CYP3A variation, premenopausal estrone levels, and breast cancer risk

Nichola Johnson, Kate Walker-Springett, Lorna J Gibson, Nick Orr, Elizabeth Folkerd, Ben Haynes, Claire Palles, Ben Coupland, Minouk Schoemaker, Michael Jones, Peter Broderick, Elinor Sawyer, Michael J Kerin, Ian P Tomlinson, Marketa Zvelebil, Sarah Chilcott-Burns, Katarzyna Tomczyk, Gemma Simpson, Jill Williamson, Stephen G HillierGillian Ross, Richard S Houlston, Anthony J Swerdlow, Alan Ashworth, Mitch Dowsett, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.

METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.

RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).

CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Original languageEnglish
Pages (from-to)657-69
Number of pages13
JournalJournal of the National Cancer Institute
Volume104
Issue number9
DOIs
Publication statusPublished - 02 May 2012

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Cytochrome P-450 CYP3A
Estrone
Breast Neoplasms
Hormones
Confidence Intervals
Single Nucleotide Polymorphism
Odds Ratio
Steroids
Glucuronides
Risk Reduction Behavior
Menstrual Cycle
Multigene Family
Genes
Epidemiologic Studies
Chromosomes

Keywords

  • Adult
  • Age Factors
  • Androgens
  • Breast Neoplasms
  • Case-Control Studies
  • Cross-Sectional Studies
  • Cytochrome P-450 CYP3A
  • Estrone
  • European Continental Ancestry Group
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Glucuronides
  • Humans
  • Life Style
  • Linkage Disequilibrium
  • Mammography
  • Menstrual Cycle
  • Odds Ratio
  • Polymorphism, Single Nucleotide
  • Predictive Value of Tests
  • Pregnanediol
  • Premenopause
  • Reproductive History
  • Risk Assessment
  • Risk Factors
  • Sex Hormone-Binding Globulin
  • United Kingdom
  • Journal Article
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Cite this

Johnson, N., Walker-Springett, K., Gibson, L. J., Orr, N., Folkerd, E., Haynes, B., ... Fletcher, O. (2012). CYP3A variation, premenopausal estrone levels, and breast cancer risk. Journal of the National Cancer Institute, 104(9), 657-69. https://doi.org/10.1093/jnci/djs156
Johnson, Nichola ; Walker-Springett, Kate ; Gibson, Lorna J ; Orr, Nick ; Folkerd, Elizabeth ; Haynes, Ben ; Palles, Claire ; Coupland, Ben ; Schoemaker, Minouk ; Jones, Michael ; Broderick, Peter ; Sawyer, Elinor ; Kerin, Michael J ; Tomlinson, Ian P ; Zvelebil, Marketa ; Chilcott-Burns, Sarah ; Tomczyk, Katarzyna ; Simpson, Gemma ; Williamson, Jill ; Hillier, Stephen G ; Ross, Gillian ; Houlston, Richard S ; Swerdlow, Anthony J ; Ashworth, Alan ; Dowsett, Mitch ; Peto, Julian ; Dos-Santos-Silva, Isabel ; Fletcher, Olivia. / CYP3A variation, premenopausal estrone levels, and breast cancer risk. In: Journal of the National Cancer Institute. 2012 ; Vol. 104, No. 9. pp. 657-69.
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abstract = "BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8{\%} reduction in E1G levels (95{\%} confidence interval [CI] = 27.8{\%} to 15.3{\%} reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95{\%} CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95{\%} CI = 0.93 to 1.10; P = .82).CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.",
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author = "Nichola Johnson and Kate Walker-Springett and Gibson, {Lorna J} and Nick Orr and Elizabeth Folkerd and Ben Haynes and Claire Palles and Ben Coupland and Minouk Schoemaker and Michael Jones and Peter Broderick and Elinor Sawyer and Kerin, {Michael J} and Tomlinson, {Ian P} and Marketa Zvelebil and Sarah Chilcott-Burns and Katarzyna Tomczyk and Gemma Simpson and Jill Williamson and Hillier, {Stephen G} and Gillian Ross and Houlston, {Richard S} and Swerdlow, {Anthony J} and Alan Ashworth and Mitch Dowsett and Julian Peto and Isabel Dos-Santos-Silva and Olivia Fletcher",
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Johnson, N, Walker-Springett, K, Gibson, LJ, Orr, N, Folkerd, E, Haynes, B, Palles, C, Coupland, B, Schoemaker, M, Jones, M, Broderick, P, Sawyer, E, Kerin, MJ, Tomlinson, IP, Zvelebil, M, Chilcott-Burns, S, Tomczyk, K, Simpson, G, Williamson, J, Hillier, SG, Ross, G, Houlston, RS, Swerdlow, AJ, Ashworth, A, Dowsett, M, Peto, J, Dos-Santos-Silva, I & Fletcher, O 2012, 'CYP3A variation, premenopausal estrone levels, and breast cancer risk', Journal of the National Cancer Institute, vol. 104, no. 9, pp. 657-69. https://doi.org/10.1093/jnci/djs156

