CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers
Authors:   NBCS Collaborators, Johnson Nichola ,   AOCS Group,   ABCTB Investigators,   kConFab Investigators, Maguire Sarah , Morra Anna , Kapoor Pooja Middha , Tomczyk Katarzyna , Jones Michael E. , Schoemaker Minouk J. , Gilham Clare , Bolla Manjeet K. , Wang Qin , Dennis Joe , Ahearn Thomas U. , Andrulis Irene L. , Anton-Culver Hoda , Antonenkova Natalia N. , Arndt Volker , Aronson Kristan J. , Augustinsson Annelie , Baynes Caroline , Freeman Laura E. Beane , Beckmann Matthias W. , Benitez Javier , Bermisheva Marina , Blomqvist Carl , Boeckx Bram , Bogdanova Natalia V. , Bojesen Stig E. , Brauch Hiltrud , Brenner Hermann , Burwinkel Barbara , Campa Daniele , Canzian Federico , Castelao Jose E. , Chanock Stephen J. , Chenevix-Trench Georgia , Clarke Christine L. , Conroy Don M. , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Dörk Thilo , Eliassen A. Heather , Engel Christoph , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine , Floris Giuseppe , Flyger Henrik , Gago-Dominguez Manuela , Gapstur Susan M. , García-Closas Montserrat , Gaudet Mia M. , Giles Graham G. , Goldberg Mark S. , González-Neira Anna , Guénel Pascal , Hahnen Eric , Haiman Christopher A. , Håkansson Niclas , Hall Per , Hamann Ute , Harrington Patricia A. , Hart Steven N. , Hooning Maartje J. , Hopper John L. , Howell Anthony , Hunter David J. , Jager Agnes , Jakubowska Anna , John Esther M. , Kaaks Rudolf , Keeman Renske , Khusnutdinova Elza , Kitahara Cari M. , Kosma Veli-Matti , Koutros Stella , Kraft Peter , Kristensen Vessela N. , Kurian Allison W. , Lambrechts Diether , Le Marchand Loic , Linet Martha , Lubiński Jan , Mannermaa Arto , Manoukian Siranoush , Margolin Sara , Martens John W. M. , Mavroudis Dimitrios , Mayes Rebecca , Meindl Alfons , Milne Roger L. , Neuhausen Susan L. , Nevanlinna Heli , Newman William G. , Nielsen Sune F. , Nordestgaard Børge G. , Obi Nadia , Olshan Andrew F. , Olson Janet E. , Olsson Håkan , Orban Ester , Park-Simon Tjoung-Won , Peterlongo Paolo , Plaseska-Karanfilska Dijana , Pylkäs Katri , Rennert Gad , Rennert Hedy S. , Ruddy Kathryn J. , Saloustros Emmanouil , Sandler Dale P. , Sawyer Elinor J. , Schmutzler Rita K. , Scott Christopher , Shu Xiao-Ou , Simard Jacques , Smichkoska Snezhana , Sohn Christof , Southey Melissa C. , Spinelli John J. , Stone Jennifer , Tamimi Rulla M. , Taylor Jack A. , Tollenaar Rob A. E. M. , Tomlinson Ian , Troester Melissa A. , Truong Thérèse , Vachon Celine M. , van Veen Elke M. , Wang Sophia S. , Weinberg Clarice R. , Wendt Camilla , Wildiers Hans , Winqvist Robert , Wolk Alicja , Zheng Wei , Ziogas Argyrios , Dunning Alison M. , Pharoah Paul D. P. , Easton Douglas F. , Howie A. Forbes , Peto Julian , dos-Santos-Silva Isabel , Swerdlow Anthony J. , Chang-Claude Jenny , Schmidt Marjanka K. , Orr Nick , Fletcher Olivia 
Published: January 2021

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.