Identification of novel genetic markers of breast cancer survival

Qi Guo; Marjanka K. Schmidt; Peter Kraft; Sander Canisius; Constance Chen; Sofia Khan; Jonathan Tyrer; Manjeet K. Bolla; Qin Wang; Joe Dennis; Kyriaki Michailidou; Michael Lush; Siddhartha Kar; Jonathan Beesley; Alison M. Dunning; Mitul Shah; Kamila Czene; Hatef Darabi; Mikael Eriksson; Diether Lambrechts; Caroline Weltens; Karin Leunen; Stig E. Bojesen; Børge G. Nordestgaard; Sune F. Nielsen; Henrik Flyger; Jenny Chang-Claude; Anja Rudolph; Petra Seibold; Dieter Flesch-Janys; Carl Blomqvist; Kristiina Aittomäki; Rainer Fagerholm; Taru A. Muranen; Fergus J. Couch; Janet E. Olson; Celine Vachon; Irene L. Andrulis; Julia A. Knight; Gord Glendon; Anna Marie Mulligan; Annegien Broeks; Frans B. Hogervorst; Christopher A. Haiman; Brian E. Henderson; Fredrick Schumacher; Loic Le Marchand; John L. Hopper; Helen Tsimiklis; Carmel Apicella; Melissa C. Southey; Angela Cox; Simon S. Cross; Malcolm W.R. Reed; Graham G. Giles; Roger L. Milne; Catriona McLean; Robert Winqvist; Katri Pylkäs; Arja Jukkola-Vuorinen; Mervi Grip; Maartje J. Hooning; Antoinette Hollestelle; John W.M. Martens; Ans M.W. Van Den Ouweland; Federik Marme; Andreas Schneeweiss; Rongxi Yang; Barbara Burwinkel; Jonine Figueroa; Stephen J. Chanock; Jolanta Lissowska; Elinor J. Sawyer; Ian Tomlinson; Michael J. Kerin; Nicola Miller; Hermann Brenner; Aida Karina Dieffenbach; Volker Arndt; Bernd Holleczek; Arto Mannermaa; Vesa Kataja; Veli Matti Kosma; Jaana M. Hartikainen; Jingmei Li; Judith S. Brand; Keith Humphreys; Peter Devilee; Rob A.E.M. Tollenaar; Caroline Seynaeve; Paolo Radice; Paolo Peterlongo; Bernardo Bonanni; Paolo Mariani; Peter A. Fasching; Matthias W. Beckmann; Alexander Hein; Arif B. Ekici; Georgia Chenevix-Trench; Rosemary Balleine; Kelly Anne Phillips; Javier Benitez; M. Pilar Zamora; Jose Ignacio Arias Perez; Primitiva Menéndez; Anna Jakubowska; Jan Lubinski; Katarzyna Jaworska-Bieniek; Katarzyna Durda; Ute Hamann; Maria Kabisch; Hans Ulrich Ulmer; Thomas Rüdiger; Sara Margolin; Vessela Kristensen; Silje Nord; D. Gareth Evans; Jean E. Abraham; Helena M. Earl; Louise Hiller; Janet A. Dunn; Sarah Bowden; Christine Berg; Daniele Campa; W. Ryan Diver; Susan M. Gapstur; Mia M. Gaudet; Susan E. Hankinson; Robert N. Hoover; Anika Hüsing; Rudolf Kaaks; Mitchell J. Machiela; Walter Willett; Myrto Barrdahl; Federico Canzian; Suet Feung Chin; Carlos Caldas; David J. Hunter; Sara Lindstrom; Montserrat García-Closas; Per Hall; Douglas F. Easton; Diana M. Eccles; Nazneen Rahman; Heli Nevanlinna; Paul D.P. Pharoah

