nordestgaard; Andrew F. Olshan; Håkan Olsson; Nick Orr; Tjoung-won Park-simon; Alpa V. Patel; Bernard Peissel; Paolo Peterlongo; Dijana Plaseska-karanfilska; Karolina Prajzendanc; Ross Prentice; Nadege Presneau; Brigitte Rack; Gad Rennert; Hedy S. Rennert; Valerie Rhenius; Atocha Romero; Rebecca Roylance; Matthias Ruebner; Emmanouil Saloustros; Elinor J. Sawyer; Rita K. Schmutzler; Andreas Schneeweiss; Christopher Scott; Mitul Shah; Snezhana Smichkoska; Melissa C. Southey; Jennifer Stone; Harald Surowy; Anthony J. Swerdlow; Rulla M. Tamimi; William J. Tapper; Lauren R. Teras; Mary Beth Terry; Rob A. E. M. Tollenaar; Ian Tomlinson; Melissa A. Troester; Thérèse Truong; Celine M. Vachon; Qin Wang; Amber N. Hurson; Robert Winqvist; Alicja Wolk; Argyrios Ziogas; Hiltrud Brauch; Montserrat García-closas; Paul D. P. Pharoah; Douglas F. Easton; Georgia Chenevix-trench; Marjanka K. Schmidt

doi:10.1186/s13058-021-01450-7

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

Anna Morra, Maria Escala-garcia, Jonathan Beesley, Renske Keeman, Sander Canisius, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Thomas Brüning, Saundra S. BuysBette Caan, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang-claude, Stephen J. Chanock, Ting-yuan David Cheng, Christine L. Clarke, Anne-lise Børresen-dale, Kristine K. Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Olav Engebråten, Bjørn Naume, Alexander Fosså, Cecile E. Kiserud, Kristin V. Reinertsen, Åslaug Helland, Margit Riis, Jürgen Geisler, Grethe I. Grenaker Alnæs, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Thilo Dörk, Laure Dossus, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Lin Fritschi, Manuela Gago-dominguez, José A. García-sáenz, Graham G. Giles, Mervi Grip, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Jaana M. Hartikainen, Arndt Hartmann, Wei He, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, Christine Clarke, Deborah Marsh, Rodney Scott, Robert Baxter, Desmond Yip, Jane Carpenter, Alison Davis, Nirmala Pathmanathan, Peter Simpson, J. Dinny Graham, Mythily Sachchithananthan, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Machteld Keupers, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Martha Linet, Robert N. Luben, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Andrew F. Olshan, Håkan Olsson, Nick Orr, Tjoung-won Park-simon, Alpa V. Patel, Bernard Peissel, Paolo Peterlongo, Dijana Plaseska-karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Brigitte Rack, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiss, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Lauren R. Teras, Mary Beth Terry, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Amber N. Hurson, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, Hiltrud Brauch, Montserrat García-closas, Paul D. P. Pharoah, Douglas F. Easton, Georgia Chenevix-trench, Marjanka K. Schmidt

Research output: Contribution to journal › Article › peer-review

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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).ResultsEvidence 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.ConclusionsWe 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 cancer-specific survival might be limited.

Original language	English
Journal	Breast Cancer Research
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13058-021-01450-7
Publication status	Published - 18 Aug 2021

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Morra, A., Escala-garcia, M., Beesley, J., Keeman, R., Canisius, S., Ahearn, T. U., Andrulis, I. L., Anton-culver, H., Arndt, V., Auer, P. L., Augustinsson, A., Beane Freeman, L. E., Becher, H., Beckmann, M. W., Behrens, S., Bojesen, S. E., Bolla, M. K., Brenner, H., Brüning, T., ... Schmidt, M. K. (2021). 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. Breast Cancer Research, 23(1). https://doi.org/10.1186/s13058-021-01450-7

