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

Nichola Johnson ORCID logo ; Sarah Maguire ; Anna Morra ; Pooja Middha Kapoor ORCID logo ; Katarzyna Tomczyk ; Michael E Jones ; Minouk J Schoemaker ; Clare Gilham ORCID logo ; Manjeet K Bolla ; Qin Wang ; +142 more... Joe Dennis ORCID logo ; Thomas U Ahearn ; Irene L Andrulis ; Hoda Anton-Culver ; Natalia N Antonenkova ; Volker Arndt ; Kristan J Aronson ; Annelie Augustinsson ; Caroline Baynes ; Laura E Beane Freeman ; Matthias W Beckmann ; Javier Benitez ; Marina Bermisheva ; Carl Blomqvist ; Bram Boeckx ; Natalia V Bogdanova ; Stig E Bojesen ; Hiltrud Brauch ; Hermann Brenner ORCID logo ; Barbara Burwinkel ; Daniele Campa ; Federico Canzian ORCID logo ; Jose E Castelao ; Stephen J Chanock ; Georgia Chenevix-Trench ; Christine L Clarke ; NBCS Collaborators ; Don M Conroy ; Fergus J Couch ; Angela Cox ORCID logo ; Simon S Cross ; Kamila Czene ; Thilo Dörk ; A Heather Eliassen ; Christoph Engel ; D Gareth Evans ; Peter A Fasching ORCID logo ; Jonine Figueroa ; Giuseppe Floris ; Henrik Flyger ; Manuela Gago-Dominguez ; Susan M Gapstur ; Montserrat García-Closas ; Mia M Gaudet ; Graham G Giles ; Mark S Goldberg ; Anna González-Neira ; AOCS Group ; Pascal Guénel ; Eric Hahnen ; Christopher A Haiman ; Niclas Håkansson ; Per Hall ; Ute Hamann ; Patricia A Harrington ; Steven N Hart ORCID logo ; Maartje J Hooning ; John L Hopper ; Anthony Howell ; David J Hunter ; ABCTB Investigators ; kConFab Investigators ; Agnes Jager ; Anna Jakubowska ORCID logo ; Esther M John ; Rudolf Kaaks ; Renske Keeman ; Elza Khusnutdinova ; Cari M Kitahara ; Veli-Matti Kosma ; Stella Koutros ; Peter Kraft ; Vessela N Kristensen ; Allison W Kurian ORCID logo ; Diether Lambrechts ; Loic Le Marchand ; Martha Linet ; Jan Lubiński ; Arto Mannermaa ; Siranoush Manoukian ; Sara Margolin ; John WM Martens ; Dimitrios Mavroudis ; Rebecca Mayes ; Alfons Meindl ; Roger L Milne ; Susan L Neuhausen ; Heli Nevanlinna ; William G Newman ; Sune F Nielsen ; Børge G Nordestgaard ; Nadia Obi ; Andrew F Olshan ; Janet E Olson ; Håkan Olsson ; Ester Orban ; Tjoung-Won Park-Simon ; Paolo Peterlongo ORCID logo ; Dijana Plaseska-Karanfilska ; Katri Pylkäs ; Gad Rennert ; Hedy S Rennert ; Kathryn J Ruddy ; Emmanouil Saloustros ; Dale P Sandler ; Elinor J Sawyer ORCID logo ; Rita K Schmutzler ; Christopher Scott ; Xiao-Ou Shu ; Jacques Simard ; Snezhana Smichkoska ; Christof Sohn ; Melissa C Southey ; John J Spinelli ; Jennifer Stone ; Rulla M Tamimi ; Jack A Taylor ; Rob AEM Tollenaar ; Ian Tomlinson ORCID logo ; Melissa A Troester ; Thérèse Truong ORCID logo ; Celine M Vachon ; Elke M van Veen ; Sophia S Wang ; Clarice R Weinberg ; Camilla Wendt ; Hans Wildiers ; Robert Winqvist ; Alicja Wolk ; Wei Zheng ; Argyrios Ziogas ; Alison M Dunning ; Paul DP Pharoah ORCID logo ; Douglas F Easton ; A Forbes Howie ; Julian Peto ORCID logo ; Isabel Dos-Santos-Silva ORCID logo ; Anthony J Swerdlow ; Jenny Chang-Claude ; Marjanka K Schmidt ; Nick Orr ; Olivia Fletcher ; (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
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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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