Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade
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2014-06-13Author
Purrington, Kristen S.
Slettedahl, Seth
Bolla, Manjeet K.
Michailidou, Kyriaki
Czene, Kamila
Nevanlinna, Heli
Bojesen, Stig E.
Andrulis, Irene L.
Cox, Angela
Hall, Per
Carpenter, Jane
Yannoukakos, Drakoulis
Haiman, Christopher A.
Fasching, Peter A.
Mannermaa, Arto
Winqvist, Robert
Brenner, Hermann
Lindblom, Annika
Chenevix-Trench, Georgia
Benitez, Javier
Swerdlow, Anthony
Kristensen, Vessela
Guénel, Pascal
Meindl, Alfons
Darabi, Hatef
Eriksson, Mikael
Fagerholm, Rainer
Aittomäki, Kristiina
Blomqvist, Carl
Nordestgaard, Børge G.
Nielsen, Sune F.
Flyger, Henrik
Wang, Xianshu
Olswold, Curtis
Olson, Janet E.
Mulligan, Anna Marie
Knight, Julia A.
Tchatchou, Sandrine
Reed, Malcolm W.R.
Cross, Simon S.
Liu, Jianjun
Li, Jingmei
Humphreys, Keith
Clarke, Christine
Scott, Rodney
Fostira, Florentia
Fountzilas, George
Konstantopoulou, Irene
Henderson, Brian E.
Schumacher, Fredrick
Le Marchand, Loic
Ekici, Arif B.
Hartmann, Arndt
Beckmann, Matthias W.
Hartikainen, Jaana M.
Kosma, Veli-Matti
Kataja, Vesa
Jukkola-Vuorinen, Arja
Pylkäs, Katri
Kauppila, Saila
Dieffenbach, Aida Karina
Stegmaier, Christa
Arndt, Volker
Margolin, Sara
Balleine, Rosemary
Arias Perez, Jose Ignacio
Pilar Zamora, M.
Menéndez, Primitiva
Ashworth, Alan
Jones, Michael
Orr, Nick
Arveux, Patrick
Kerbrat, Pierre
Truong, Thérèse
Bugert, Peter
Toland, Amanda E.
Ambrosone, Christine B.
Labrèche, France
Goldberg, Mark S.
Dumont, Martine
Ziogas, Argyrios
Lee, Eunjung
Dite, Gillian S.
Apicella, Carmel
Southey, Melissa C.
Long, Jirong
Shrubsole, Martha
Deming-Halverson, Sandra
Ficarazzi, Filomena
Barile, Monica
Peterlongo, Paolo
Durda, Katarzyna
Jaworska-Bieniek, Katarzyna
Tollenaar, Robert A.E.M.
Seynaeve, Caroline
Brüning, Thomas
Ko, Yon-Dschun
Van Deurzen, Carolien H.M.
Martens, John W.M.
Kriege, Mieke
Figueroa, Jonine D.
Chanock, Stephen J.
Lissowska, Jolanta
Tomlinson, Ian
Kerin, Michael J.
Miller, Nicola
Schneeweiss, Andreas
Tapper, William J.
Gerty, Susan M.
Durcan, Lorraine
Mclean, Catriona
Milne, Roger L.
Baglietto, Laura
dos Santos Silva, Isabel
Fletcher, Olivia
Johnson, Nichola
Van'T Veer, Laura J.
Cornelissen, Sten
Försti, Asta
Torres, Diana
Rüdiger, Thomas
Rudolph, Anja
Flesch-Janys, Dieter
Nickels, Stefan
Weltens, Caroline
Floris, Giuseppe
Moisse, Matthieu
Dennis, Joe
Wang, Qin
Dunning, Alison M.
Shah, Mitul
Brown, Judith
Simard, Jacques
Anton-Culver, Hoda
Neuhausen, Susan L.
Hopper, John L.
Bogdanova, Natalia
Dörk, Thilo
Zheng, Wei
Radice, Paolo
Jakubowska, Anna
Lubinski, Jan
Devillee, Peter
Brauch, Hiltrud
Hooning, Maartje
García-Closas, Montserrat
Sawyer, Elinor
Burwinkel, Barbara
Marmee, Frederick
Eccles, Diana M.
Giles, Graham G.
Peto, Julian
Schmidt, Marjanka
Broeks, Annegien
Hamann, Ute
Chang-Claude, Jenny
Lambrechts, Diether
Pharoah, Paul D.P.
Easton, Douglas
Pankratz, V. Shane
Slager, Susan
Vachon, Celine M.
