Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Arif B. Ekici; Arndt Hartmann; Matthias W. Beckmann; Jaana M. Hartikainen; Veli-Matti Kosma; Vesa Kataja; Arja Jukkola-Vuorinen; Katri Pylkäs; Saila Kauppila; Aida Karina Dieffenbach; Christa Stegmaier; Volker Arndt; Sara Margolin; Jose Ignacio Arias Perez; M. Pilar Zamora; Alan Ashworth; Michael Jones; Nick Orr; Patrick Arveux; Pierre Kerbrat; Thérèse Truong; Peter Bugert; Amanda E. Toland; Christine B. Ambrosone; France Labrèche; Mark S. Goldberg; Martine Dumont; Argyrios Ziogas; Gillian S. Dite; Carmel Apicella; Melissa C. Southey; Jirong Long; Martha Shrubsole; Sandra Deming-Halverson; Filomena Ficarazzi; Monica Barile; Paolo Peterlongo; Katarzyna Durda; Katarzyna Jaworska-Bieniek; Robert A. E. M. Tollenaar; Caroline Seynaeve; Thomas Brüning; Yon-Dschun Ko; Carolien H.M. Van Deurzen; John W. M. Martens; Mieke Kriege; Jonine D. Figueroa; Stephen J. Chanock; Jolanta Lissowska; Ian Tomlinson; Andreas Schneeweiss; William J. Tapper; Susan M. Gerty; Lorraine Durcan; Catriona McLean; Roger L. Milne; Laura Baglietto; Isabel Dos Santos Silva; Olivia Fletcher; Nichola Johnson; Laura J. Van'T Veer; Sten Cornelissen; Asta Försti; Diana Torres; Thomas Rüdiger; Anja Rudolph; Dieter Flesch-Janys; Stefan Nickels; Caroline Weltens; Giuseppe Floris; Matthieu Moisse; Joe Dennis; Qin Wang; Alison M. Dunning; Mitul Shah; Judith Brown; Jacques Simard; Hoda Anton-Culver; Susan L. Neuhausen; John L. Hopper; Natalia Bogdanova; Thilo Dörk; Wei Zheng; Paolo Radice; Anna Jakubowska; Jan Lubinski; Peter Devillee; Hiltrud Brauch; Maartje Hooning; Montserrat García-Closas; Elinor Sawyer; Barbara Burwinkel; Frederick Marmee; Diana M. Eccles; Graham G. Giles; Julian Peto; Marjanka Schmidt; Annegien Broeks; Ute Hamann; Jenny Chang-Claude; Diether Lambrechts; Paul D.P. Pharoah; Douglas Easton; V. Shane Pankratz; Susan Slager; Celine M. Vachon; Fergus J. Couch

doi:10.13025/29046

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Arif B. Ekici
, Arndt Hartmann
, Matthias W. Beckmann
, Jaana M. Hartikainen
, Veli-Matti Kosma
, Vesa Kataja
, Arja Jukkola-Vuorinen
, Katri Pylkäs
, Saila Kauppila
, Aida Karina Dieffenbach
, Christa Stegmaier
, Volker Arndt
, Sara Margolin
, Jose Ignacio Arias Perez
, M. Pilar Zamora
, Alan Ashworth
, Michael Jones
, Nick Orr
, Patrick Arveux
, Pierre Kerbrat

