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.; 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.; Borresen-Dale, A. -L.; Alnaes, G. I. G.; Sahlberg, K. K.; Ottestad, L.; Karesen, R.; Schlichting, E.; Holmen, M. M.; Sauer, T.; Haakensen, V.; Engebraten, O.; Naume, B.; Fossa, A.; Kiserud, C. E.; Reinertsen, K. V.; Helland, A.; Riis, M.; Geisler, J.; 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.; Bowtell, D. D. L.; Defazio, A.; Webb, P. M.; 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.; Clarke, C.; Marsh, D.; Scott, R.; Baxter, R.; Yip, D.; Carpenter, J.; Davis, A.; Pathmanathan, N.; Simpson, P.; Graham, D.; Sachchithananthan, M.; Amor, D.; Andrews, L.; Antill, Y.; Balleine, R.; Beesley, J.; Bennett, I.; Bogwitz, M.; Botes, L.; Brennan, M.; Brown, M.; Buckley, M.; Burke, J.; Butow, P.; Caldon, L.; Campbell, I.; Chauhan, D.; Chauhan, M.; Christian, A.; Cohen, P.; Colley, A.; Crook, A.; Cui, J.; Cummings, M.; Dawson, S. -J.; Delatycki, M.; Dickson, R.; Dixon, J.; Edkins, T.; Edwards, S.; Farshid, G.; Fellows, A.; Fenton, G.; Field, M.; Flanagan, J.; Fong, P.; Forrest, L.; Fox, S.; French, J.; Friedlander, M.; Gaff, C.; Gattas, M.; George, P.; Greening, S.; Harris, M.; Hart, S.; Hayward, N.; Hopper, J.; Hoskins, C.; Hunt, C.; James, P.; Jenkins, M.; Kidd, A.; Kirk, J.; Koehler, J.; Kollias, J.; Lakhani, S.; Lawrence, M.; Lindeman, G.; Lipton, L.; Lobb, L.; Mann, G.; Marsh, D.; Mclachlan, S. A.; Meiser, B.; Milne, R. L.; Nightingale, S.; O'Connell, S.; O'Sullivan, S.; Ortega, D. G.; Pachter, N.; Patterson, B.; Pearn, A.; Phillips, K.; Pieper, E.; Rickard, E.; Robinson, B.; Saleh, M.; Salisbury, E.; Saunders, C.; Saunus, J.; Scott, C.; Sexton, A.; Shelling, A.; Simpson, P.; Southey, M. C.; Spurdle, A.; Taylor, J.; Taylor, R.; Thorne, H.; Trainer, A.; Tucker, K.; Visvader, J.; Walker, L.; Williams, R.; Winship, I.; Young, M. A.; Jager, A.; Jakubowska, A.; Jakubowska, A.; Kaaks, R.; Keeman, R.; Khusnutdinova, E.; Khusnutdinova, E.; Kitahara, C. M.; Kosma, V. -M.; Koutros, S.; Kraft, P.; Kristensen, V. N.; Kurian, A. W.; Lambrechts, D.; Le Marchand, L.; Linet, M.; Lubinski, J.; Mannermaa, A.; Manoukian, S.; Margolin, S.; Martens, J. W. M.; Mavroudis, D.; Mayes, R.; Meindl, A.; 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.; 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.; Van Veen, E. M.; 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.

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.