doi:10.1093/jnci/djv081

Identification of novel genetic markers of breast cancer survival

Qi Guo, Marjanka K. Schmidt, Peter Kraft, Sander Canisius, Constance Chen, Sofia Khan, Jonathan Tyrer, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Michael Lush, Siddhartha Kar, Jonathan Beesley, Alison M. Dunning, Mitul Shah, Kamila Czene, Hatef Darabi, Mikael Eriksson, Diether LambrechtsCaroline Weltens, Karin Leunen, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Jenny Chang-Claude, Anja Rudolph, Petra Seibold, Dieter Flesch-Janys, Carl Blomqvist, Kristiina Aittomäki, Rainer Fagerholm, Taru A. Muranen, Fergus J. Couch, Janet E. Olson, Celine Vachon, Irene L. Andrulis, Julia A. Knight, Gord Glendon, Anna Marie Mulligan, Annegien Broeks, Frans B. Hogervorst, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, John L. Hopper, Helen Tsimiklis, Carmel Apicella, Melissa C. Southey, Angela Cox, Simon S. Cross, Malcolm W.R. Reed, Graham G. Giles, Roger L. Milne, Catriona McLean, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Maartje J. Hooning, Antoinette Hollestelle, John W.M. Martens, Ans M.W. Van Den Ouweland, Federik Marme, Andreas Schneeweiss, Rongxi Yang, Barbara Burwinkel, Jonine Figueroa, Stephen J. Chanock, Jolanta Lissowska, Elinor J. Sawyer, Ian Tomlinson, Michael J. Kerin, Nicola Miller, Hermann Brenner, Aida Karina Dieffenbach, Volker Arndt, Bernd Holleczek, Arto Mannermaa, Vesa Kataja, Veli Matti Kosma, Jaana M. Hartikainen, Jingmei Li, Judith S. Brand, Keith Humphreys, Peter Devilee, Rob A.E.M. Tollenaar, Caroline Seynaeve, Paolo Radice, Paolo Peterlongo, Bernardo Bonanni, Paolo Mariani, Peter A. Fasching, Matthias W. Beckmann, Alexander Hein, Arif B. Ekici, Georgia Chenevix-Trench, Rosemary Balleine, Kelly Anne Phillips, Javier Benitez, M. Pilar Zamora, Jose Ignacio Arias Perez, Primitiva Menéndez, Anna Jakubowska, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Ute Hamann, Maria Kabisch, Hans Ulrich Ulmer, Thomas Rüdiger, Sara Margolin, Vessela Kristensen, Silje Nord, D. Gareth Evans, Jean E. Abraham, Helena M. Earl, Louise Hiller, Janet A. Dunn, Sarah Bowden, Christine Berg, Daniele Campa, W. Ryan Diver, Susan M. Gapstur, Mia M. Gaudet, Susan E. Hankinson, Robert N. Hoover, Anika Hüsing, Rudolf Kaaks, Mitchell J. Machiela, Walter Willett, Myrto Barrdahl, Federico Canzian, Suet Feung Chin, Carlos Caldas, David J. Hunter, Sara Lindstrom, Montserrat García-Closas, Per Hall, Douglas F. Easton, Diana M. Eccles, Nazneen Rahman, Heli Nevanlinna, Paul D.P. Pharoah

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

35 Scopus citations

Abstract

Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10^-8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

Original language	English (US)
Journal	Journal of the National Cancer Institute
Volume	107
Issue number	5
DOIs	https://doi.org/10.1093/jnci/djv081
State	Published - May 1 2015

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1093/jnci/djv081

Cite this

Guo, Q., Schmidt, M. K., Kraft, P., Canisius, S., Chen, C., Khan, S., Tyrer, J., Bolla, M. K., Wang, Q., Dennis, J., Michailidou, K., Lush, M., Kar, S., Beesley, J., Dunning, A. M., Shah, M., Czene, K., Darabi, H., Eriksson, M., ... Pharoah, P. D. P. (2015). Identification of novel genetic markers of breast cancer survival. Journal of the National Cancer Institute, 107(5). https://doi.org/10.1093/jnci/djv081