Thérèse Truong, Peter Bugert, Amanda E. Toland, Christine B. Ambrosone, France Labrèche, Mark S. Goldberg, Martine Dumont, Argyrios Ziogas, Gillian S. Dite, Carmel Apicella, Melissa C. Southey, Jirong Long, Martha Shrubsole, Sandra Deming-Halverson, Filomena Ficarazzi, Monica Barile, Paolo Peterlongo, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Robert A. E. M. Tollenaar, Caroline Seynaeve, Thomas Brüning, Yon-Dschun Ko, Carolien H.M. Van Deurzen, John W. M. Martens, Mieke Kriege, Jonine D. Figueroa, Stephen J. Chanock, Jolanta Lissowska, Ian Tomlinson, Andreas Schneeweiss, William J. Tapper, Susan M. Gerty, Lorraine Durcan, Catriona McLean, Roger L. Milne, Laura Baglietto, Isabel Dos Santos Silva, Olivia Fletcher, Nichola Johnson, Laura J. Van'T Veer, Sten Cornelissen, Asta Försti, Diana Torres, Thomas Rüdiger, Anja Rudolph, Dieter Flesch-Janys, Stefan Nickels, Caroline Weltens, Giuseppe Floris, Matthieu Moisse, Joe Dennis, Qin Wang, Alison M. Dunning, Mitul Shah, Judith Brown, Jacques Simard, Hoda Anton-Culver, Susan L. Neuhausen, John L. Hopper, Natalia Bogdanova, Thilo Dörk, Wei Zheng, Paolo Radice, Anna Jakubowska, Jan Lubinski, Peter Devillee, Hiltrud Brauch, Maartje Hooning, Montserrat García-Closas, Elinor Sawyer, Barbara Burwinkel, Frederick Marmee, Diana M. Eccles, Graham G. Giles, Julian Peto, Marjanka Schmidt, Annegien Broeks, Ute Hamann, Jenny Chang-Claude, Diether Lambrechts, Paul D.P. Pharoah, Douglas Easton, V. Shane Pankratz, Susan Slager, Celine M. Vachon, Fergus J. Couch

Institute of Pathology
Medical Faculty of the University of Bonn
Institute for Occupational Medicine and Maritime Medicine
University Medical Center Hamburg-Eppendorf
University of Tübingen
Westmead Millennium Institute
Peter MacCallum Cancer Institute
Molecular Genetics of Breast Cancer
German Cancer Research Center
Ruhr-Universität Bochum
Department of Internal Medicine
Johanniter Krankenhaus
Mayo Clinic
Wayne State University School of Medicine
Centre for Cancer Genetic Epidemiology
Department of Medical Epidemiology and Biostatistics
University of Helsinki
Gentofte University Hospital
Mount Sinai Hospital, Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute
University of Toronto
University of Sheffield
University of Heidelberg
University of California, Irvine
Institute of Biosciences and Applications
Keck School of Medicine of USC
University Hospital Erlangen
McGill University
University of Eastern Finland
Imaging Center
University of Oulu
Division of Clinical Epidemiology and Aging Research
Department of Molecular Medicine and Surgery
QIMR Berghofer Medical Research Institute
Cell Division and Cancer Group
CIBERER Spanish Network for Rare Diseases
Divisions of Molecular Pathology and Cancer Therapeutics
Faculty of Medicine
University of Oslo
National Institutes of Health (NIH)
Hormones and Women's Health Team
Technical University Munich
University of Toronto Faculty of Medicine
University Health Network
Prosserman Centre for Health Research
University of Toronto/Lunenfeld-Tanenbaum Research Institute
A*STAR
Hunter Area Pathology Service
La Paz University Hospital
Aristotle University of Thessaloniki
The University of Hawaii Cancer Center
Galway University Hospital
Kuopio University Hospital
University Hospital of Oulu
Saarland Cancer Registry
Karolinska Institutet
National Breast Cancer Foundation Cancer
Faculty of Pharmacy
McGill University Health Centre, Royal Victoria Hospital
McGill University
Hospital Monte Naranco
Centre Georges-François Leclerc
Centre Eugène Marquis Rennes
German Red Cross Blood Service of Baden-Wurttemberg-Hessen
Heidelberg University
Ohio State University
Roswell Park Cancer Institute
Université de Montréal
Centre hospitalier universitaire de Québec
Melbourne School of Population and Global Health
University of Melbourne
Vanderbilt-Ingram Cancer Center
Cogentech Cancer Genetic Test Laboratory
IFOM - The FIRC Institute of Molecular Oncology
Department of Experimental Oncology
University
Leiden University Medical Center
Erasmus MC
Molecular Genetics of Breast Cancer
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance
University of Bonn
University of Southampton, Faculty of Medicine
Alfred Hospital
Cancer Council Victoria
London School of Hygiene and Tropical Medicine
Antoni Van Leeuwenhoek Hospital
Division of Molecular Genetic Epidemiology
Lund University
Pontificia Universidad Javeriana
Städtisches Klinikum Karlsruhe
Division of Cancer Epidemiology
KU Leuven– University Hospital Leuven
University of Leuven
VIB Center for the Biology of Disease
University of Cambridge
City of Hope National Med Center
Hannover Medical School
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
Guy's Hospital

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

12 Citations (Scopus)

Abstract

Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10^-10)and EIF3H(rs799890: OR = 1.07, 95% C11.041.11, P = 8.7 × 10^-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95% C11.07-1.23, P = 7.9 × 10^-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10^-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

Original language	English
Pages (from-to)	6034-6046
Number of pages	13
Journal	Human Molecular Genetics
Volume	23
Issue number	22
DOIs	https://doi.org/10.13025/29046 https://doi.org/10.1093/hmg/ddu300
Publication status	Published - 15 Nov 2014
Externally published	Yes

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10.13025/29046Licence: CC BY-NC-ND
10.1093/hmg/ddu300

Cite this

Ekici, A. B., Hartmann, A., Beckmann, M. W., Hartikainen, J. M., Kosma, V.-M., Kataja, V., Jukkola-Vuorinen, A., Pylkäs, K., Kauppila, S., Dieffenbach, A. K., Stegmaier, C., Arndt, V., Margolin, S., Arias Perez, J. I., Pilar Zamora, M., Ashworth, A., Jones, M., Orr, N., Arveux, P., ... Couch, F. J. (2014). Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. Human Molecular Genetics, 23(22), 6034-6046. https://doi.org/10.13025/29046, https://doi.org/10.1093/hmg/ddu300

@article{f94c71605b384dbabaab7d58d9a21447,

title = "Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade",

abstract = "Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95\% confidence interval (CI) 1.16-1.33, P = 4.2 × 10-10)and EIF3H(rs799890: OR = 1.07, 95\% C11.041.11, P = 8.7 × 10-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95\% C11.07-1.23, P = 7.9 × 10-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.",

