학술논문
CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
Document Type
Author
Johnson, Nichola; Maguire, Sarah; Morra, Anna; Kapoor, Pooja Middha; Tomczyk, Katarzyna; Jones, Michael E.; Schoemaker, Minouk J.; Gilham, Clare; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Ahearn, Thomas U.; Andrulis, Irene L.; Anton-Culver, Hoda; Antonenkova, Natalia N.; Arndt, Volker; Aronson, Kristan J.; Augustinsson, Annelie; Baynes, Caroline; Freeman, Laura E. Beane; Beckmann, Matthias W.; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Boeckx, Bram; Bogdanova, Natalia V.; Bojesen, Stig E.; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Campa, Daniele; Canzian, Federico; Castelao, Jose E.; Chanock, Stephen J.; Chenevix-Trench, Georgia; Clarke, Christine L.; Conroy, Don M.; Couch, Fergus J.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Doerk, Thilo; Eliassen, A. Heather; Engel, Christoph; Evans, D. Gareth; Fasching, Peter A.; Figueroa, Jonine; Floris, Giuseppe; Flyger, Henrik; Gago-Dominguez, Manuela; Gapstur, Susan M.; Garcia-Closas, Montserrat; Gaudet, Mia M.; Giles, Graham G.; Goldberg, Mark S.; Gonzalez-Neira, Anna; Guenel, Pascal; Hahnen, Eric; Haiman, Christopher A.; Hakansson, Niclas; Hall, Per; Hamann, Ute; Harrington, Patricia A.; Hart, Steven N.; Hooning, Maartje J.; Hopper, John L.; Howell, Anthony; Hunter, David J.; Jager, Agnes; Jakubowska, Anna; John, Esther M.; Kaaks, Rudolf; Keeman, Renske; Khusnutdinova, Elza; Kitahara, Cari M.; Kosma, Veli-Matti; Koutros, Stella; Kraft, Peter; Kristensen, Vessela N.; Kurian, Allison W.; Lambrechts, Diether; Le Marchand, Loic; Linet, Martha; Lubinski, Jan; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Martens, John W. M.; Mavroudis, Dimitrios; Mayes, Rebecca; Meindl, Alfons; Milne, Roger L.; Neuhausen, Susan L.; Nevanlinna, Heli; Newman, William G.; Nielsen, Sune F.; Nordestgaard, Borge G.; Obi, Nadia; Olshan, Andrew F.; Olson, Janet E.; Olsson, Hakan; Orban, Ester; Park-Simon, Tjoung-Won; Peterlongo, Paolo; Plaseska-Karanfilska, Dijana; Pylkas, Katri; Rennert, Gad; Rennert, Hedy S.; Ruddy, Kathryn J.; Saloustros, Emmanouil; Sandler, Dale P.; Sawyer, Elinor J.; Schmutzler, Rita K.; Scott, Christopher; Shu, Xiao-Ou; Simard, Jacques; Smichkoska, Snezhana; Sohn, Christof; Southey, Melissa C.; Spinelli, John J.; Stone, Jennifer; Tamimi, Rulla M.; Taylor, Jack A.; Tollenaar, Rob A. E. M.; Tomlinson, Ian; Troester, Melissa A.; Truong, Therese; Vachon, Celine M.; van Veen, Elke M.; Wang, Sophia S.; Weinberg, Clarice R.; Wendt, Camilla; Wildiers, Hans; Winqvist, Robert; Wolk, Alicja; Zheng, Wei; Ziogas, Argyrios; Dunning, Alison M.; Pharoah, Paul D. P.; Easton, Douglas F.; Howie, A. Forbes; Peto, Julian; dos-Santos-Silva, Isabel; Swerdlow, Anthony J.; Chang-Claude, Jenny; Schmidt, Marjanka K.; Orr, Nick; Fletcher, Olivia
Source
British Journal of Cancer. 124(4):842-854
Subject
Language
English
Abstract
Background Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk. Methods We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry. Results For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 x 10(-18)); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 x 10(-8)). Conclusions The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.