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Article ; Online: Endometrial cancer and genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2 within a population-based case-control study.

Lacey, James V / Yang, Hannah / Gaudet, Mia M / Dunning, Alison / Lissowska, Jolanta / Sherman, Mark E / Peplonska, Beata / Brinton, Louise A / Healey, Catherine S / Ahmed, Shahana / Pharoah, Paul / Easton, Douglas / Chanock, Stephen / Garcia-Closas, Montserrat

Gynecologic oncology

2010 Volume 120, Issue 2, Page(s) 167–173

Abstract: Objective: We assessed whether common genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2-genes that reportedly are frequently altered in endometrial cancer-was associated with risk of endometrial cancer.: Methods: Using data from a population- ... ...

Abstract	Objective: We assessed whether common genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2-genes that reportedly are frequently altered in endometrial cancer-was associated with risk of endometrial cancer. Methods: Using data from a population-based case-control study in Poland (PECS) of 417 cases and 407 matched controls, we genotyped 76 tagging single nucleotide polymorphisms (tagSNPs; located in or within 10 kb upstream or 5 kb downstream of the gene of interest, minor allele frequency >=5% among various ethnic groups, and not already represented by another tagSNP at a LD of r(2) >=0.80) on an Illumina Custom Infinium iSelect assay that included over 29,000 SNPs in 1316 genes. For individual SNPs, we used unconditional logistic regression models, adjusted for age and site, to generate odds ratios (ORs) and 95% confidence intervals (CIs). To replicate the one statistically significant association in PECS, we independently genotyped that tagSNP among 1141 endometrial cancer cases and 2275 controls from the SEARCH study in the UK. We assessed haplotypes via extended haplotype blocks and the sequential haplotype scan method. Results: The rs2677764 tagSNP in PIK3CA was statistically significantly associated with endometrial cancer in PECS (OR=1.42, 95% CI, 1.03-1.95; P=0.03) but not SEARCH (OR=0.98, 95% CI=0.82-1.17). Of the 25 haplotypes observed in at least 5% of cases and controls in PECS, only 1, in PIK3CA, was statistically significantly associated with endometrial cancer (OR=1.39, 95% CI, 1.00-1.93). All haplotype global p-values were null. Conclusion: Common genetic variation in PTEN, PIK3CA, AKT1, MLH1, or MSH2 was not statistically significantly associated with endometrial cancer.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adult ; Aged ; Case-Control Studies ; Class I Phosphatidylinositol 3-Kinases ; Endometrial Neoplasms/genetics ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Middle Aged ; MutL Protein Homolog 1 ; MutS Homolog 2 Protein/genetics ; Nuclear Proteins/genetics ; PTEN Phosphohydrolase/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Polymorphism, Single Nucleotide ; Proto-Oncogene Proteins c-akt/genetics ; Young Adult
Chemical Substances	Adaptor Proteins, Signal Transducing ; MLH1 protein, human ; Nuclear Proteins ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CA protein, human (EC 2.7.1.137) ; AKT1 protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; PTEN Phosphohydrolase (EC 3.1.3.67) ; PTEN protein, human (EC 3.1.3.67) ; MSH2 protein, human (EC 3.6.1.3) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; MutS Homolog 2 Protein (EC 3.6.1.3)
Language	English
Publishing date	2010-11-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2010.10.016
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Article ; Online: The functional ALDH2 polymorphism is associated with breast cancer risk: A pooled analysis from the Breast Cancer Association Consortium.

Ugai, Tomotaka / Milne, Roger L / Ito, Hidemi / Aronson, Kristan J / Bolla, Manjeet K / Chan, Tsun / Chan, Ching W / Choi, Ji-Yeob / Conroy, Don M / Dennis, Joe / Dunning, Alison M / Easton, Douglas F / Gaborieau, Valerie / Gonzalez-Neira, Anna / Hartman, Mikael / Healey, Catherine S / Iwasaki, Motoki / John, Esther M / Kang, Daehee /

Molecular genetics & genomic medicine

2019 Volume 7, Issue 6, Page(s) e707

Abstract: Background: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on ... ...