Guo, Q, Schmidt, MK, Kraft, P, Canisius, S, Chen, C, Khan, S, Tyrer, J, Bolla, MK, Wang, Q, Dennis, J, Michailidou, K, Lush, M, Kar, S, Beesley, J, Dunning, AM, Shah, M, Czene, K, Darabi, H, Eriksson, M, Lambrechts, D, Weltens, C, Leunen, K, Bojesen, SE, Nordestgaard, BG, Nielsen, SF, Flyger, H, Chang-Claude, J, Rudolph, A, Seibold, P, Flesch-Janys, D, Blomqvist, C, Aittomäki, K, Fagerholm, R, Muranen, TA, Couch, FJ , Olson, JE , Vachon, C, Andrulis, IL, Knight, JA, Glendon, G, Mulligan, AM, Broeks, A, Hogervorst, FB, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Hopper, JL, Tsimiklis, H, Apicella, C, Southey, MC, Cox, A, Cross, SS, Reed, MWR, Giles, GG, Milne, RL, McLean, C, Winqvist, R, Pylkäs, K, Jukkola-Vuorinen, A, Grip, M, Hooning, MJ, Hollestelle, A, Martens, JWM, Van Den Ouweland, AMW, Marme, F, Schneeweiss, A, Yang, R, Burwinkel, B, Figueroa, J, Chanock, SJ, Lissowska, J, Sawyer, EJ, Tomlinson, I, Kerin, MJ, Miller, N, Brenner, H, Dieffenbach, AK, Arndt, V, Holleczek, B, Mannermaa, A, Kataja, V, Kosma, VM, Hartikainen, JM, Li, J, Brand, JS, Humphreys, K, Devilee, P, Tollenaar, RAEM, Seynaeve, C, Radice, P, Peterlongo, P, Bonanni, B, Mariani, P, Fasching, PA, Beckmann, MW, Hein, A, Ekici, AB, Chenevix-Trench, G, Balleine, R, Phillips, KA, Benitez, J, Zamora, MP, Arias Perez, JI, Menéndez, P, Jakubowska, A, Lubinski, J, Jaworska-Bieniek, K, Durda, K, Hamann, U, Kabisch, M, Ulmer, HU, Rüdiger, T, Margolin, S, Kristensen, V, Nord, S, Evans, DG, Abraham, JE, Earl, HM, Hiller, L, Dunn, JA, Bowden, S, Berg, C, Campa, D, Diver, WR, Gapstur, SM, Gaudet, MM, Hankinson, SE, Hoover, RN, Hüsing, A, Kaaks, R, Machiela, MJ, Willett, W, Barrdahl, M, Canzian, F, Chin, SF, Caldas, C, Hunter, DJ, Lindstrom, S, García-Closas, M, Hall, P, Easton, DF, Eccles, DM, Rahman, N, Nevanlinna, H & Pharoah, PDP 2015, 'Identification of novel genetic markers of breast cancer survival', Journal of the National Cancer Institute, vol. 107, no. 5. https://doi.org/10.1093/jnci/djv081

@article{df47489620cb479d9861148cc95bdef5,

title = "Identification of novel genetic markers of breast cancer survival",

abstract = "Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10-8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.",

