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; Henrik Flyger; Sune F Nielsen; Børge G Nordestgaard; NBCS Collaborators

doi:10.1038/s41416-020-01185-w

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 FreemanMatthias 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, Henrik Flyger, Sune F Nielsen, Børge G Nordestgaard, NBCS Collaborators

7 Citations (Scopus)

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.

Original language	English
Journal	British Journal of Cancer
Volume	124
Issue number	4
Pages (from-to)	842-854
Number of pages	13
ISSN	0007-0920
DOIs	https://doi.org/10.1038/s41416-020-01185-w
Publication status	Published - 16 Feb 2021

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Johnson, N., Maguire, S., Morra, A., Kapoor, P. M., Tomczyk, K., Jones, M. E., Schoemaker, M. J., Gilham, C., Bolla, M. K., Wang, Q., Dennis, J., Ahearn, T. U., Andrulis, I. L., Anton-Culver, H., Antonenkova, N. N., Arndt, V., Aronson, K. J., Augustinsson, A., Baynes, C., ... NBCS Collaborators (2021). CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. British Journal of Cancer, 124(4), 842-854. https://doi.org/10.1038/s41416-020-01185-w

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, Conroy, DM, Couch, FJ, Cox, A, Cross, SS, Czene, K, Dörk, T, Eliassen, AH, Engel, C, Evans, DG, Fasching, PA, Figueroa, J, Flyger, H , Nielsen, SF , Nordestgaard, BG & NBCS Collaborators 2021, 'CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers', British Journal of Cancer, vol. 124, no. 4, pp. 842-854. https://doi.org/10.1038/s41416-020-01185-w

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

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.",

author = "Nichola Johnson and Sarah Maguire and Anna Morra and Kapoor, {Pooja Middha} and Katarzyna Tomczyk and Jones, {Michael E} and Schoemaker, {Minouk J} and Clare Gilham and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Ahearn, {Thomas U} and Andrulis, {Irene L} and Hoda Anton-Culver and Antonenkova, {Natalia N} and Volker Arndt and Aronson, {Kristan J} and Annelie Augustinsson and Caroline Baynes and Freeman, {Laura E Beane} and Beckmann, {Matthias W} and Javier Benitez and Marina Bermisheva and Carl Blomqvist and Bram Boeckx and Bogdanova, {Natalia V} and Bojesen, {Stig E} and Hiltrud Brauch and Hermann Brenner and Barbara Burwinkel and Daniele Campa and Federico Canzian and Castelao, {Jose E} and Chanock, {Stephen J} and Georgia Chenevix-Trench and Clarke, {Christine L} and Conroy, {Don M} and Couch, {Fergus J} and Angela Cox and Cross, {Simon S} and Kamila Czene and Thilo D{\"o}rk and Eliassen, {A Heather} and Christoph Engel and Evans, {D Gareth} and Fasching, {Peter A} and Jonine Figueroa and Henrik Flyger and Nielsen, {Sune F} and Nordestgaard, {B{\o}rge G} and {NBCS Collaborators}",

year = "2021",

month = feb,

day = "16",

doi = "10.1038/s41416-020-01185-w",

language = "English",

volume = "124",

pages = "842--854",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - CYP3A7*1C allele

T2 - linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers

AU - Johnson, Nichola

AU - Maguire, Sarah

AU - Morra, Anna

AU - Kapoor, Pooja Middha

AU - Tomczyk, Katarzyna

AU - Jones, Michael E

AU - Schoemaker, Minouk J

AU - Gilham, Clare

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Ahearn, Thomas U

AU - Andrulis, Irene L

AU - Anton-Culver, Hoda

AU - Antonenkova, Natalia N

AU - Arndt, Volker

AU - Aronson, Kristan J

AU - Augustinsson, Annelie

AU - Baynes, Caroline

AU - Freeman, Laura E Beane

AU - Beckmann, Matthias W

AU - Benitez, Javier

AU - Bermisheva, Marina

AU - Blomqvist, Carl

AU - Boeckx, Bram

AU - Bogdanova, Natalia V

AU - Bojesen, Stig E

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Burwinkel, Barbara

AU - Campa, Daniele

AU - Canzian, Federico

AU - Castelao, Jose E

AU - Chanock, Stephen J

AU - Chenevix-Trench, Georgia

AU - Clarke, Christine L

AU - Conroy, Don M

AU - Couch, Fergus J

AU - Cox, Angela

AU - Cross, Simon S

AU - Czene, Kamila

AU - Dörk, Thilo

AU - Eliassen, A Heather

AU - Engel, Christoph

AU - Evans, D Gareth

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - Nielsen, Sune F

AU - Nordestgaard, Børge G

AU - NBCS Collaborators

PY - 2021/2/16

Y1 - 2021/2/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85099996359&partnerID=8YFLogxK

U2 - 10.1038/s41416-020-01185-w

DO - 10.1038/s41416-020-01185-w

M3 - Journal article

C2 - 33495599

SN - 0007-0920

VL - 124

SP - 842

EP - 854

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -

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

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