Abstract	Background: Epidemiological studies consistently indicate that alcohol consumption is an independent risk factor for female breast cancer (BC). Although the aldehyde dehydrogenase 2 (ALDH2) polymorphism (rs671: Glu>Lys) has a strong effect on acetaldehyde metabolism, the association of rs671 with BC risk and its interaction with alcohol intake have not been fully elucidated. We conducted a pooled analysis of 14 case-control studies, with individual data on Asian ancestry women participating in the Breast Cancer Association Consortium. Methods: We included 12,595 invasive BC cases and 12,884 controls for the analysis of rs671 and BC risk, and 2,849 invasive BC cases and 3,680 controls for the analysis of the gene-environment interaction between rs671 and alcohol intake for BC risk. The pooled odds ratios (OR) with 95% confidence intervals (CI) associated with rs671 and its interaction with alcohol intake for BC risk were estimated using logistic regression models. Results: The Lys/Lys genotype of rs671 was associated with increased BC risk (OR = 1.16, 95% CI 1.03-1.30, p = 0.014). According to tumor characteristics, the Lys/Lys genotype was associated with estrogen receptor (ER)-positive BC (OR = 1.19, 95% CI 1.05-1.36, p = 0.008), progesterone receptor (PR)-positive BC (OR = 1.19, 95% CI 1.03-1.36, p = 0.015), and human epidermal growth factor receptor 2 (HER2)-negative BC (OR = 1.25, 95% CI 1.05-1.48, p = 0.012). No evidence of a gene-environment interaction was observed between rs671 and alcohol intake (p = 0.537). Conclusion: This study suggests that the Lys/Lys genotype confers susceptibility to BC risk among women of Asian ancestry, particularly for ER-positive, PR-positive, and HER2-negative tumor types.
MeSH term(s)	Adult ; Aged ; Alcohol Drinking/epidemiology ; Aldehyde Dehydrogenase, Mitochondrial/genetics ; Asian People/genetics ; Breast Neoplasms/epidemiology ; Breast Neoplasms/genetics ; Female ; Gene-Environment Interaction ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide
Chemical Substances	ALDH2 protein, human (EC 1.2.1.3) ; Aldehyde Dehydrogenase, Mitochondrial (EC 1.2.1.3)
Language	English
Publishing date	2019-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2734884-2
ISSN	2324-9269 ; 2324-9269
ISSN (online)	2324-9269
ISSN	2324-9269
DOI	10.1002/mgg3.707
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Article: CHEK2, MGMT, SULT1E1 and SULT1A1 polymorphisms and endometrial cancer risk.

O'Mara, Tracy A / Ferguson, Kaltin / Fahey, Paul / Marquart, Louise / Yang, Hannah P / Lissowska, Jolanta / Chanock, Stephen / Garcia-Closas, Montserrat / Thompson, Deborah J / Healey, Catherine S / Dunning, Alison M / Easton, Douglas F / Webb, Penelope M / Spurdle, Amanda B

Twin research and human genetics : the official journal of the International Society for Twin Studies

2011 Volume 14, Issue 4, Page(s) 328–332

Abstract: Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample ... ...

Abstract	Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.
MeSH term(s)	Arylsulfotransferase/genetics ; Biomarkers, Tumor/genetics ; Case-Control Studies ; Checkpoint Kinase 2 ; DNA Modification Methylases/genetics ; DNA Repair Enzymes/genetics ; DNA, Neoplasm/genetics ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/pathology ; Endometrium/metabolism ; Female ; Genotype ; Humans ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Serine-Threonine Kinases/genetics ; Risk Factors ; Sulfotransferases/genetics ; Tumor Suppressor Proteins/genetics
Chemical Substances	Biomarkers, Tumor ; DNA, Neoplasm ; Tumor Suppressor Proteins ; DNA Modification Methylases (EC 2.1.1.-) ; MGMT protein, human (EC 2.1.1.63) ; Checkpoint Kinase 2 (EC 2.7.1.11) ; CHEK2 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Sulfotransferases (EC 2.8.2.-) ; Arylsulfotransferase (EC 2.8.2.1) ; SULT1A1 protein, human (EC 2.8.2.1) ; estrone sulfotransferase (EC 2.8.2.4) ; DNA Repair Enzymes (EC 6.5.1.-)
Language	English
Publishing date	2011-07-22
Publishing country	England
Document type	Comparative Study ; Journal Article
ZDB-ID	2182682-1
ISSN	1839-2628 ; 1832-4274
ISSN (online)	1839-2628
ISSN	1832-4274
DOI	10.1375/twin.14.4.328
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Zs.A 5127: Show issues

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Article ; Online: Common variants in the ATM, BRCA1, BRCA2, CHEK2 and TP53 cancer susceptibility genes are unlikely to increase breast cancer risk.

