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 language | English |
|---|---|
| Pages (from-to) | 657-69 |
| Number of pages | 13 |
| Journal | Journal of the National Cancer Institute |
| Volume | 104 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 02 May 2012 |
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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
}
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 journal › Article
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 -