Couch, Fergus J.
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Purrington, Kristen S. Slettedahl, Seth; Bolla, Manjeet K.; Michailidou, Kyriaki; Czene, Kamila; Nevanlinna, Heli; Bojesen, Stig E.; Andrulis, Irene L.; Cox, Angela; Hall, Per; Carpenter, Jane; Yannoukakos, Drakoulis; Haiman, Christopher A.; Fasching, Peter A.; Mannermaa, Arto; Winqvist, Robert; Brenner, Hermann; Lindblom, Annika; Chenevix-Trench, Georgia; Benitez, Javier; Swerdlow, Anthony; Kristensen, Vessela; Guénel, Pascal; Meindl, Alfons; Darabi, Hatef; Eriksson, Mikael; Fagerholm, Rainer; Aittomäki, Kristiina; Blomqvist, Carl; Nordestgaard, Børge G.; Nielsen, Sune F.; Flyger, Henrik; Wang, Xianshu; Olswold, Curtis; Olson, Janet E.; Mulligan, Anna Marie; Knight, Julia A.; Tchatchou, Sandrine; Reed, Malcolm W.R.; Cross, Simon S.; Liu, Jianjun; Li, Jingmei; Humphreys, Keith; Clarke, Christine; Scott, Rodney; Fostira, Florentia; Fountzilas, George; Konstantopoulou, Irene; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Ekici, Arif B.; Hartmann, Arndt; Beckmann, Matthias W.; Hartikainen, Jaana M.; Kosma, Veli-Matti; Kataja, Vesa; Jukkola-Vuorinen, Arja; Pylkäs, Katri; Kauppila, Saila; Dieffenbach, Aida Karina; Stegmaier, Christa; Arndt, Volker; Margolin, Sara; Balleine, Rosemary; Arias Perez, Jose Ignacio; Pilar Zamora, M.; Menéndez, Primitiva; Ashworth, Alan; Jones, Michael; Orr, Nick; Arveux, Patrick; Kerbrat, Pierre; Truong, Thérèse; Bugert, Peter; Toland, Amanda E.; Ambrosone, Christine B.; Labrèche, France; Goldberg, Mark S.; Dumont, Martine; Ziogas, Argyrios; Lee, Eunjung; Dite, Gillian S.; Apicella, Carmel; Southey, Melissa C.; Long, Jirong; Shrubsole, Martha; Deming-Halverson, Sandra; Ficarazzi, Filomena; Barile, Monica; Peterlongo, Paolo; Durda, Katarzyna; Jaworska-Bieniek, Katarzyna; Tollenaar, Robert A.E.M.; Seynaeve, Caroline; Brüning, Thomas; Ko, Yon-Dschun; Van Deurzen, Carolien H.M.; Martens, John W.M.; Kriege, Mieke; Figueroa, Jonine D.; Chanock, Stephen J.; Lissowska, Jolanta; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Schneeweiss, Andreas; Tapper, William J.; Gerty, Susan M.; Durcan, Lorraine; Mclean, Catriona; Milne, Roger L.; Baglietto, Laura; dos Santos Silva, Isabel; Fletcher, Olivia; Johnson, Nichola; Van'T Veer, Laura J.; Cornelissen, Sten; Försti, Asta; Torres, Diana; Rüdiger, Thomas; Rudolph, Anja; Flesch-Janys, Dieter; Nickels, Stefan; Weltens, Caroline; Floris, Giuseppe; Moisse, Matthieu; Dennis, Joe; Wang, Qin; Dunning, Alison M.; Shah, Mitul; Brown, Judith; Simard, Jacques; Anton-Culver, Hoda; Neuhausen, Susan L.; Hopper, John L.; Bogdanova, Natalia; Dörk, Thilo; Zheng, Wei; Radice, Paolo; Jakubowska, Anna; Lubinski, Jan; Devillee, Peter; Brauch, Hiltrud; Hooning, Maartje; García-Closas, Montserrat; Sawyer, Elinor; Burwinkel, Barbara; Marmee, Frederick; Eccles, Diana M.; Giles, Graham G.; Peto, Julian; Schmidt, Marjanka; Broeks, Annegien; Hamann, Ute; Chang-Claude, Jenny; Lambrechts, Diether; Pharoah, Paul D.P.; Easton, Douglas; Pankratz, V. Shane; Slager, Susan; Vachon, Celine M.; Couch, Fergus J. (2014). Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. Human Molecular Genetics 23 (22), 6034-6046
Published Version
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 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.