Baynes, Caroline / Healey, Catherine S / Pooley, Karen A / Scollen, Serena / Luben, Robert N / Thompson, Deborah J / Pharoah, Paul D P / Easton, Douglas F / Ponder, Bruce A J / Dunning, Alison M

Breast cancer research : BCR

2007 Volume 9, Issue 2, Page(s) R27

Abstract: Introduction: Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk.: ... ...

Abstract	Introduction: Certain rare, familial mutations in the ATM, BRCA1, BRCA2, CHEK2 or TP53 genes increase susceptibility to breast cancer but it has not, until now, been clear whether common polymorphic variants in the same genes also increase risk. Methods: We have attempted a comprehensive, single nucleotide polymorphism (SNP)- and haplotype-tagging association study on each of these five genes in up to 4,474 breast cancer cases from the British, East Anglian SEARCH study and 4,560 controls from the EPIC-Norfolk study, using a two-stage study design. Nine tag SNPs were genotyped in ATM, together with five in BRCA1, sixteen in BRCA2, ten in CHEK2 and five in TP53, with the aim of tagging all other known, common variants. SNPs generating the common amino acid substitutions were specifically forced into the tagging set for each gene. Results: No significant breast cancer associations were detected with any individual or combination of tag SNPs. Conclusion: It is unlikely that there are any other common variants in these genes conferring measurably increased risks of breast cancer in our study population.
MeSH term(s)	Adult ; Aged ; Ataxia Telangiectasia Mutated Proteins ; Breast Neoplasms/genetics ; Cell Cycle Proteins/genetics ; Checkpoint Kinase 2 ; DNA-Binding Proteins/genetics ; Female ; Genes, BRCA1 ; Genes, BRCA2 ; Genes, p53 ; Genetic Predisposition to Disease ; Haplotypes ; Humans ; Middle Aged ; Polymorphism, Single Nucleotide ; Protein Serine-Threonine Kinases/genetics ; Risk ; Tumor Suppressor Proteins/genetics
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Tumor Suppressor Proteins ; Checkpoint Kinase 2 (EC 2.7.1.11) ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1) ; CHEK2 protein, human (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2007-04-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/bcr1669
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Zs.A 5494: Show issues

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Article ; Online: Common germline polymorphisms in COMT, CYP19A1, ESR1, PGR, SULT1E1 and STS and survival after a diagnosis of breast cancer.

Udler, Miriam S / Azzato, Elizabeth M / Healey, Catherine S / Ahmed, Shahana / Pooley, Karen A / Greenberg, David / Shah, Mitul / Teschendorff, Andrew E / Caldas, Carlos / Dunning, Alison M / Ostrander, Elaine A / Caporaso, Neil E / Easton, Douglas / Pharoah, Paul D

International journal of cancer

2009 Volume 125, Issue 11, Page(s) 2687–2696

Abstract: Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 ... ...

Abstract	Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population-based case-control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69-0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted.
MeSH term(s)	Breast Neoplasms/diagnosis ; Breast Neoplasms/genetics ; Breast Neoplasms/mortality ; Carcinoma, Ductal, Breast/diagnosis ; Carcinoma, Ductal, Breast/genetics ; Carcinoma, Ductal, Breast/mortality ; Carcinoma, Lobular/diagnosis ; Carcinoma, Lobular/genetics ; Carcinoma, Lobular/mortality ; Carrier Proteins/genetics ; Case-Control Studies ; Catechol O-Methyltransferase/genetics ; Cytochrome P-450 CYP1A1/genetics ; Estrogen Receptor alpha/genetics ; Female ; Follow-Up Studies ; Genotype ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Middle Aged ; Neoplasm Proteins/genetics ; Nuclear Proteins/genetics ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Tyrosine Phosphatases ; Risk Factors ; Sulfotransferases/genetics ; Survival Rate
Chemical Substances	Carrier Proteins ; ESR1 protein, human ; Estrogen Receptor alpha ; Intracellular Signaling Peptides and Proteins ; MRFAP1 protein, human ; Neoplasm Proteins ; Nuclear Proteins ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Catechol O-Methyltransferase (EC 2.1.1.6) ; Sulfotransferases (EC 2.8.2.-) ; estrone sulfotransferase (EC 2.8.2.4) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; UBASH3B protein, human (EC 3.1.3.48)
Language	English
Publishing date	2009-06-24
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.24678
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Zs.A 478: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 576: Show issues

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Article: Associations among mammographic density, circulating sex hormones, and polymorphisms in sex hormone metabolism genes in postmenopausal women.

