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; Anne Lise Børresen-Dale; Grethe I.Grenaker Alnæs; Kristine K. Sahlberg; Lars Ottestad; Rolf Kåresen; Ellen Schlichting; Marit Muri Holmen; Toril Sauer; Vilde Haakensen; Margit Riis; Henrik Flyger; Sune F. Nielsen; Børge G. Nordestgaard; Christopher Scott; NBCS Collaborators; AOCS Group; ABCTB Investigators; kConFab Investigators

doi:10.1038/s41416-020-01185-w

CYP3A71C* 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, Anne Lise Børresen-Dale, Grethe I.Grenaker Alnæs, Kristine K. Sahlberg, Lars Ottestad, Rolf Kåresen, Ellen Schlichting, Marit Muri Holmen, Toril Sauer, Vilde Haakensen, Margit Riis, Henrik Flyger, Sune F. Nielsen, Børge G. Nordestgaard, Christopher Scott, NBCS Collaborators, AOCS Group, ABCTB Investigators, kConFab Investigators

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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 - 2021

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Publisher Copyright:
© 2021, The Author(s).

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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., ... kConFab Investigators (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, Børresen-Dale, AL, Alnæs, GIG, Sahlberg, KK, Ottestad, L, Kåresen, R, Schlichting, E, Holmen, MM, Sauer, T, Haakensen, V, Riis, M, Flyger, H, Nielsen, SF, Nordestgaard, BG, Scott, C, NBCS Collaborators, AOCS Group, ABCTB Investigators & kConFab Investigators 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

@article{635020ce494e441398ae799efb553e08,

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 B{\o}rresen-Dale, {Anne Lise} and Aln{\ae}s, {Grethe I.Grenaker} and Sahlberg, {Kristine K.} and Lars Ottestad and Rolf K{\aa}resen and Ellen Schlichting and Holmen, {Marit Muri} and Toril Sauer and Vilde Haakensen and Margit Riis and Henrik Flyger and Nielsen, {Sune F.} and Nordestgaard, {B{\o}rge G.} and Christopher Scott and {NBCS Collaborators} and {AOCS Group} and {ABCTB Investigators} and {kConFab Investigators}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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 - Børresen-Dale, Anne Lise

AU - Alnæs, Grethe I.Grenaker

AU - Sahlberg, Kristine K.

AU - Ottestad, Lars

AU - Kåresen, Rolf

AU - Schlichting, Ellen

AU - Holmen, Marit Muri

AU - Sauer, Toril

AU - Haakensen, Vilde

AU - Riis, Margit

AU - Flyger, Henrik

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Scott, Christopher

AU - NBCS Collaborators

AU - AOCS Group

AU - ABCTB Investigators

AU - kConFab Investigators

PY - 2021

Y1 - 2021

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.

U2 - 10.1038/s41416-020-01185-w

DO - 10.1038/s41416-020-01185-w

M3 - Journal article

C2 - 33495599

AN - SCOPUS:85099996359

SN - 0007-0920

VL - 124

SP - 842

EP - 854

JO - British Journal of Cancer

JF - British Journal of Cancer

IS - 4

ER -