Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade.
Purrington, Kristen S. 1,3; Slettedahl, Seth 1; Bolla, Manjeet K. 4; Michailidou, Kyriaki 4; Czene, Kamila 6; Nevanlinna, Heli 9; Bojesen, Stig E. 13,14; Andrulis, Irene L. 15,18; Cox, Angela 21; Hall, Per 6; Carpenter, Jane 23; Yannoukakos, Drakoulis 25; Haiman, Christopher A. 26; Fasching, Peter A. 27,30; Mannermaa, Arto 31,32; Winqvist, Robert 34; Brenner, Hermann 35,40; Lindblom, Annika 7; Chenevix-Trench, Georgia 41; Benitez, Javier 43,44; Swerdlow, Anthony 45,46; Kristensen, Vessela 47,48; Guenel, Pascal 49,50; Meindl, Alfons 51; Darabi, Hatef 6; Eriksson, Mikael 6; Fagerholm, Rainer 10; Aittomaki, Kristiina 11; Blomqvist, Carl 12; Nordestgaard, Borge G. 14; Nielsen, Sune F. 13; Flyger, Henrik 52; Wang, Xianshu 2; Olswold, Curtis 1; Olson, Janet E. 1; Mulligan, Anna Marie 19,53; Knight, Julia A. 16,20; Tchatchou, Sandrine 17; Reed, Malcolm W.R. 21; Cross, Simon S. 22; Liu, Jianjun 54; Li, Jingmei 54; Humphreys, Keith 6; Clarke, Christine 24; Scott, Rodney 55; ABCTB Investigators 23; Fostira, Florentia 25; Fountzilas, George 56; Konstantopoulou, Irene 25; Henderson, Brian E. 26; Schumacher, Fredrick 26; Le Marchand, Loic 57; Ekici, Arif B. 28; Hartmann, Arndt 29; Beckmann, Matthias W. 27; Hartikainen, Jaana M. 31,32; Kosma, Veli-Matti 31,32; Kataja, Vesa 31,33; Jukkola-Vuorinen, Arja 58; Pylkas, Katri 34; Kauppila, Saila 59; Dieffenbach, Aida Karina 35,40; Stegmaier, Christa 60; Arndt, Volker 35; Margolin, Sara 8; Australian Ovarian Cancer Study Group 42,61; kConFab Investigators 61; Balleine, Rosemary 62; Arias Perez, Jose Ignacio 63; Pilar Zamora, M. 65; Menendez, Primitiva 64; Ashworth, Alan 66; Jones, Michael 45; Orr, Nick 66; Arveux, Patrick 68; Kerbrat, Pierre 69; Truong, Therese 49,50; Bugert, Peter 70,71; Toland, Amanda E. 72; Ambrosone, Christine B. 73; Labreche, France 74; Goldberg, Mark S. 75,76; Dumont, Martine 77; Ziogas, Argyrios 78; Lee, Eunjung 26; Dite, Gillian S. 79; Apicella, Carmel 79; Southey, Melissa C. 80; Long, Jirong 82; Shrubsole, Martha 72; Deming-Halverson, Sandra 82; Ficarazzi, Filomena 83,84; Barile, Monica 85; Peterlongo, Paolo 84; Durda, Katarzyna 86; Jaworska-Bieniek, Katarzyna 86; Tollenaar, Robert A.E.M. 87; Seynaeve, Caroline 89; The GENICA Network 36,90,91,92,93,94,95; Bruning, Thomas 90; Ko, Yon-Dschun 91; Van Deurzen, Carolien H.M. 96; Martens, John W.M. 97; Kriege, Mieke 97; Figueroa, Jonine D. 98; Chanock, Stephen J. 98; Lissowska, Jolanta 99; Tomlinson, Ian 100; Kerin, Michael J. 101; Miller, Nicola 101; Schneeweiss, Andreas 102,103; Tapper, William J. 104; Gerty, Susan M. 104; Durcan, Lorraine 104; Mclean, Catriona 105; Milne, Roger L. 81,106; Baglietto, Laura 81,106; dos Santos Silva, Isabel 107; Fletcher, Olivia 67; Johnson, Nichola 67; Van'T Veer, Laura J. 108; Cornelissen, Sten 108; Forsti, Asta 37,109; Torres, Diana 36,110; Rudiger, Thomas 111; Rudolph, Anja 38; Flesch-Janys, Dieter 112; Nickels, Stefan 38; Weltens, Caroline 113; Floris, Giuseppe 113; Moisse, Matthieu 114,115; Dennis, Joe 4; Wang, Qin 4; Dunning, Alison M. 5; Shah, Mitul 5; Brown, Judith 4; Simard, Jacques 77; Anton-Culver, Hoda 78; Neuhausen, Susan L. 116; Hopper, John L. 79; Bogdanova, Natalia 117; Dork, Thilo 118; Zheng, Wei 82; Radice, Paolo 119; Jakubowska, Anna 86; Lubinski, Jan 86; Devillee, Peter 88; Brauch, Hiltrud 94,95; Hooning, Maartje 97; Garcia-Closas, Montserrat 66; Sawyer, Elinor 120; Burwinkel, Barbara 102,39; Marmee, Frederick 102,103; Eccles, Diana M. 104; Giles, Graham G. 81,106; Peto, Julian 107; Schmidt, Marjanka 108; Broeks, Annegien 108; Hamann, Ute 36; Chang-Claude, Jenny 38; Lambrechts, Diether 114,115; Pharoah, Paul D.P. 4,5; Easton, Douglas 4,5; Pankratz, V. Shane 1; Slager, Susan 1; Vachon, Celine M. 1; Couch, Fergus J. 1,2,*
[Article]
Human Molecular Genetics.
23(22):6034-6046, November 15, 2014.
(Format: HTML, PDF)
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 x 10-10) and EIF3H (rs799890: OR = 1.07, 95% CI 1.04-1.11, P = 8.7 x 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 x 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 x 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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