Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Kristen S Purrington,
Seth Slettedahl,
Manjeet K Bolla,
Kyriaki Michailidou,
Kamila Czene,
Heli Nevanlinna,
Stig E Bojesen,
Irene L Andrulis,
Angela Cox,
Per Hall,
Jane Carpenter,
Drakoulis Yannoukakos,
Christopher A Haiman,
Peter A Fasching,
Arto Mannermaa,
Robert Winqvist,
Hermann Brenner,
Annika Lindblom,
Georgia Chenevix-Trench,
Javier Benitez,
Anthony Swerdlow,
Vessela Kristensen,
Pascal Guénel,
Alfons Meindl,
Hatef Darabi,
Mikael Eriksson,
Rainer Fagerholm,
Kristiina Aittomäki,
Carl Blomqvist,
Børge G Nordestgaard,
Sune F Nielsen,
Henrik Flyger,
Xianshu Wang,
Curtis Olswold,
Janet E Olson,
Anna Marie Mulligan,
Julia A Knight,
Sandrine Tchatchou,
Malcolm W R Reed,
Simon S Cross,
Jianjun Liu,
Jingmei Li,
Keith Humphreys,
Christine Clarke,
Rodney Scott,
,
Florentia Fostira,
George Fountzilas,
Irene Konstantopoulou,
Brian E Henderson,
Fredrick Schumacher,
Loic Le Marchand,
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,
,
,
Rosemary Balleine,
Jose Ignacio Arias Perez,
M Pilar Zamora,
Primitiva Menéndez,
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,
Eunjung Lee,
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,
Michael J Kerin,
Nicola Miller,
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
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 = 39 067 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% CI 1.04-1.11, P = 8.7 × 10(-6)) were significantly associated with risk of low-grade breast cancer. The TACC2 signal was retained (rs17550038: OR = 1.15, 95% CI 1.07-1.23, P = 7.9 × 10(-5)) after adjustment for breast cancer risk SNPs in the nearby FGFR2 gene, 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.