author = "Purrington, \{Kristen S.\} and Seth Slettedahl and Bolla, \{Manjeet K.\} and Kyriaki Michailidou and Kamila Czene and Heli Nevanlinna and Bojesen, \{Stig E.\} and Andrulis, \{Irene L.\} and Angela Cox and Per Hall and Jane Carpenter and Drakoulis Yannoukakos and \{A. Haiman\}, Christopher and Fasching, \{Peter A.\} and Arto Mannermaa and Robert Winqvist and Hermann Brenner and Annika Lindblom and Georgia Chenevix-Trench and Javier Benitez and Anthony Swerdlow and Vessela Kristensen and Pascal Gu{\'e}nel and Alfons Meindl and Hatef Darabi and Mikael Eriksson and Rainer Fagerholm and Kristiina Aittomaki and Carl Blomqvist and Nordestgaard, \{B{\o}rge G.\} and Nielsen, \{Sune F.\} and Henrik Flyger and Xianshu Wang and Curtis Olswold and Olson, \{Janet E.\} and Mulligan, \{Anna Marie\} and Knight, \{Julia A.\} and Sandrine Tchatchou and Reed, \{Malcolm W.R.\} and Cross, \{Simon S.\} and Jianjun Liu and Jingmei Li and Keith Humphreys and Christine Clarke and Rodney Scott and Florentia Fostira and George Fountzilas and Irene Konstantopoulou and Henderson, \{Brian E.\} and Fred Schumacher and \{Le Marchand\}, Loic and Ekici, \{Arif B.\} and Arndt Hartmann and Beckmann, \{Matthias W.\} and Hartikainen, \{Jaana M.\} and Veli-Matti Kosma and Vesa Kataja and Arja Jukkola-Vuorinen and Katri Pylk{\"a}s and Saila Kauppila and Dieffenbach, \{Aida Karina\} and Christa Stegmaier and Volker Arndt and Sara Margolin and Rosemary Balleine and \{Arias Perez\}, \{Jose Ignacio\} and \{Pilar Zamora\}, M. and Primitiva Menendez and Alan Ashworth and Michael Jones and Nick Orr and Patrick Arveux and Pierre Kerbrat and Th{\'e}r{\`e}se Truong and Peter Bugert and Toland, \{Amanda E.\} and Ambrosone, \{Christine B.\} and France Labr{\`e}che and Goldberg, \{Mark S.\} and Martine Dumont and Argyrios Ziogas and Eunjung Lee and Dite, \{Gillian S.\} and Carmel Apicella and Southey, \{Melissa C.\} and Jirong Long and Martha Shrubsole and Sandra Deming-Halverson and Filomena Ficarazzi and Monica Barile and Paolo Peterlongo and Katarzyna Durda and Katarzyna Jaworska-Bieniek and Tollenaar, \{Robert A. E. M.\} and Caroline Seynaeve and Thomas Br{\"u}ning and Yon-Dschun Ko and \{Van Deurzen\}, \{Carolien H.M.\} and Martens, \{John W. M.\} and Mieke Kriege and Figueroa, \{Jonine D.\} and Chanock, \{Stephen J.\} and Jolanta Lissowska and Ian Tomlinson and Kerin, \{Michael J.\} and Nicola Miller and Andreas Schneeweiss and Tapper, \{William J.\} and Gerty, \{Susan M.\} and Lorraine Durcan and Catriona McLean and Milne, \{Roger L.\} and Laura Baglietto and \{Dos Santos Silva\}, Isabel and Olivia Fletcher and Nichola Johnson and \{Van'T Veer\}, \{Laura J.\} and Sten Cornelissen and Asta F{\"o}rsti and Diana Torres and Thomas R{\"u}diger and Anja Rudolph and Dieter Flesch-Janys and Stefan Nickels and Caroline Weltens and Giuseppe Floris and Matthieu Moisse and Joe Dennis and Qin Wang and Dunning, \{Alison M.\} and Mitul Shah and Judith Brown and Jacques Simard and Hoda Anton-Culver and Neuhausen, \{Susan L.\} and Hopper, \{John L.\} and Natalia Bogdanova and Thilo D{\"o}rk and Wei Zheng and Paolo Radice and Anna Jakubowska and Jan Lubinski and Peter Devillee and Hiltrud Brauch and Maartje Hooning and Montserrat Garc{\'i}a-Closas and Elinor Sawyer and Barbara Burwinkel and Frederick Marmee and Eccles, \{Diana M.\} and Giles, \{Graham G.\} and Julian Peto and Marjanka Schmidt and Annegien Broeks and Ute Hamann and Jenny Chang-Claude and Diether Lambrechts and Pharoah, \{Paul D.P.\} and Douglas Easton and Pankratz, \{V. Shane\} and Susan Slager and Vachon, \{Celine M.\} and Couch, \{Fergus J.\}",

note = "Publisher Copyright: {\textcopyright} Published by Oxford University Press 2014.",

year = "2014",

month = nov,

day = "15",

doi = "10.13025/29046",

language = "English",

volume = "23",

pages = "6034--6046",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "22",

}

Ekici, AB, Hartmann, A, Beckmann, MW, Hartikainen, JM, Kosma, V-M, Kataja, V, Jukkola-Vuorinen, A, Pylkäs, K, Kauppila, S, Dieffenbach, AK, Stegmaier, C, Arndt, V, Margolin, S, Arias Perez, JI, Pilar Zamora, M, Ashworth, A, Jones, M, Orr, N, Arveux, P, Kerbrat, P, Truong, T, Bugert, P, Toland, AE, Ambrosone, CB, Labrèche, F, Goldberg, MS, Dumont, M, Ziogas, A, Dite, GS, Apicella, C, Southey, MC, Long, J, Shrubsole, M, Deming-Halverson, S, Ficarazzi, F, Barile, M, Peterlongo, P, Durda, K, Jaworska-Bieniek, K, Tollenaar, RAEM, Seynaeve, C, Brüning, T, Ko, Y-D, Van Deurzen, CHM, Martens, JWM, Kriege, M, Figueroa, JD, Chanock, SJ, Lissowska, J, Tomlinson, I, Schneeweiss, A, Tapper, WJ, Gerty, SM, Durcan, L, McLean, C, Milne, RL, Baglietto, L, Dos Santos Silva, I, Fletcher, O, Johnson, N, Van'T Veer, LJ, Cornelissen, S, Försti, A, Torres, D, Rüdiger, T, Rudolph, A, Flesch-Janys, D, Nickels, S, Weltens, C, Floris, G, Moisse, M, Dennis, J, Wang, Q, Dunning, AM, Shah, M, Brown, J, Simard, J, Anton-Culver, H, Neuhausen, SL, Hopper, JL, Bogdanova, N, Dörk, T, Zheng, W, Radice, P, Jakubowska, A, Lubinski, J, Devillee, P, Brauch, H, Hooning, M, García-Closas, M, Sawyer, E, Burwinkel, B, Marmee, F, Eccles, DM, Giles, GG, Peto, J, Schmidt, M, Broeks, A, Hamann, U, Chang-Claude, J, Lambrechts, D, Pharoah, PDP, Easton, D, Pankratz, VS, Slager, S, Vachon, CM & Couch, FJ 2014, 'Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade', Human Molecular Genetics, vol. 23, no. 22, pp. 6034-6046. https://doi.org/10.13025/29046, https://doi.org/10.1093/hmg/ddu300

TY - JOUR

T1 - Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

AU - Purrington, Kristen S.

AU - Slettedahl, Seth

AU - Bolla, Manjeet K.

AU - Michailidou, Kyriaki

AU - Czene, Kamila

AU - Nevanlinna, Heli

AU - Bojesen, Stig E.

AU - Andrulis, Irene L.

AU - Cox, Angela

AU - Hall, Per

AU - Carpenter, Jane

AU - Yannoukakos, Drakoulis

AU - A. Haiman, Christopher

AU - Fasching, Peter A.

AU - Mannermaa, Arto

AU - Winqvist, Robert

AU - Brenner, Hermann

AU - Lindblom, Annika

AU - Chenevix-Trench, Georgia

AU - Benitez, Javier

AU - Swerdlow, Anthony

AU - Kristensen, Vessela

AU - Guénel, Pascal

AU - Meindl, Alfons

AU - Darabi, Hatef

AU - Eriksson, Mikael

AU - Fagerholm, Rainer

AU - Aittomaki, Kristiina

AU - Blomqvist, Carl

AU - Nordestgaard, Børge G.

AU - Nielsen, Sune F.

AU - Flyger, Henrik

AU - Wang, Xianshu

AU - Olswold, Curtis

AU - Olson, Janet E.

AU - Mulligan, Anna Marie

AU - Knight, Julia A.

AU - Tchatchou, Sandrine

AU - Reed, Malcolm W.R.

AU - Cross, Simon S.

AU - Liu, Jianjun

AU - Li, Jingmei

AU - Humphreys, Keith

AU - Clarke, Christine

AU - Scott, Rodney

AU - Fostira, Florentia

AU - Fountzilas, George

AU - Konstantopoulou, Irene

AU - Henderson, Brian E.

AU - Schumacher, Fred

AU - Le Marchand, Loic

AU - Ekici, Arif B.

AU - Hartmann, Arndt

AU - Beckmann, Matthias W.

AU - Hartikainen, Jaana M.

AU - Kosma, Veli-Matti

AU - Kataja, Vesa

AU - Jukkola-Vuorinen, Arja

AU - Pylkäs, Katri

AU - Kauppila, Saila

AU - Dieffenbach, Aida Karina

AU - Stegmaier, Christa

AU - Arndt, Volker

AU - Margolin, Sara

AU - Balleine, Rosemary

AU - Arias Perez, Jose Ignacio

AU - Pilar Zamora, M.

AU - Menendez, Primitiva

AU - Ashworth, Alan

AU - Jones, Michael

AU - Orr, Nick

AU - Arveux, Patrick

AU - Kerbrat, Pierre

AU - Truong, Thérèse

AU - Bugert, Peter

AU - Toland, Amanda E.

AU - Ambrosone, Christine B.

AU - Labrèche, France

AU - Goldberg, Mark S.

AU - Dumont, Martine

AU - Ziogas, Argyrios

AU - Lee, Eunjung

AU - Dite, Gillian S.

AU - Apicella, Carmel

AU - Southey, Melissa C.

AU - Long, Jirong

AU - Shrubsole, Martha

AU - Deming-Halverson, Sandra

AU - Ficarazzi, Filomena

AU - Barile, Monica

AU - Peterlongo, Paolo

AU - Durda, Katarzyna

AU - Jaworska-Bieniek, Katarzyna

AU - Tollenaar, Robert A. E. M.

