Inherited variants in the inner centromere protein (INCENP) gene of the chromosomal passenger complex contribute to the susceptibility of ER-negative breast cancer.
Maria Kabisch,
Justo Lorenzo Bermejo,
Thomas Dünnebier,
Shibo Ying,
Kyriaki Michailidou,
Manjeet K Bolla,
Qin Wang,
Joe Dennis,
Mitul Shah,
Barbara J Perkins,
Kamila Czene,
Hatef Darabi,
Mikael Eriksson,
Stig E Bojesen,
Børge G Nordestgaard,
Sune F Nielsen,
Henrik Flyger,
Diether Lambrechts,
Patrick Neven,
Stephanie Peeters,
Caroline Weltens,
Fergus J Couch,
Janet E Olson,
Xianshu Wang,
Kristen Purrington,
Jenny Chang-Claude,
Anja Rudolph,
Petra Seibold,
Dieter Flesch-Janys,
Julian Peto,
Isabel dos-Santos-Silva,
Nichola Johnson,
Olivia Fletcher,
Heli Nevanlinna,
Taru A Muranen,
Kristiina Aittomäki,
Carl Blomqvist,
Marjanka K Schmidt,
Annegien Broeks,
Sten Cornelissen,
Frans B L Hogervorst,
Jingmei Li,
Judith S Brand,
Keith Humphreys,
Pascal Guénel,
Thérèse Truong,
Florence Menegaux,
Marie Sanchez,
Barbara Burwinkel,
Frederik Marmé,
Rongxi Yang,
Peter Bugert,
Anna González-Neira,
Javier Benitez,
M Pilar Zamora,
Jose I Arias Perez,
Angela Cox,
Simon S Cross,
Malcolm W R Reed,
Irene L Andrulis,
Julia A Knight,
Gord Glendon,
Sandrine Tchatchou,
Elinor J Sawyer,
Ian Tomlinson,
Michael J Kerin,
Nicola Miller,
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Christopher A Haiman,
Fredrick Schumacher,
Brian E Henderson,
Loic Le Marchand,
Annika Lindblom,
Sara Margolin,
Maartje J Hooning,
Antoinette Hollestelle,
Mieke Kriege,
Linetta B Koppert,
John L Hopper,
Melissa C Southey,
Helen Tsimiklis,
Carmel Apicella,
Seth Slettedahl,
Amanda E Toland,
Celine Vachon,
Drakoulis Yannoukakos,
Graham G Giles,
Roger L Milne,
Catriona McLean,
Peter A Fasching,
Matthias Ruebner,
Arif B Ekici,
Matthias W Beckmann,
Hermann Brenner,
Aida K Dieffenbach,
Volker Arndt,
Christa Stegmaier,
Alan Ashworth,
Nicholas Orr,
Minouk J Schoemaker,
Anthony Swerdlow,
Montserrat García-Closas,
Jonine Figueroa,
Stephen J Chanock,
Jolanta Lissowska,
Mark S Goldberg,
France Labrèche,
Martine Dumont,
Robert Winqvist,
Katri Pylkäs,
Arja Jukkola-Vuorinen,
Mervi Grip,
Hiltrud Brauch,
Thomas Brüning,
Yon-Dschun Ko,
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Paolo Radice,
Paolo Peterlongo,
Giulietta Scuvera,
Stefano Fortuzzi,
Natalia Bogdanova,
Thilo Dörk,
Arto Mannermaa,
Vesa Kataja,
Veli-Matti Kosma,
Jaana M Hartikainen,
Peter Devilee,
Robert A E M Tollenaar,
Caroline Seynaeve,
Christi J Van Asperen,
Anna Jakubowska,
Jan Lubinski,
Katarzyna Jaworska-Bieniek,
Katarzyna Durda,
Wei Zheng,
Martha J Shrubsole,
Qiuyin Cai,
Diana Torres,
Hoda Anton-Culver,
Vessela Kristensen,
François Bacot,
Daniel C Tessier,
Daniel Vincent,
Craig Luccarini,
Caroline Baynes,
Shahana Ahmed,
Mel Maranian,
Jacques Simard,
Georgia Chenevix-Trench,
Per Hall,
Paul D P Pharoah,
Alison M Dunning,
Douglas F Easton,
Ute Hamann
Abstract
The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore, inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP, AURKB, BIRC5 and CDCA8) were genotyped in 88 911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk [per A allele odds ratio (OR) 0.95, 95% confidence interval (CI) 0.92-0.98, P = 0.007] and particularly with estrogen receptor (ER)-negative breast tumors (per A allele OR 0.89, 95% CI 0.83-0.95, P = 0.0005). SNPs not directly genotyped were imputed based on 1000 Genomes. The SNPs rs1047739 in the 3' untranslated region and rs144045115 downstream of INCENP showed the strongest association signals for overall (per T allele OR 1.03, 95% CI 1.00-1.06, P = 0.0009) and ER-negative breast cancer risk (per A allele OR 1.06, 95% CI 1.02-1.10, P = 0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, P = 0.002). The data suggest that INCENP in the CPC pathway contributes to ER-negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC-inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated.