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

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 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

Research output: Contribution to journal › Article › peer-review

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
Early online date	26 Jan 2021
DOIs	https://doi.org/10.1038/s41416-020-01185-w
Publication status	Published - 26 Jan 2021

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http://www.nature.com/articles/s41416-020-01185-w

Cite this

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., ... Fletcher, O. (2021). CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers. British Journal of Cancer. https://doi.org/10.1038/s41416-020-01185-w

@article{74c4afd2adb54aee9e8ec31d7ac3108f,

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 Giuseppe Floris and Henrik Flyger and Manuela Gago-dominguez and Gapstur, \{Susan M.\} and Montserrat Garc{\'i}a-closas and Gaudet, \{Mia M.\} and Giles, \{Graham G.\} and Goldberg, \{Mark S.\} and Anna Gonz{\'a}lez-neira and Pascal Gu{\'e}nel and Eric Hahnen and Haiman, \{Christopher A.\} and Niclas H{\aa}kansson and Per Hall and Ute Hamann and Harrington, \{Patricia A.\} and Hart, \{Steven N.\} and Hooning, \{Maartje J.\} and Hopper, \{John L.\} and Anthony Howell and Hunter, \{David J.\} and Agnes Jager and Anna Jakubowska and John, \{Esther M.\} and Rudolf Kaaks and Renske Keeman and Elza Khusnutdinova and Kitahara, \{Cari M.\} and Veli-matti Kosma and Stella Koutros and Peter Kraft and Kristensen, \{Vessela N.\} and Kurian, \{Allison W.\} and Diether Lambrechts and \{Le Marchand\}, Loic and Martha Linet and Jan Lubi{\'n}ski and Arto Mannermaa and Siranoush Manoukian and Sara Margolin and Martens, \{John W. M.\} and Dimitrios Mavroudis and Rebecca Mayes and Alfons Meindl and Milne, \{Roger L.\} and Neuhausen, \{Susan L.\} and Heli Nevanlinna and Newman, \{William G.\} and Nielsen, \{Sune F.\} and Nordestgaard, \{B{\o}rge G.\} and Nadia Obi and Olshan, \{Andrew F.\} and Olson, \{Janet E.\} and H{\aa}kan Olsson and Ester Orban and Tjoung-won Park-simon and Paolo Peterlongo and Dijana Plaseska-karanfilska and Katri Pylk{\"a}s and Gad Rennert and Rennert, \{Hedy S.\} and Ruddy, \{Kathryn J.\} and Emmanouil Saloustros and Sandler, \{Dale P.\} and Sawyer, \{Elinor J.\} and Schmutzler, \{Rita K.\} and Christopher Scott and Xiao-ou Shu and Jacques Simard and Snezhana Smichkoska and Christof Sohn and Southey, \{Melissa C.\} and Spinelli, \{John J.\} and Jennifer Stone and Tamimi, \{Rulla M.\} and Taylor, \{Jack A.\} and Tollenaar, \{Rob A. E. M.\} and Ian Tomlinson and Troester, \{Melissa A.\} and Th{\'e}r{\`e}se Truong and Vachon, \{Celine M.\} and \{Van Veen\}, \{Elke M.\} and Wang, \{Sophia S.\} and Weinberg, \{Clarice R.\} and Camilla Wendt and Hans Wildiers and Robert Winqvist and Alicja Wolk and Wei Zheng and Argyrios Ziogas and Dunning, \{Alison M.\} and Pharoah, \{Paul D. P.\} and Easton, \{Douglas F.\} and Howie, \{A. Forbes\} and Julian Peto and Isabel Dos-santos-silva and Swerdlow, \{Anthony J.\} and Jenny Chang-claude and Schmidt, \{Marjanka K.\} and Nick Orr and Olivia Fletcher",

year = "2021",

month = jan,

day = "26",

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

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Springer Nature",

}

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, Floris, G, Flyger, H, Gago-dominguez, M, Gapstur, SM, García-closas, M, Gaudet, MM, Giles, GG, Goldberg, MS, González-neira, A, Guénel, P, Hahnen, E, Haiman, CA, Håkansson, N, Hall, P, Hamann, U, Harrington, PA, Hart, SN, Hooning, MJ, Hopper, JL, Howell, A, Hunter, DJ, Jager, A, Jakubowska, A, John, EM, Kaaks, R, Keeman, R, Khusnutdinova, E, Kitahara, CM, Kosma, V, 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, T, Peterlongo, P, Plaseska-karanfilska, D, Pylkäs, K, Rennert, G, Rennert, HS, Ruddy, KJ, Saloustros, E, Sandler, DP, Sawyer, EJ, Schmutzler, RK, Scott, C, Shu, X, 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 2021, 'CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers', British Journal of Cancer. https://doi.org/10.1038/s41416-020-01185-w

