CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.
; Maguire, S; Morra, A; Kapoor, PM; Tomczyk, K; Jones, ME; Schoemaker, MJ; Gilham, C; Bolla, MK; Wang, Q; +142 more...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; NBCS Collaborators; Conroy, DM; Couch, FJ; Cox, A; Cross, SS; 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; AOCS Group; Guénel, P; Hahnen, E; Haiman, CA; Håkansson, N; Hall, P; Hamann, U; Harrington, PA; Hart, SN; Hooning, MJ; Hopper, JL; Howell, A; Hunter, DJ; ABCTB Investigators; kConFab Investigators; Jager, A; Jakubowska, A; John, EM; Kaaks, R; Keeman, R; Khusnutdinova, E; Kitahara, CM; Kosma, V; Koutros, S; Kraft, P; Kristensen, VN; Kurian, AW; Lambrechts, D; Le Marchand, L; Linet, M; Lubiński, J; Mannermaa, A; Manoukian, S; Margolin, S; Martens, JW; 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; 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; Simard, J; Smichkoska, S; Sohn, C; Southey, MC; Spinelli, JJ; Stone, J; Tamimi, RM; Taylor, JA; Tollenaar, RA; 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, PD; Easton, DF; Howie, AF; Peto, J; Dos-Santos-Silva, I; Swerdlow, AJ; Chang-Claude, J; Schmidt, MK; Orr, N; Fletcher, O and
(2021)
CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.
British journal of cancer, 124 (4).
pp. 842-854.
ISSN 0007-0920
DOI: 10.1038/s41416-020-01185-w
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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