CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.
Nichola Johnson,
Sarah Maguire,
Anna Morra,
Pooja Middha Kapoor,
Katarzyna Tomczyk,
Michael E Jones,
Minouk J Schoemaker,
Clare Gilham,
Manjeet K Bolla,
Qin Wang,
Joe Dennis,
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,
Barbara Burwinkel,
Daniele Campa,
Federico Canzian,
Jose E Castelao,
Stephen J Chanock,
Georgia Chenevix-Trench,
Christine L Clarke,
,
Don M Conroy,
Fergus J Couch,
Angela Cox,
Simon S Cross,
Kamila Czene,
Thilo Dörk,
A Heather Eliassen,
Christoph Engel,
D Gareth Evans,
Peter A Fasching,
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,
,
Pascal Guénel,
Eric Hahnen,
Christopher A Haiman,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Patricia A Harrington,
Steven N Hart,
Maartje J Hooning,
John L Hopper,
Anthony Howell,
David J Hunter,
,
,
Agnes Jager,
Anna Jakubowska,
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,
Diether Lambrechts,
Loic Le Marchand,
Martha Linet,
Jan Lubiński,
Arto Mannermaa,
Siranoush Manoukian,
Sara Margolin,
John W M 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,
Dijana Plaseska-Karanfilska,
Katri Pylkäs,
Gad Rennert,
Hedy S Rennert,
Kathryn J Ruddy,
Emmanouil Saloustros,
Dale P Sandler,
Elinor J Sawyer,
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 A E M Tollenaar,
Ian Tomlinson,
Melissa A Troester,
Thérèse Truong,
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 D P Pharoah,
Douglas F Easton,
A Forbes Howie,
Julian Peto,
Isabel Dos-Santos-Silva,
Anthony J Swerdlow,
Jenny Chang-Claude,
Marjanka K Schmidt,
Nick Orr,
Olivia Fletcher
Abstract
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.
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.
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).
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.