TY - JOUR

T1 - CYP3A7*1C allele: 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 - Floris, Giuseppe

AU - Flyger, Henrik

AU - Gago-dominguez, Manuela

AU - Gapstur, Susan M.

AU - García-closas, Montserrat

AU - Gaudet, Mia M.

AU - Giles, Graham G.

AU - Goldberg, Mark S.

AU - González-neira, Anna

AU - Guénel, Pascal

AU - Hahnen, Eric

AU - Haiman, Christopher A.

AU - Håkansson, Niclas

AU - Hall, Per

AU - Hamann, Ute

AU - Harrington, Patricia A.

AU - Hart, Steven N.

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Howell, Anthony

AU - Hunter, David J.

AU - Jager, Agnes

AU - Jakubowska, Anna

AU - John, Esther M.

AU - Kaaks, Rudolf

AU - Keeman, Renske

AU - Khusnutdinova, Elza

AU - Kitahara, Cari M.

AU - Kosma, Veli-matti

AU - Koutros, Stella

AU - Kraft, Peter

AU - Kristensen, Vessela N.

AU - Kurian, Allison W.

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Linet, Martha

AU - Lubiński, Jan

AU - Mannermaa, Arto

AU - Manoukian, Siranoush

AU - Margolin, Sara

AU - Martens, John W. M.

AU - Mavroudis, Dimitrios

AU - Mayes, Rebecca

AU - Meindl, Alfons

AU - Milne, Roger L.

AU - Neuhausen, Susan L.

AU - Nevanlinna, Heli

AU - Newman, William G.

AU - Nielsen, Sune F.

AU - Nordestgaard, Børge G.

AU - Obi, Nadia

AU - Olshan, Andrew F.

AU - Olson, Janet E.

AU - Olsson, Håkan

AU - Orban, Ester

AU - Park-simon, Tjoung-won

AU - Peterlongo, Paolo

AU - Plaseska-karanfilska, Dijana

AU - Pylkäs, Katri

AU - Rennert, Gad

AU - Rennert, Hedy S.

AU - Ruddy, Kathryn J.

AU - Saloustros, Emmanouil

AU - Sandler, Dale P.

AU - Sawyer, Elinor J.

AU - Schmutzler, Rita K.

AU - Scott, Christopher

AU - Shu, Xiao-ou

AU - Simard, Jacques

AU - Smichkoska, Snezhana

AU - Sohn, Christof

AU - Southey, Melissa C.

AU - Spinelli, John J.

AU - Stone, Jennifer

AU - Tamimi, Rulla M.

AU - Taylor, Jack A.

AU - Tollenaar, Rob A. E. M.

AU - Tomlinson, Ian

AU - Troester, Melissa A.

AU - Truong, Thérèse

AU - Vachon, Celine M.

AU - Van Veen, Elke M.

AU - Wang, Sophia S.

AU - Weinberg, Clarice R.

AU - Wendt, Camilla

AU - Wildiers, Hans

AU - Winqvist, Robert

AU - Wolk, Alicja

AU - Zheng, Wei

AU - Ziogas, Argyrios

AU - Dunning, Alison M.

AU - Pharoah, Paul D. P.

AU - Easton, Douglas F.

AU - Howie, A. Forbes

AU - Peto, Julian

AU - Dos-santos-silva, Isabel

AU - Swerdlow, Anthony J.

AU - Chang-claude, Jenny

AU - Schmidt, Marjanka K.

AU - Orr, Nick

AU - Fletcher, Olivia

PY - 2021/1/26

Y1 - 2021/1/26

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 - Article

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

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