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Title: CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.
Authors: Johnson N,  Maguire S,  Morra A,  Kapoor PM,  Tomczyk K,  Jones ME,  Schoemaker MJ,  Gilham C,  Bolla MK,  Wang Q,  Dennis J,  Ahearn TU,  Andrulis IL,  Anton-Culver H,  Antonenkova NN,  Arndt V,  Aronson KJ,  Augustinsson A,  Baynes C,  Freeman LEB,  Beckmann MW,  Benitez J,  Bermisheva M,  Blomqvist C,  Boeckx B,  Bogdanova NV,  Bojesen SE,  Brauch H,  Brenner H,  Burwinkel B,  Campa D,  Canzian F,  Castelao JE,  Chanock SJ,  Chenevix-Trench G,  Clarke CL,  NBCS Collaborators,  Conroy DM,  Couch FJ,  Cox A,  Cross SS,  Czene K,  Dörk T,  Eliassen AH,  Engel C,  Evans DG,  Fasching PA,  Figueroa J,  Floris G,  Flyger H,  Gago-Dominguez M,  Gapstur SM,  García-Closas M,  Gaudet MM,  Giles GG,  Goldberg MS,  González-Neira A,  AOCS Group,  Guénel P,  Hahnen E,  Haiman CA,  Håkansson N,  Hall P,  Hamann U,  Harrington PA,  Hart SN,  Hooning MJ,  Hopper JL,  Howell A,  Hunter DJ,  ABCTB Investigators,  kConFab Investigators,  Jager A,  Jakubowska A,  John EM,  Kaaks R,  Keeman R,  Khusnutdinova E,  Kitahara CM,  Kosma VM,  Koutros S,  Kraft P,  Kristensen VN,  Kurian AW,  Lambrechts D,  Le Marchand L,  Linet M,  Lubiński J,  Mannermaa A,  Manoukian S,  Margolin S,  Martens JWM,  Mavroudis D,  Mayes R,  Meindl A,  Milne RL,  Neuhausen SL,  Nevanlinna H,  Newman WG,  Nielsen SF,  Nordestgaard BG,  Obi N,  Olshan AF,  Olson JE,  Olsson H,  Orban E,  Park-Simon TW,  Peterlongo P,  Plaseska-Karanfilska D,  Pylkäs K,  Rennert G,  Rennert HS,  Ruddy KJ,  Saloustros E,  Sandler DP,  Sawyer EJ,  Schmutzler RK,  Scott C,  Shu XO,  Simard J,  Smichkoska S,  Sohn C,  Southey MC,  Spinelli JJ,  Stone J,  Tamimi RM,  Taylor JA,  Tollenaar RAEM,  Tomlinson I,  Troester MA,  Truong T,  Vachon CM,  van Veen EM,  Wang SS,  Weinberg CR,  Wendt C,  Wildiers H,  Winqvist R,  Wolk A,  Zheng W,  Ziogas A,  Dunning AM,  Pharoah PDP,  Easton DF,  Howie AF,  Peto J,  Dos-Santos-Silva I,  Swerdlow AJ,  Chang-Claude J,  Schmidt MK,  Orr N,  Fletcher O
Journal: Br J Cancer
Date: 2021 Feb
Branches: CGR, OD, OEEB, REB, TDRP
PubMed ID: 33495599
PMC ID: PMC7884683
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.