CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
Journal
British Journal of Cancer
Date Issued
2021-01-26
Author(s)
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
Dörk, Thilo
Eliassen, A. Heather
Engel, Christoph
Evans, D. Gareth
Fasching, Peter A.
Figueroa, Jonine
Floris, Giuseppe
Flyger, Henrik
Gago-Dominguez, Manuela
Gapstur, Susan M.
García-Closas, Montserrat
Gaudet, Mia M.
Giles, Graham G.
Goldberg, Mark S.
González-Neira, Anna
Guénel, Pascal
Hahnen, Eric
Haiman, Christopher A.
Håkansson, 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
Lubiński, 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, Børge G.
Obi, Nadia
Olshan, Andrew F.
Olson, Janet E.
Olsson, Håkan
Orban, Ester
Park-Simon, Tjoung-Won
Peterlongo, Paolo
Plaseska-Karanfilska, Dijana
Pylkäs, 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
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, Thérèse
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
DOI
10.1038/s41416-020-01185-w
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 <jats:italic>CYP3A</jats:italic> 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%, <jats:italic>P</jats:italic> = 3.1 × 10<jats:sup>–18</jats:sup>); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, <jats:italic>P</jats:italic> = 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 × 10.
Conclusions
The CYP3A7*1C</jats:italic> 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.
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 <jats:italic>CYP3A</jats:italic> 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%, <jats:italic>P</jats:italic> = 3.1 × 10<jats:sup>–18</jats:sup>); in follow-up analyses, rs45446698-C was also associated with lower progesterone (−26.7%, 95% CI −39.4% to −11.6%, <jats:italic>P</jats:italic> = 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 × 10.
Conclusions
The CYP3A7*1C</jats:italic> 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.