Warren, Ruth / Skinner, Jane / Sala, Evis / Denton, Erika / Dowsett, Mitch / Folkerd, Elizabeth / Healey, Catherine S / Dunning, Alison / Doody, Deborah / Ponder, Bruce / Luben, Robert N / Day, N E / Easton, Douglas

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2006 Volume 15, Issue 8, Page(s) 1502–1508

Abstract: Mammographic density and serum sex hormone levels are important risk factors for breast cancer, but their associations with one another are unclear. We studied these phenotypes, together with single nucleotide polymorphisms (SNP) in genes related to sex ... ...

Abstract	Mammographic density and serum sex hormone levels are important risk factors for breast cancer, but their associations with one another are unclear. We studied these phenotypes, together with single nucleotide polymorphisms (SNP) in genes related to sex hormone metabolism, in a cross-sectional study of 1,413 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition-Norfolk. All women were >1 year postmenopausal and had not taken hormone replacement therapy for >3 months before sampling. Serum levels of 7 sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG), androstenedione, 17-OH-progesterone, estrone, and estrone sulfate] and 15 SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were studied. Mammograms nearest in time to the blood sampling were identified through the national breast screening program and visually assessed by three radiologists using the Boyd six-category and Wolfe four-category scales. We found a weak positive association between mammographic density and SHBG levels (P = 0.09) but no association with any other hormones. None of the SNPs, including those shown previously to be associated with estradiol or SHBG, showed significant associations with density. We conclude that mammographic density is largely independent of postmenopausal steroid hormone levels, indicating that these risk factors have, to a large extent, an independent etiology and suggesting that they may be independent predictors of breast cancer risk.
MeSH term(s)	Aged ; Aromatase/genetics ; Aryl Hydrocarbon Hydroxylases/genetics ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cytochrome P-450 CYP1B1 ; Female ; Gonadal Steroid Hormones/blood ; Humans ; Mammography ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Postmenopause/blood ; Postmenopause/genetics ; Risk Factors ; Sex Hormone-Binding Globulin/genetics ; Steroid 17-alpha-Hydroxylase/genetics
Chemical Substances	Gonadal Steroid Hormones ; Sex Hormone-Binding Globulin ; Aromatase (EC 1.14.14.1) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; Steroid 17-alpha-Hydroxylase (EC 1.14.14.19)
Language	English
Publishing date	2006-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1153420-5
ISSN	1055-9965
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-05-0828
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Zs.A 3693: Show issues

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Article: Association of the progesterone receptor gene with breast cancer risk: a single-nucleotide polymorphism tagging approach.

Pooley, Karen A / Healey, Catherine S / Smith, Paula L / Pharoah, Paul D P / Thompson, Deborah / Tee, Louise / West, Judith / Jordan, Clare / Easton, Douglas F / Ponder, Bruce A J / Dunning, Alison M

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2006 Volume 15, Issue 4, Page(s) 675–682

Abstract: Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging ... ...

Abstract	Association studies on susceptibility to breast cancer using single nucleotide polymorphisms (SNP) in the progesterone receptor (PGR) gene have been previously published, but the results have been inconclusive. We used a comprehensive SNP-tagging approach to search for low-penetrance susceptibility alleles in a study of up to 4,647 cases and 4,564 controls, in a two-stage study design. We identified seven tagging SNPs using genotype data from the National Institute of Environmental Health Sciences (NIEHS) Environmental Genome Project and typed these, and an additional three SNPs, in 2,345 breast cancer cases and 2,284 controls (set 1). Three SNPs showed no evidence for association and were not studied further, whereas seven SNPs (rs11571171, rs7116336, rs660149, rs10895068, rs500760, rs566351, and rs1042838) exhibited significant associations at P < 0.1 using either a heterogeneity or trend test and progressed to be genotyped in set 2. After both stages, only one SNP was significantly associated with an increased risk of breast cancer - the PGR-12 (rs1042638) V660L valine to leucine polymorphism [VL heterozygotes (odds ratio, 1.13; 95% confidence interval, 1.03-1.24) and the LL homozygotes (odds ratio, 1.30; 95% confidence interval, 0.98-1.73), P(het) = 0.008, P(trend) = 0.002]. Similar estimates were obtained in a combined analysis of our data with those from three other published studies. We conclude that the 660L allele may be associated with a moderately increased risk of breast cancer, but that other common SNPs in the PGR gene are unlikely to be associated with a substantial risk of breast cancer.
MeSH term(s)	Aged ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Case-Control Studies ; Female ; Gene Frequency ; Genetic Predisposition to Disease ; Haplotypes ; Humans ; Linkage Disequilibrium ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Receptors, Progesterone/genetics ; Risk ; Sequence Tagged Sites ; United Kingdom ; Valine/genetics
Chemical Substances	Receptors, Progesterone ; Valine (HG18B9YRS7)
Language	English
Publishing date	2006-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1153420-5
ISSN	1055-9965
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-05-0679
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Article: Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

