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CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

  • 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
  • NBCS Collaborators
  • 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
  • AOCS Group
  • 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
  • ABCTB Investigators
  • kConFab Investigators
  • 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 WM
  • 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
  • Smichkoska, Snezhana
  • Sohn, Christof
  • Southey, Melissa C
  • Spinelli, John J
  • Stone, Jennifer
  • Tamimi, Rulla M
  • Taylor, Jack A
  • Tollenaar, Rob AEM
  • 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 DP
  • 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
  • et al.
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 × 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 × 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.

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