author = "Qi Guo and Schmidt, {Marjanka K.} and Peter Kraft and Sander Canisius and Constance Chen and Sofia Khan and Jonathan Tyrer and Bolla, {Manjeet K.} and Qin Wang and Joe Dennis and Kyriaki Michailidou and Michael Lush and Siddhartha Kar and Jonathan Beesley and Dunning, {Alison M.} and Mitul Shah and Kamila Czene and Hatef Darabi and Mikael Eriksson and Diether Lambrechts and Caroline Weltens and Karin Leunen and Bojesen, {Stig E.} and Nordestgaard, {B{\o}rge G.} and Nielsen, {Sune F.} and Henrik Flyger and Jenny Chang-Claude and Anja Rudolph and Petra Seibold and Dieter Flesch-Janys and Carl Blomqvist and Kristiina Aittom{\"a}ki and Rainer Fagerholm and Muranen, {Taru A.} and Couch, {Fergus J.} and Olson, {Janet E.} and Celine Vachon and Andrulis, {Irene L.} and Knight, {Julia A.} and Gord Glendon and Mulligan, {Anna Marie} and Annegien Broeks and Hogervorst, {Frans B.} and Haiman, {Christopher A.} and Henderson, {Brian E.} and Fredrick Schumacher and {Le Marchand}, Loic and Hopper, {John L.} and Helen Tsimiklis and Carmel Apicella and Southey, {Melissa C.} and Angela Cox and Cross, {Simon S.} and Reed, {Malcolm W.R.} and Giles, {Graham G.} and Milne, {Roger L.} and Catriona McLean and Robert Winqvist and Katri Pylk{\"a}s and Arja Jukkola-Vuorinen and Mervi Grip and Hooning, {Maartje J.} and Antoinette Hollestelle and Martens, {John W.M.} and {Van Den Ouweland}, {Ans M.W.} and Federik Marme and Andreas Schneeweiss and Rongxi Yang and Barbara Burwinkel and Jonine Figueroa and Chanock, {Stephen J.} and Jolanta Lissowska and Sawyer, {Elinor J.} and Ian Tomlinson and Kerin, {Michael J.} and Nicola Miller and Hermann Brenner and Dieffenbach, {Aida Karina} and Volker Arndt and Bernd Holleczek and Arto Mannermaa and Vesa Kataja and Kosma, {Veli Matti} and Hartikainen, {Jaana M.} and Jingmei Li and Brand, {Judith S.} and Keith Humphreys and Peter Devilee and Tollenaar, {Rob A.E.M.} and Caroline Seynaeve and Paolo Radice and Paolo Peterlongo and Bernardo Bonanni and Paolo Mariani and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Alexander Hein and Ekici, {Arif B.} and Georgia Chenevix-Trench and Rosemary Balleine and Phillips, {Kelly Anne} and Javier Benitez and Zamora, {M. Pilar} and {Arias Perez}, {Jose Ignacio} and Primitiva Men{\'e}ndez and Anna Jakubowska and Jan Lubinski and Katarzyna Jaworska-Bieniek and Katarzyna Durda and Ute Hamann and Maria Kabisch and Ulmer, {Hans Ulrich} and Thomas R{\"u}diger and Sara Margolin and Vessela Kristensen and Silje Nord and Evans, {D. Gareth} and Abraham, {Jean E.} and Earl, {Helena M.} and Louise Hiller and Dunn, {Janet A.} and Sarah Bowden and Christine Berg and Daniele Campa and Diver, {W. Ryan} and Gapstur, {Susan M.} and Gaudet, {Mia M.} and Hankinson, {Susan E.} and Hoover, {Robert N.} and Anika H{\"u}sing and Rudolf Kaaks and Machiela, {Mitchell J.} and Walter Willett and Myrto Barrdahl and Federico Canzian and Chin, {Suet Feung} and Carlos Caldas and Hunter, {David J.} and Sara Lindstrom and Montserrat Garc{\'i}a-Closas and Per Hall and Easton, {Douglas F.} and Eccles, {Diana M.} and Nazneen Rahman and Heli Nevanlinna and Pharoah, {Paul D.P.}",

note = "Publisher Copyright: {\textcopyright} 2015 {\textcopyright} The Author 2015. Published by Oxford University Press.",

year = "2015",

month = may,

day = "1",

doi = "10.1093/jnci/djv081",

language = "English (US)",

volume = "107",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "5",

}

TY - JOUR

T1 - Identification of novel genetic markers of breast cancer survival

AU - Guo, Qi

AU - Schmidt, Marjanka K.

AU - Kraft, Peter

AU - Canisius, Sander

AU - Chen, Constance

AU - Khan, Sofia

AU - Tyrer, Jonathan

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Dennis, Joe

AU - Michailidou, Kyriaki

AU - Lush, Michael

AU - Kar, Siddhartha

AU - Beesley, Jonathan

AU - Dunning, Alison M.

AU - Shah, Mitul

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Lambrechts, Diether

AU - Weltens, Caroline

AU - Leunen, Karin

AU - Bojesen, Stig E.

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Seibold, Petra

AU - Flesch-Janys, Dieter

AU - Blomqvist, Carl

AU - Aittomäki, Kristiina

AU - Fagerholm, Rainer

AU - Muranen, Taru A.

AU - Couch, Fergus J.

AU - Olson, Janet E.