AU - Seynaeve, Caroline

AU - Brüning, Thomas

AU - Ko, Yon-Dschun

AU - Van Deurzen, Carolien H.M.

AU - Martens, John W. M.

AU - Kriege, Mieke

AU - Figueroa, Jonine D.

AU - Chanock, Stephen J.

AU - Lissowska, Jolanta

AU - Tomlinson, Ian

AU - Kerin, Michael J.

AU - Miller, Nicola

AU - Schneeweiss, Andreas

AU - Tapper, William J.

AU - Gerty, Susan M.

AU - Durcan, Lorraine

AU - McLean, Catriona

AU - Milne, Roger L.

AU - Baglietto, Laura

AU - Dos Santos Silva, Isabel

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Van'T Veer, Laura J.

AU - Cornelissen, Sten

AU - Försti, Asta

AU - Torres, Diana

AU - Rüdiger, Thomas

AU - Rudolph, Anja

AU - Flesch-Janys, Dieter

AU - Nickels, Stefan

AU - Weltens, Caroline

AU - Floris, Giuseppe

AU - Moisse, Matthieu

AU - Dennis, Joe

AU - Wang, Qin

AU - Dunning, Alison M.

AU - Shah, Mitul

AU - Brown, Judith

AU - Simard, Jacques

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L.

AU - Hopper, John L.

AU - Bogdanova, Natalia

AU - Dörk, Thilo

AU - Zheng, Wei

AU - Radice, Paolo

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Devillee, Peter

AU - Brauch, Hiltrud

AU - Hooning, Maartje

AU - García-Closas, Montserrat

AU - Sawyer, Elinor

AU - Burwinkel, Barbara

AU - Marmee, Frederick

AU - Eccles, Diana M.

AU - Giles, Graham G.

AU - Peto, Julian

AU - Schmidt, Marjanka

AU - Broeks, Annegien

AU - Hamann, Ute

AU - Chang-Claude, Jenny

AU - Lambrechts, Diether

AU - Pharoah, Paul D.P.

AU - Easton, Douglas

AU - Pankratz, V. Shane

AU - Slager, Susan

AU - Vachon, Celine M.

AU - Couch, Fergus J.

PY - 2014/11/15

Y1 - 2014/11/15

N2 - Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10-10)and EIF3H(rs799890: OR = 1.07, 95% C11.041.11, P = 8.7 × 10-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95% C11.07-1.23, P = 7.9 × 10-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

AB - Mitotic index is an important component of histologic grade and has an etiologic role in breast tumorigenesis. Several small candidate gene studies have reported associations between variation in mitotic genes and breast cancer risk. We measured associations between 2156 single nucleotide polymorphisms (SNPs) from 194 mitotic genes and breast cancer risk, overall and by histologic grade, in the Breast Cancer Association Consortium (BCAC) iCOGS study (n = 39067 cases; n = 42 106 controls). SNPs in TACC2 [rs17550038: odds ratio (OR) = 1.24, 95% confidence interval (CI) 1.16-1.33, P = 4.2 × 10-10)and EIF3H(rs799890: OR = 1.07, 95% C11.041.11, P = 8.7 × 10-6) were significantly associated with risk of low-grade breast cancer. The TACC2signal was retained (rs17550038: OR = 1.15, 95% C11.07-1.23, P = 7.9 × 10-5) after adjustment for breast cancer risk SNPs in the nearby FGFR2gene, suggesting that TACC2 is a novel, independent genome-wide significant genetic risk locus for low-grade breast cancer. While no SNPs were individually associated with high-grade disease, a pathway-level gene set analysis showed that variation across the 194 mitotic genes was associated with high-grade breast cancer risk(P = 2.1 × 10-3). These observations will provide insight into the contribution of mitotic defects to histological grade and the etiology of breast cancer.

UR - http://hdl.handle.net/10379/13539

UR - https://www.scopus.com/pages/publications/84911431178

U2 - 10.13025/29046

DO - 10.13025/29046

M3 - Article

C2 - 24927736

SN - 0964-6906

VL - 23

SP - 6034

EP - 6046

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 22

ER -

Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade

Abstract

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