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

Authors:
Dr. Jonine Figueroa, PhD
Dr. Jonine Figueroa, PhD
Usher Institute of Population Health Sciences and Informatics
Chancellor's Fellow
Molecular epidemiology
Edinburgh, Scotland | United Kingdom
Dieter Flesch-Janys
Dieter Flesch-Janys
United Kingdom
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 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

Hum Mol Genet 2014 Nov 13;23(22):6034-46. Epub 2014 Jun 13.

Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA,

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.

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Source
http://dx.doi.org/10.1093/hmg/ddu300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204763PMC
November 2014
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