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

Johnson, N Maguire, S Morra, A Kapoor, PM Tomczyk, K Jones, ME Schoemaker, MJ Gilham, C Bolla, MK Wang, Q Dennis, J Floris, G Flyger, H Gago-Dominguez, M Gapstur, SM García-Closas, M Gaudet, MM Giles, GG Goldberg, MS González-Neira, A AOCS Group, Nordestgaard, BG Guénel, P Hahnen, E Haiman, CA Håkansson, N Hall, P Hamann, U Harrington, PA Hart, SN Hooning, MJ Hopper, JL Obi, N Howell, A Hunter, DJ ABCTB Investigators, kConFab Investigators, Jager, A Jakubowska, A John, EM Kaaks, R Keeman, R Khusnutdinova, E Olshan, AF Kitahara, CM Kosma, V-M Koutros, S Kraft, P Kristensen, VN Kurian, AW Lambrechts, D Le Marchand, L Linet, M Lubiński, J Olson, JE Mannermaa, A Manoukian, S Margolin, S Martens, JWM Mavroudis, D Mayes, R Meindl, A Milne, RL Neuhausen, SL Nevanlinna, H Olsson, H Newman, WG Nielsen, SF Orban, E Park-Simon, T-W Peterlongo, P Plaseska-Karanfilska, D Pylkäs, K Ahearn, TU Rennert, G Rennert, HS Ruddy, KJ Saloustros, E Sandler, DP Sawyer, EJ Schmutzler, RK Scott, C Shu, X-O Simard, J Andrulis, IL Smichkoska, S Sohn, C Southey, MC Spinelli, JJ Stone, J Tamimi, RM Taylor, JA Tollenaar, RAEM Tomlinson, I Troester, MA Anton-Culver, H Truong, T Vachon, CM van Veen, EM Wang, SS Weinberg, CR Wendt, C Wildiers, H Winqvist, R Wolk, A Zheng, W Antonenkova, NN Ziogas, A Dunning, AM Pharoah, PDP Easton, DF Howie, AF Peto, J Dos-Santos-Silva, I Swerdlow, AJ Chang-Claude, J Schmidt, MK Arndt, V Orr, N Fletcher, O Aronson, KJ Augustinsson, A Baynes, C Freeman, LEB Beckmann, MW Benitez, J Bermisheva, M Blomqvist, C Boeckx, B Bogdanova, NV Bojesen, SE Brauch, H Brenner, H Burwinkel, B Campa, D Canzian, F Castelao, JE Chanock, SJ Chenevix-Trench, G Clarke, CL NBCS Collaborators, Conroy, DM Couch, FJ Cox, A Cross, SS Czene, K Dörk, T Eliassen, AH Engel, C Evans, DG Fasching, PA Figueroa, J
Publisher:
Springer Science and Business Media LLC
Publication Type:
Journal Article
Citation:
British journal of cancer, 2021, 124, (4), pp. 842-854
Issue Date:
2021-02
Full metadata record

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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