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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.

SUBMITTER: Purrington KS

PROVIDER: S-EPMC4204763 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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

Purrington Kristen S KS Slettedahl Seth S Bolla Manjeet K MK Michailidou Kyriaki K Czene Kamila K Nevanlinna Heli H Bojesen Stig E SE Andrulis Irene L IL Cox Angela A Hall Per P Carpenter Jane J Yannoukakos Drakoulis D Haiman Christopher A CA Fasching Peter A PA Mannermaa Arto A Winqvist Robert R Brenner Hermann H Lindblom Annika A Chenevix-Trench Georgia G Benitez Javier J Swerdlow Anthony A Kristensen Vessela V Guénel Pascal P Meindl Alfons A Darabi Hatef H Eriksson Mikael M Fagerholm Rainer R Aittomäki Kristiina K Blomqvist Carl C Nordestgaard Børge G BG Nielsen Sune F SF Flyger Henrik H Wang Xianshu X Olswold Curtis C Olson Janet E JE Mulligan Anna Marie AM Knight Julia A JA Tchatchou Sandrine S Reed Malcolm W R MW Cross Simon S SS Liu Jianjun J Li Jingmei J Humphreys Keith K Clarke Christine C Scott Rodney R Fostira Florentia F Fountzilas George G Konstantopoulou Irene I Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Ekici Arif B AB Hartmann Arndt A Beckmann Matthias W MW Hartikainen Jaana M JM Kosma Veli-Matti VM Kataja Vesa V Jukkola-Vuorinen Arja A Pylkäs Katri K Kauppila Saila S Dieffenbach Aida Karina AK Stegmaier Christa C Arndt Volker V Margolin Sara S Balleine Rosemary R Arias Perez Jose Ignacio JI Pilar Zamora M M Menéndez Primitiva P Ashworth Alan A Jones Michael M Orr Nick N Arveux Patrick P Kerbrat Pierre P Truong Thérèse T Bugert Peter P Toland Amanda E AE Ambrosone Christine B CB Labrèche France F Goldberg Mark S MS Dumont Martine M Ziogas Argyrios A Lee Eunjung E Dite Gillian S GS Apicella Carmel C Southey Melissa C MC Long Jirong J Shrubsole Martha M Deming-Halverson Sandra S Ficarazzi Filomena F Barile Monica M Peterlongo Paolo P Durda Katarzyna K Jaworska-Bieniek Katarzyna K Tollenaar Robert A E M RA Seynaeve Caroline C Brüning Thomas T Ko Yon-Dschun YD Van Deurzen Carolien H M CH Martens John W M JW Kriege Mieke M Figueroa Jonine D JD Chanock Stephen J SJ Lissowska Jolanta J Tomlinson Ian I Kerin Michael J MJ Miller Nicola N Schneeweiss Andreas A Tapper William J WJ Gerty Susan M SM Durcan Lorraine L Mclean Catriona C Milne Roger L RL Baglietto Laura L dos Santos Silva Isabel I Fletcher Olivia O Johnson Nichola N Van'T Veer Laura J LJ Cornelissen Sten S Försti Asta A Torres Diana D Rüdiger Thomas T Rudolph Anja A Flesch-Janys Dieter D Nickels Stefan S Weltens Caroline C Floris Giuseppe G Moisse Matthieu M Dennis Joe J Wang Qin Q Dunning Alison M AM Shah Mitul M Brown Judith J Simard Jacques J Anton-Culver Hoda H Neuhausen Susan L SL Hopper John L JL Bogdanova Natalia N Dörk Thilo T Zheng Wei W Radice Paolo P Jakubowska Anna A Lubinski Jan J Devillee Peter P Brauch Hiltrud H Hooning Maartje M García-Closas Montserrat M Sawyer Elinor E Burwinkel Barbara B Marmee Frederick F Eccles Diana M DM Giles Graham G GG Peto Julian J Schmidt Marjanka M Broeks Annegien A Hamann Ute U Chang-Claude Jenny J Lambrechts Diether D Pharoah Paul D P PD Easton Douglas D Pankratz V Shane VS Slager Susan S Vachon Celine M CM Couch Fergus J FJ

Human molecular genetics 20140613 22

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 ...[more]

PMID: 24927736

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

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

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