@article{48ba40ccf2464157aea1b4a1a56f8a27,

title = "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",

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).ResultsEvidence 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.ConclusionsWe 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 cancer-specific survival might be limited.",

author = "Anna Morra and Maria Escala-garcia and Jonathan Beesley and Renske Keeman and Sander Canisius and Ahearn, {Thomas U.} and Andrulis, {Irene L.} and Hoda Anton-culver and Volker Arndt and Auer, {Paul L.} and Annelie Augustinsson and {Beane Freeman}, {Laura E.} and Heiko Becher and Beckmann, {Matthias W.} and Sabine Behrens and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Hermann Brenner and Thomas Br{\"u}ning and Buys, {Saundra S.} and Bette Caan and Daniele Campa and Federico Canzian and Castelao, {Jose E.} and Jenny Chang-claude and Chanock, {Stephen J.} and Cheng, {Ting-yuan David} and Clarke, {Christine L.} and Anne-lise B{\o}rresen-dale and Sahlberg, {Kristine K.} and Lars Ottestad and Rolf K{\aa}resen and Ellen Schlichting and Holmen, {Marit Muri} and Toril Sauer and Vilde Haakensen and Olav Engebr{\aa}ten and Bj{\o}rn Naume and Alexander Foss{\aa} and Kiserud, {Cecile E.} and Reinertsen, {Kristin V.} and {\AA}slaug Helland and Margit Riis and J{\"u}rgen Geisler and {Grenaker Aln{\ae}s}, {Grethe I.} and Colonna, {Sarah V.} and Couch, {Fergus J.} and Angela Cox and Cross, {Simon S.} and Kamila Czene and Daly, {Mary B.} and Joe Dennis and Thilo D{\"o}rk and Laure Dossus and Dunning, {Alison M.} and Miriam Dwek and Eccles, {Diana M.} and Ekici, {Arif B.} and Eliassen, {A. Heather} and Mikael Eriksson and Evans, {D. Gareth} and Fasching, {Peter A.} and Henrik Flyger and Lin Fritschi and Manuela Gago-dominguez and Garc{\'i}a-s{\'a}enz, {Jos{\'e} A.} and Giles, {Graham G.} and Mervi Grip and Pascal Gu{\'e}nel and Melanie G{\"u}ndert and Eric Hahnen and Haiman, {Christopher A.} and Niclas H{\aa}kansson and Per Hall and Ute Hamann and Hart, {Steven N.} and Hartikainen, {Jaana M.} and Arndt Hartmann and Wei He and Hooning, {Maartje J.} and Reiner Hoppe and Hopper, {John L.} and Anthony Howell and Hunter, {David J.} and Christine Clarke and Deborah Marsh and Rodney Scott and Robert Baxter and Desmond Yip and Jane Carpenter and Alison Davis and Nirmala Pathmanathan and Peter Simpson and Graham, {J. Dinny} and Mythily Sachchithananthan and Agnes Jager and Anna Jakubowska and Wolfgang Janni and John, {Esther M.} and Jung, {Audrey Y.} and Rudolf Kaaks and Machteld Keupers and Kitahara, {Cari M.} and Stella Koutros and Peter Kraft and Kristensen, {Vessela N.} and Kurian, {Allison W.} and Lacey, {James V.} and Diether Lambrechts and {Le Marchand}, Loic and Annika Lindblom and Martha Linet and Luben, {Robert N.} and Jan Lubi{\'n}ski and Michael Lush and Arto Mannermaa and Mehdi Manoochehri and Sara Margolin and Martens, {John W. M.} and Martinez, {Maria Elena} and Dimitrios Mavroudis and Kyriaki Michailidou and Milne, {Roger L.} and Mulligan, {Anna Marie} and Muranen, {Taru A.} and Heli Nevanlinna and Newman, {William G.} and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Olshan, {Andrew F.} and H{\aa}kan Olsson and Nick Orr and Tjoung-won Park-simon and Patel, {Alpa V.} and Bernard Peissel and Paolo Peterlongo and Dijana Plaseska-karanfilska and Karolina Prajzendanc and Ross Prentice and Nadege Presneau and Brigitte Rack and Gad Rennert and Rennert, {Hedy S.} and Valerie Rhenius and Atocha Romero and Rebecca Roylance and Matthias Ruebner and Emmanouil Saloustros and Sawyer, {Elinor J.} and Schmutzler, {Rita K.} and Andreas Schneeweiss and Christopher Scott and Mitul Shah and Snezhana Smichkoska and Southey, {Melissa C.} and Jennifer Stone and Harald Surowy and Swerdlow, {Anthony J.} and Tamimi, {Rulla M.} and Tapper, {William J.} and Teras, {Lauren R.} and Terry, {Mary Beth} and Tollenaar, {Rob A. E. M.} and Ian Tomlinson and Troester, {Melissa A.} and Th{\'e}r{\`e}se Truong and Vachon, {Celine M.} and Qin Wang and Hurson, {Amber N.} and Robert Winqvist and Alicja Wolk and Argyrios Ziogas and Hiltrud Brauch and Montserrat Garc{\'i}a-closas and Pharoah, {Paul D. P.} and Easton, {Douglas F.} and Georgia Chenevix-trench and Schmidt, {Marjanka K.}",

