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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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