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 = 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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authors.affiliation: Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
authors.forename: Jan
authors.initials: J
authors.lastname: Lubinski
authors.affiliation: Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devillee
authors.affiliation: Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany, University of Tübingen, Tübingen, Germany.
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
authors.affiliation: Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Hooning
authors.affiliation: Breakthrough Breast Cancer Research Centre and Division of Breast Cancer Research.
authors.forename: Montserrat
authors.initials: M
authors.lastname: García-Closas
authors.affiliation: Division of Cancer Studies, Kings College London, Guy's Hospital, London, UK.
authors.forename: Elinor
authors.initials: E
authors.lastname: Sawyer
authors.affiliation: Department of Obstetrics and Gynecology, Molecular Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.affiliation: Department of Obstetrics and Gynecology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Frederick
authors.initials: F
authors.lastname: Marmee
authors.affiliation: Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.affiliation: Centre for Molecular, Environmental, Genetic, and Analytic Epidemiology, The University of Melbourne, Melbourne, Australia, Cancer Epidemiology Centre, The Cancer Council Victoria, Melbourne, Australia.
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.affiliation: Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Peto
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Marjanka
authors.initials: M
authors.lastname: Schmidt
authors.affiliation: Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.affiliation: Molecular Genetics of Breast Cancer.
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.affiliation: Division of Cancer Epidemiology.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium, Vesalius Research Center (VRC), VIB, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Paul D P
authors.initials: PD
authors.lastname: Pharoah
authors.affiliation: Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
authors.forename: Douglas
authors.initials: D
authors.lastname: Easton
authors.affiliation: Department of Health Sciences Research.
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.affiliation: Department of Health Sciences Research.
authors.forename: Susan
authors.initials: S
authors.lastname: Slager
authors.affiliation: Department of Health Sciences Research.
authors.forename: Celine M
authors.initials: CM
authors.lastname: Vachon
authors.affiliation: Department of Health Sciences Research, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, USA, couch.fergus@mayo.edu.
authors.forename: Fergus J
authors.initials: FJ
authors.lastname: Couch
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D016022:Case-Control Studies; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D002352:Carrier Proteins; C410333:TACC2 protein, human; D025521:Tumor Suppressor Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2