year = "2021",

month = aug,

day = "18",

doi = "10.1186/s13058-021-01450-7",

language = "English",

volume = "23",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "Springer Nature",

number = "1",

}

Morra, A, Escala-garcia, M, Beesley, J, Keeman, R, Canisius, S, Ahearn, TU, Andrulis, IL, Anton-culver, H, Arndt, V, Auer, PL, Augustinsson, A, Beane Freeman, LE, Becher, H, Beckmann, MW, Behrens, S, Bojesen, SE, Bolla, MK, Brenner, H, Brüning, T, Buys, SS, Caan, B, Campa, D, Canzian, F, Castelao, JE, Chang-claude, J, Chanock, SJ, Cheng, TD, Clarke, CL, Børresen-dale, A, 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, Grenaker Alnæs, GI, Colonna, SV, Couch, FJ, Cox, A, Cross, SS, Czene, K, Daly, MB, Dennis, J, Dörk, 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, García-sáenz, JA, Giles, GG, Grip, M, Guénel, P, Gündert, M, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Hart, SN, Hartikainen, JM, Hartmann, A, He, W, Hooning, MJ, Hoppe, R, Hopper, JL, Howell, A, Hunter, DJ, Clarke, C, Marsh, D, Scott, R, Baxter, R, Yip, D, Carpenter, J, Davis, A, Pathmanathan, N, Simpson, P, Graham, JD, Sachchithananthan, M, 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, JV, Lambrechts, D, Le Marchand, L, Lindblom, A, Linet, M, Luben, RN, Lubiński, J, 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, Patel, AV, 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, 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, García-closas, M, Pharoah, PDP, Easton, DF, Chenevix-trench, G & Schmidt, MK 2021, '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', Breast Cancer Research, vol. 23, no. 1. https://doi.org/10.1186/s13058-021-01450-7

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. / Morra, Anna; Escala-garcia, Maria; Beesley, Jonathan et al.
In: Breast Cancer Research, Vol. 23, No. 1, 18.08.2021.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - 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

AU - Morra, Anna

AU - Escala-garcia, Maria

AU - Beesley, Jonathan

AU - Keeman, Renske

AU - Canisius, Sander

AU - Ahearn, Thomas U.

AU - Andrulis, Irene L.

AU - Anton-culver, Hoda

AU - Arndt, Volker

AU - Auer, Paul L.

AU - Augustinsson, Annelie

AU - Beane Freeman, Laura E.

AU - Becher, Heiko

AU - Beckmann, Matthias W.

AU - Behrens, Sabine

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Buys, Saundra S.

AU - Caan, Bette

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E.

AU - Chang-claude, Jenny

AU - Chanock, Stephen J.

AU - Cheng, Ting-yuan David

AU - Clarke, Christine L.

AU - Børresen-dale, Anne-lise

AU - Sahlberg, Kristine K.

AU - Ottestad, Lars

AU - Kåresen, Rolf

AU - Schlichting, Ellen

AU - Holmen, Marit Muri

AU - Sauer, Toril

AU - Haakensen, Vilde

AU - Engebråten, Olav

AU - Naume, Bjørn

AU - Fosså, Alexander

AU - Kiserud, Cecile E.

AU - Reinertsen, Kristin V.

AU - Helland, Åslaug

AU - Riis, Margit

AU - Geisler, Jürgen

AU - Grenaker Alnæs, Grethe I.

AU - Colonna, Sarah V.

AU - Couch, Fergus J.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Czene, Kamila

AU - Daly, Mary B.

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dossus, Laure

AU - Dunning, Alison M.

AU - Dwek, Miriam

AU - Eccles, Diana M.