AU - Vachon, Celine

AU - Andrulis, Irene L.

AU - Knight, Julia A.

AU - Glendon, Gord

AU - Mulligan, Anna Marie

AU - Broeks, Annegien

AU - Hogervorst, Frans B.

AU - Haiman, Christopher A.

AU - Henderson, Brian E.

AU - Schumacher, Fredrick

AU - Le Marchand, Loic

AU - Hopper, John L.

AU - Tsimiklis, Helen

AU - Apicella, Carmel

AU - Southey, Melissa C.

AU - Cox, Angela

AU - Cross, Simon S.

AU - Reed, Malcolm W.R.

AU - Giles, Graham G.

AU - Milne, Roger L.

AU - McLean, Catriona

AU - Winqvist, Robert

AU - Pylkäs, Katri

AU - Jukkola-Vuorinen, Arja

AU - Grip, Mervi

AU - Hooning, Maartje J.

AU - Hollestelle, Antoinette

AU - Martens, John W.M.

AU - Van Den Ouweland, Ans M.W.

AU - Marme, Federik

AU - Schneeweiss, Andreas

AU - Yang, Rongxi

AU - Burwinkel, Barbara

AU - Figueroa, Jonine

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Sawyer, Elinor J.

AU - Tomlinson, Ian

AU - Kerin, Michael J.

AU - Miller, Nicola

AU - Brenner, Hermann

AU - Dieffenbach, Aida Karina

AU - Arndt, Volker

AU - Holleczek, Bernd

AU - Mannermaa, Arto

AU - Kataja, Vesa

AU - Kosma, Veli Matti

AU - Hartikainen, Jaana M.

AU - Li, Jingmei

AU - Brand, Judith S.

AU - Humphreys, Keith

AU - Devilee, Peter

AU - Tollenaar, Rob A.E.M.

AU - Seynaeve, Caroline

AU - Radice, Paolo

AU - Peterlongo, Paolo

AU - Bonanni, Bernardo

AU - Mariani, Paolo

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Hein, Alexander

AU - Ekici, Arif B.

AU - Chenevix-Trench, Georgia

AU - Balleine, Rosemary

AU - Phillips, Kelly Anne

AU - Benitez, Javier

AU - Zamora, M. Pilar

AU - Arias Perez, Jose Ignacio

AU - Menéndez, Primitiva

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Hamann, Ute

AU - Kabisch, Maria

AU - Ulmer, Hans Ulrich

AU - Rüdiger, Thomas

AU - Margolin, Sara

AU - Kristensen, Vessela

AU - Nord, Silje

AU - Evans, D. Gareth

AU - Abraham, Jean E.

AU - Earl, Helena M.

AU - Hiller, Louise

AU - Dunn, Janet A.

AU - Bowden, Sarah

AU - Berg, Christine

AU - Campa, Daniele

AU - Diver, W. Ryan

AU - Gapstur, Susan M.

AU - Gaudet, Mia M.

AU - Hankinson, Susan E.

AU - Hoover, Robert N.

AU - Hüsing, Anika

AU - Kaaks, Rudolf

AU - Machiela, Mitchell J.

AU - Willett, Walter

AU - Barrdahl, Myrto

AU - Canzian, Federico

AU - Chin, Suet Feung

AU - Caldas, Carlos

AU - Hunter, David J.

AU - Lindstrom, Sara

AU - García-Closas, Montserrat

AU - Hall, Per

AU - Easton, Douglas F.

AU - Eccles, Diana M.

AU - Rahman, Nazneen

AU - Nevanlinna, Heli

AU - Pharoah, Paul D.P.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10-8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

AB - Background: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. Methods: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. Results: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10-8). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. Conclusions: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

UR - http://www.scopus.com/inward/record.url?scp=84930015982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84930015982&partnerID=8YFLogxK

U2 - 10.1093/jnci/djv081

DO - 10.1093/jnci/djv081

M3 - Article

C2 - 25890600

AN - SCOPUS:84930015982

SN - 0027-8874

VL - 107

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 5

ER -

Identification of novel genetic markers of breast cancer survival

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