Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Aayah Nounu; Siddhartha P Kar; Caroline L Relton; Rebecca C Richmond

doi:10.1186/s13058-022-01553-9

Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Aayah Nounu^*, Siddhartha P Kar, Caroline L Relton, Rebecca C Richmond

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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64 Downloads (Pure)

Abstract

BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.

METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.

RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.

CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

Original language	English
Article number	66
Journal	Breast Cancer Research
Volume	24
Issue number	1
DOIs	https://doi.org/10.1186/s13058-022-01553-9
Publication status	Published - 8 Oct 2022

Bibliographical note

Funding Information:
AN and CLR were funded by Cancer Research UK (C18281/A29019, CLR). RCR is a de Pass Vice Chancellor Research Fellow at the University of Bristol. AN and SK are currently supported by a UK Research and Innovation Future Leaders Fellowship (UKRI FLF) to SK (MR/T043202/1).

Publisher Copyright:
© 2022, The Author(s).

Research Groups and Themes

ICEP

Keywords

17-alpha-Hydroxyprogesterone
Adult
Aldosterone
Androstenedione
Breast Neoplasms/epidemiology
Dehydroepiandrosterone Sulfate
Estradiol
Female
Genome-Wide Association Study
Gonadal Steroid Hormones
Humans
Hydrocortisone
Longitudinal Studies
Mendelian Randomization Analysis
Progesterone
Sex Hormone-Binding Globulin
Testosterone

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1186/s13058-022-01553-9

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This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://doi.org/10.1186/s13058-022-01553-9 . Please refer to any applicable terms of use of the publisher.
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Persistent link

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival
Martin, R. M. (Principal Investigator)
1/10/20 → 30/09/25
Project: Research

Additional file 1 of Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study
Nounu, A. (Creator), Kar, S. P. (Creator), Relton, C. L. (Creator) & Richmond, R. C. (Creator), figshare, 10 Oct 2022
DOI: 10.6084/m9.figshare.21303008, https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Sex_steroid_hormones_and_risk_of_breast_cancer_a_two-sample_Mendelian_randomization_study/21303008
Dataset
Additional file 1 of Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study, Version 1
Nounu, A. (Creator), Kar, S. P. (Creator), Relton, C. L. (Creator) & Richmond, R. C. (Creator), figshare, 10 Oct 2022
DOI: 10.6084/m9.figshare.21303008.v1, https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Sex_steroid_hormones_and_risk_of_breast_cancer_a_two-sample_Mendelian_randomization_study/21303008/1
Dataset

Cite this

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title = "Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study",

abstract = "BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.",

keywords = "17-alpha-Hydroxyprogesterone, Adult, Aldosterone, Androstenedione, Breast Neoplasms/epidemiology, Dehydroepiandrosterone Sulfate, Estradiol, Female, Genome-Wide Association Study, Gonadal Steroid Hormones, Humans, Hydrocortisone, Longitudinal Studies, Mendelian Randomization Analysis, Progesterone, Sex Hormone-Binding Globulin, Testosterone",

author = "Aayah Nounu and Kar, {Siddhartha P} and Relton, {Caroline L} and Richmond, {Rebecca C}",

note = "Funding Information: AN and CLR were funded by Cancer Research UK (C18281/A29019, CLR). RCR is a de Pass Vice Chancellor Research Fellow at the University of Bristol. AN and SK are currently supported by a UK Research and Innovation Future Leaders Fellowship (UKRI FLF) to SK (MR/T043202/1). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = oct,

day = "8",

doi = "10.1186/s13058-022-01553-9",

language = "English",

volume = "24",

journal = "Breast Cancer Research",

issn = "1465-5411",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Sex steroid hormones and risk of breast cancer

T2 - a two-sample Mendelian randomization study

AU - Nounu, Aayah

AU - Kar, Siddhartha P

AU - Relton, Caroline L

AU - Richmond, Rebecca C

N1 - Funding Information: AN and CLR were funded by Cancer Research UK (C18281/A29019, CLR). RCR is a de Pass Vice Chancellor Research Fellow at the University of Bristol. AN and SK are currently supported by a UK Research and Innovation Future Leaders Fellowship (UKRI FLF) to SK (MR/T043202/1). Publisher Copyright: © 2022, The Author(s).

PY - 2022/10/8

Y1 - 2022/10/8

N2 - BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

AB - BACKGROUND: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.METHODS: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.RESULTS: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.CONCLUSIONS: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

KW - 17-alpha-Hydroxyprogesterone

KW - Adult

KW - Aldosterone

KW - Androstenedione

KW - Breast Neoplasms/epidemiology

KW - Dehydroepiandrosterone Sulfate

KW - Estradiol

KW - Female

KW - Genome-Wide Association Study

KW - Gonadal Steroid Hormones

KW - Humans

KW - Hydrocortisone

KW - Longitudinal Studies

KW - Mendelian Randomization Analysis

KW - Progesterone

KW - Sex Hormone-Binding Globulin

KW - Testosterone

U2 - 10.1186/s13058-022-01553-9

DO - 10.1186/s13058-022-01553-9

M3 - Article (Academic Journal)

C2 - 36209141

SN - 1465-5411

VL - 24

JO - Breast Cancer Research

JF - Breast Cancer Research

IS - 1

M1 - 66

ER -

Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Abstract

Bibliographical note

Research Groups and Themes

Keywords

UN SDGs

Access to Document

Handle.net

Fingerprint

Projects

8074 (C18281/A29019) ICEP2 - Programme Award: Towards improved casual evidence and enhanced prediction of cancer risk and survival

Datasets

Additional file 1 of Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Additional file 1 of Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study, Version 1

Cite this