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Hum Mol Genet. 2014 Nov 15;23(22):6034-46. doi: 10.1093/hmg/ddu300. Epub 2014 Jun 13.

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

Purrington KS, Slettedahl S, Bolla MK, Michailidou K, Czene K, Nevanlinna H, Bojesen SE, Andrulis IL, Cox A, Hall P, Carpenter J, Yannoukakos D, Haiman CA, Fasching PA, Mannermaa A, Winqvist R, Brenner H, Lindblom A, Chenevix-Trench G, Benitez J, Swerdlow A, Kristensen V, Guénel P, Meindl A, Darabi H, Eriksson M, Fagerholm R, Aittomäki K, Blomqvist C, Nordestgaard BG, Nielsen SF, Flyger H, Wang X, Olswold C, Olson JE, Mulligan AM, Knight JA, Tchatchou S, Reed MW, Cross SS, Liu J, Li J, Humphreys K, Clarke C, Scott R; ABCTB Investigators, Fostira F, Fountzilas G, Konstantopoulou I, Henderson BE, Schumacher F, Le Marchand L, Ekici AB, Hartmann A, Beckmann MW, Hartikainen JM, Kosma VM, Kataja V, Jukkola-Vuorinen A, Pylkäs K, Kauppila S, Dieffenbach AK, Stegmaier C, Arndt V, Margolin S; Australian Ovarian Cancer Study Group; kConFab Investigators, Balleine R, Arias Perez JI, Pilar Zamora M, Menéndez P, 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, Lee E, 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 RA, Seynaeve C; GENICA Network, Brüning T, Ko YD, Van Deurzen CH, Martens JW, Kriege M, Figueroa JD, Chanock SJ, Lissowska J, Tomlinson I, Kerin MJ, Miller N, 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 PD, Easton D, Pankratz VS, Slager S, Vachon CM, Couch FJ.

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.

Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

PMID:
24927736
[PubMed - indexed for MEDLINE]
PMCID:
PMC4204763
Free PMC Article

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