AU - Ekici, Arif B.

AU - Eliassen, A. Heather

AU - Eriksson, Mikael

AU - Evans, D. Gareth

AU - Fasching, Peter A.

AU - Flyger, Henrik

AU - Fritschi, Lin

AU - Gago-dominguez, Manuela

AU - García-sáenz, José A.

AU - Giles, Graham G.

AU - Grip, Mervi

AU - Guénel, Pascal

AU - Gündert, Melanie

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Hart, Steven N.

AU - Hartikainen, Jaana M.

AU - Hartmann, Arndt

AU - He, Wei

AU - Hooning, Maartje J.

AU - Hoppe, Reiner

AU - Hopper, John L.

AU - Howell, Anthony

AU - Hunter, David J.

AU - Clarke, Christine

AU - Marsh, Deborah

AU - Scott, Rodney

AU - Baxter, Robert

AU - Yip, Desmond

AU - Carpenter, Jane

AU - Davis, Alison

AU - Pathmanathan, Nirmala

AU - Simpson, Peter

AU - Graham, J. Dinny

AU - Sachchithananthan, Mythily

AU - Jager, Agnes

AU - Jakubowska, Anna

AU - Janni, Wolfgang

AU - John, Esther M.

AU - Jung, Audrey Y.

AU - Kaaks, Rudolf

AU - Keupers, Machteld

AU - Kitahara, Cari M.

AU - Koutros, Stella

AU - Kraft, Peter

AU - Kristensen, Vessela N.

AU - Kurian, Allison W.

AU - Lacey, James V.

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Lindblom, Annika

AU - Linet, Martha

AU - Luben, Robert N.

AU - Lubiński, Jan

AU - Lush, Michael

AU - Mannermaa, Arto

AU - Manoochehri, Mehdi

AU - Margolin, Sara

AU - Martens, John W. M.

AU - Martinez, Maria Elena

AU - Mavroudis, Dimitrios

AU - Michailidou, Kyriaki

AU - Milne, Roger L.

AU - Mulligan, Anna Marie

AU - Muranen, Taru A.

AU - Nevanlinna, Heli

AU - Newman, William G.

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Olshan, Andrew F.

AU - Olsson, Håkan

AU - Orr, Nick

AU - Park-simon, Tjoung-won

AU - Patel, Alpa V.

AU - Peissel, Bernard

AU - Peterlongo, Paolo

AU - Plaseska-karanfilska, Dijana

AU - Prajzendanc, Karolina

AU - Prentice, Ross

AU - Presneau, Nadege

AU - Rack, Brigitte

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Rhenius, Valerie

AU - Romero, Atocha

AU - Roylance, Rebecca

AU - Ruebner, Matthias

AU - Saloustros, Emmanouil

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K.

AU - Schneeweiss, Andreas

AU - Scott, Christopher

AU - Shah, Mitul

AU - Smichkoska, Snezhana

AU - Southey, Melissa C.

AU - Stone, Jennifer

AU - Surowy, Harald

AU - Swerdlow, Anthony J.

AU - Tamimi, Rulla M.

AU - Tapper, William J.

AU - Teras, Lauren R.

AU - Terry, Mary Beth

AU - Tollenaar, Rob A. E. M.

AU - Tomlinson, Ian

AU - Troester, Melissa A.

AU - Truong, Thérèse

AU - Vachon, Celine M.

AU - Wang, Qin

AU - Hurson, Amber N.

AU - Winqvist, Robert

AU - Wolk, Alicja

AU - Ziogas, Argyrios

AU - Brauch, Hiltrud

AU - García-closas, Montserrat

AU - Pharoah, Paul D. P.

AU - Easton, Douglas F.

AU - Chenevix-trench, Georgia

AU - Schmidt, Marjanka K.

PY - 2021/8/18

Y1 - 2021/8/18

N2 - 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).ResultsEvidence 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.ConclusionsWe 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 cancer-specific survival might be limited.

AB - 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).ResultsEvidence 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.ConclusionsWe 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 cancer-specific survival might be limited.

U2 - 10.1186/s13058-021-01450-7

DO - 10.1186/s13058-021-01450-7

M3 - Article

SN - 1465-5411

VL - 23

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

ER -

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

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