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

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

doi:10.1038/s41416-020-01185-w

Abstract

BackgroundEpidemiological 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.MethodsWe 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.ResultsFor 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).ConclusionsThe 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.

Highlights

Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer
To determine whether the CYP3A7*1C allele influences metabolism of exogenous hormones, we evaluated gene-environment interactions with menopausal hormone treatment for breast cancer risk, and to investigate whether adult expression of CYP3A7 impacts on agents used in treating cancer, we analysed associations with breast cancerspecific survival
Since hormone levels may be influenced by both demographic and reproductive factors, we adjusted for age at urine collection, age at menarche, body mass index and parity; these adjustments did not alter the association

Summary

Introduction

Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. A subsequent GWAS of pre- and postmenopausal hormone levels found no association with plasma oestradiol at this locus; they did find associations at this locus with DHEAS and progesterone.[10]

Methods

Results

Conclusion