CYP3A variation, premenopausal estrone levels, and breast cancer risk. / Johnson, Nichola; Walker-Springett, Kate; Gibson, Lorna J; Orr, Nick; Folkerd, Elizabeth; Haynes, Ben; Palles, Claire; Coupland, Ben; Schoemaker, Minouk; Jones, Michael; Broderick, Peter; Sawyer, Elinor; Kerin, Michael J; Tomlinson, Ian P; Zvelebil, Marketa; Chilcott-Burns, Sarah; Tomczyk, Katarzyna; Simpson, Gemma; Williamson, Jill; Hillier, Stephen G; Ross, Gillian; Houlston, Richard S; Swerdlow, Anthony J; Ashworth, Alan; Dowsett, Mitch; Peto, Julian; Dos-Santos-Silva, Isabel; Fletcher, Olivia.

In: Journal of the National Cancer Institute, Vol. 104, No. 9, 02.05.2012, p. 657-69.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CYP3A variation, premenopausal estrone levels, and breast cancer risk

AU - Johnson, Nichola

AU - Walker-Springett, Kate

AU - Gibson, Lorna J

AU - Orr, Nick

AU - Folkerd, Elizabeth

AU - Haynes, Ben

AU - Palles, Claire

AU - Coupland, Ben

AU - Schoemaker, Minouk

AU - Jones, Michael

AU - Broderick, Peter

AU - Sawyer, Elinor

AU - Kerin, Michael J

AU - Tomlinson, Ian P

AU - Zvelebil, Marketa

AU - Chilcott-Burns, Sarah

AU - Tomczyk, Katarzyna

AU - Simpson, Gemma

AU - Williamson, Jill

AU - Hillier, Stephen G

AU - Ross, Gillian

AU - Houlston, Richard S

AU - Swerdlow, Anthony J

AU - Ashworth, Alan

AU - Dowsett, Mitch

AU - Peto, Julian

AU - Dos-Santos-Silva, Isabel

AU - Fletcher, Olivia

PY - 2012/5/2

Y1 - 2012/5/2

N2 - BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

AB - BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women.METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided.RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82).CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

KW - Adult

KW - Age Factors

KW - Androgens

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Cross-Sectional Studies

KW - Cytochrome P-450 CYP3A

KW - Estrone

KW - European Continental Ancestry Group

KW - Female

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Glucuronides

KW - Humans

KW - Life Style

KW - Linkage Disequilibrium

KW - Mammography

KW - Menstrual Cycle

KW - Odds Ratio

KW - Polymorphism, Single Nucleotide

KW - Predictive Value of Tests

KW - Pregnanediol

KW - Premenopause

KW - Reproductive History

KW - Risk Assessment

KW - Risk Factors

KW - Sex Hormone-Binding Globulin

KW - United Kingdom

KW - Journal Article

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/jnci/djs156

DO - 10.1093/jnci/djs156

M3 - Article

C2 - 22472546

VL - 104

SP - 657

EP - 669

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 9

ER -