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

Johnson, N.; Maguire, S.; Morra, A.; Kapoor, P.M.; Tomczyk, K.; Jones, M.E.; ... ; kConFab Investigators (2021)

Article / Letter to editor

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 x 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 x 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.

• All authors: Johnson, N.; Maguire, S.; Morra, A.; Kapoor, P.M.; Tomczyk, K.; Jones, M.E.; Schoemaker, M.J.; Gilham, C.; Bolla, M.K.; Wang, Q.; Dennis, J.; Ahearn, T.U.; Andrulis, I.L.; Anton-Culver, H.; Antonenkova, N.N.; Arndt, V.; Aronson, K.J.; Augustinsson, A.; Baynes, C.; Freeman, L.E.B.; Beckmann, M.W.; Benitez, J.; Bermisheva, M.; Blomqvist, C.; Boeckx, B.; Bogdanova, N.V.; Bojesen, S.E.; Brauch, H.; Brenner, H.; Burwinkel, B.; Campa, D.; Canzian, F.; Castelao, J.E.; Chanock, S.J.; Chenevix-Trench, G.; Clarke, C.L.; Conroy, D.M.; Couch, F.J.; Cox, A.; Cross, S.S.; Czene, K.; Dork, T.; Eliassen, A.H.; Engel, C.; Evans, D.G.; Fasching, P.A.; Figueroa, J.; Floris, G.; Flyger, H.; Gago-Dominguez, M.; Gapstur, S.M.; Garcia-Closas, M.; Gaudet, M.M.; Giles, G.G.; Goldberg, M.S.; Gonzalez-Neira, A.; Guenel, P.; Hahnen, E.; Haiman, C.A.; Hakansson, N.; Hall, P.; Hamann, U.; Harrington, P.A.; Hart, S.N.; Hooning, M.J.; Hopper, J.L.; Howell, A.; Hunter, D.J.; Jager, A.; Jakubowska, A.; John, E.M.; Kaaks, R.; Keeman, R.; Khusnutdinova, E.; Kitahara, C.M.; Kosma, V.M.; Koutros, S.; Kraft, P.; Kristensen, V.N.; Kurian, A.W.; Lambrechts, D.; Marchand, L. le; Linet, M.; Lubinski, J.; Mannermaa, A.; Manoukian, S.; Margolin, S.; Martens, J.W.M.; Mavroudis, D.; Mayes, R.; Meindl, A.; Milne, R.L.; Neuhausen, S.L.; Nevanlinna, H.; Newman, W.G.; Nielsen, S.F.; Nordestgaard, B.G.; Obi, N.; Olshan, A.F.; Olson, J.E.; Olsson, H.; Orban, E.; Park-Simon, T.W.; Peterlongo, P.; Plaseska-Karanfilska, D.; Pylkas, K.; Rennert, G.; Rennert, H.S.; Ruddy, K.J.; Saloustros, E.; Sandler, D.P.; Sawyer, E.J.; Schmutzler, R.K.; Scott, C.; Shu, X.O.; Simard, J.; Smichkoska, S.; Sohn, C.; Southey, M.C.; Spinelli, J.J.; Stone, J.; Tamimi, R.M.; Taylor, J.A.; Tollenaar, R.A.E.M.; Tomlinson, I.; Troester, M.A.; Truong, T.; Vachon, C.M.; Veen, E.M. van; Wang, S.S.; Weinberg, C.R.; Wendt, C.; Wildiers, H.; Winqvist, R.; Wolk, A.; Zheng, W.; Ziogas, A.; Dunning, A.M.; Pharoah, P.D.P.; Easton, D.F.; Howie, A.F.; Peto, J.; dos-Santos-Silva, I.; Swerdlow, A.J.; Chang-Claude, J.; Schmidt, M.K.; Orr, N.; Fletcher, O.; NBCS Collaborators; AOCS Grp; ABCTB Investigators; kConFab Investigators
• Date: 2021-01-26
• Journal: British Journal of Cancer
• Volume: 124
• Issue: 4
• Pages: 842 - 854
• DOI: doi:10.1038/s41416-020-01185-w
• Link: https://www.nature.com/articles/s41416-020-01185-w.pdf