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

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.

Metadata

Authors/Creators:

Johnson, N
Maguire, S
Morra, A
Kapoor, PM
Tomczyk, K
Jones, ME
Schoemaker, MJ
Gilham, C
Bolla, MK
Wang, Q
Dennis, J
Ahearn, TU
Andrulis, IL
Anton-Culver, H
Antonenkova, NN
Arndt, V
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
Conroy, DM
Couch, FJ
Cox, A https://orcid.org/0000-0002-5138-1099
Cross, SS https://orcid.org/0000-0003-2044-1754
Czene, K
Dörk, T
Eliassen, AH
Engel, C
Evans, DG
Fasching, PA
Figueroa, J
Floris, G
Flyger, H
Gago-Dominguez, M
Gapstur, SM
García-Closas, M
Gaudet, MM
Giles, GG
Goldberg, MS
González-Neira, A
Guénel, P
Hahnen, E
Haiman, CA
Håkansson, N
Hall, P
Hamann, U
Harrington, PA
Hart, SN
Hooning, MJ
Hopper, JL
Howell, A
Hunter, DJ
Jager, A
Jakubowska, A
John, EM
Kaaks, R
Keeman, R
Khusnutdinova, E
Kitahara, CM
Kosma, V-M
Koutros, S
Kraft, P
Kristensen, VN
Kurian, AW
Lambrechts, D
Le Marchand, L
Linet, M
Lubiński, J
Mannermaa, A
Manoukian, S
Margolin, S
Martens, JWM
Mavroudis, D
Mayes, R
Meindl, A
Milne, RL
Neuhausen, SL
Nevanlinna, H
Newman, WG
Nielsen, SF
Nordestgaard, BG
Obi, N
Olshan, AF
Olson, JE
Olsson, H
Orban, E
Park-Simon, T-W
Peterlongo, P
Plaseska-Karanfilska, D
Pylkäs, K
Rennert, G
Rennert, HS
Ruddy, KJ
Saloustros, E
Sandler, DP
Sawyer, EJ
Schmutzler, RK
Scott, C
Shu, X-O
Simard, J
Smichkoska, S
Sohn, C
Southey, MC
Spinelli, JJ
Stone, J
Tamimi, RM
Taylor, JA
Tollenaar, RAEM
Tomlinson, I
Troester, MA
Truong, T
Vachon, CM
van Veen, EM
Wang, SS
Weinberg, CR
Wendt, C
Wildiers, H
Winqvist, R
Wolk, A
Zheng, W
Ziogas, A
Dunning, AM
Pharoah, PDP
Easton, DF
Howie, AF
Peto, J
dos-Santos-Silva, I
Swerdlow, AJ
Chang-Claude, J
Schmidt, MK
Orr, N
Fletcher, O

© The Author(s) 2021. Published by Springer Nature on behalf of Cancer Research UK. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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