Thompson, Deborah J / Healey, Catherine S / Baynes, Caroline / Kalmyrzaev, Bolot / Ahmed, Shahana / Dowsett, Mitch / Folkerd, Elizabeth / Luben, Robert N / Cox, David / Ballinger, Dennis / Pharoah, Paul D P / Ponder, Bruce A J / Dunning, Alison M / Easton, Douglas F

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2008 Volume 17, Issue 12, Page(s) 3490–3498

Abstract: Background: Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no ... ...

Abstract	Background: Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants. Methods: We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls. Results: Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)(n) polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)(n) repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002). Conclusion: At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex.
MeSH term(s)	Aged ; Breast Neoplasms/genetics ; Case-Control Studies ; Female ; Genetic Variation ; Genotype ; Haplotypes ; Humans ; Linear Models ; Middle Aged ; Polymorphism, Single Nucleotide ; Postmenopause ; Risk ; Sex Hormone-Binding Globulin/genetics
Chemical Substances	Sex Hormone-Binding Globulin
Language	English
Publishing date	2008-12-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1153420-5
ISSN	1055-9965
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-08-0734
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Article ; Online: Red-clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165].

Atkinson, Charlotte / Warren, Ruth M L / Sala, Evis / Dowsett, Mitch / Dunning, Alison M / Healey, Catherine S / Runswick, Shirley / Day, Nicholas E / Bingham, Sheila A

Breast cancer research : BCR

2004 Volume 6, Issue 3, Page(s) R170–9

Abstract: Introduction: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone ... ...

Abstract	Introduction: Isoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed. Methods: A total of 205 women (age range 49-65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed. Results: A total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean +/- standard deviation): TT isoflavone 1.4 +/- 12.3% and TT placebo -9.6 +/- 14.2%; CT isoflavone -5.2 +/- 12.0% and CT placebo -2.8 +/- 10.3%; and CC isoflavone -3.4 +/- 9.7% and CC placebo -1.1 +/- 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms. Conclusion: In contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.
MeSH term(s)	Adipose Tissue/drug effects ; Aged ; Anticarcinogenic Agents/isolation & purification ; Anticarcinogenic Agents/pharmacology ; Anticarcinogenic Agents/therapeutic use ; Biomarkers ; Breast/anatomy & histology ; Breast/drug effects ; Connective Tissue/drug effects ; Double-Blind Method ; Estradiol/blood ; Female ; Follicle Stimulating Hormone/blood ; Genistein/pharmacology ; Genistein/urine ; Hot Flashes/drug therapy ; Humans ; Isoflavones/isolation & purification ; Isoflavones/pharmacokinetics ; Isoflavones/pharmacology ; Isoflavones/therapeutic use ; Isoflavones/urine ; Luteinizing Hormone/blood ; Lymphocytes/enzymology ; Mammography ; Menopause/drug effects ; Middle Aged ; Plant Extracts/isolation & purification ; Plant Extracts/pharmacokinetics ; Plant Extracts/pharmacology ; Plant Extracts/therapeutic use ; Protein-Tyrosine Kinases/blood ; Trifolium/chemistry
Chemical Substances	Anticarcinogenic Agents ; Biomarkers ; Isoflavones ; Plant Extracts ; Promensil ; formononetin (295DQC67BJ) ; Estradiol (4TI98Z838E) ; daidzein (6287WC5J2L) ; Luteinizing Hormone (9002-67-9) ; Follicle Stimulating Hormone (9002-68-0) ; Genistein (DH2M523P0H) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; biochanin A (U13J6U390T)
Language	English
Publishing date	2004
Publishing country	England
Document type	Clinical Trial ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/bcr773
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Article ; Online: Polymorphisms associated with circulating sex hormone levels in postmenopausal women.

Dunning, Alison M / Dowsett, Mitch / Healey, Catherine S / Tee, Louise / Luben, Robert N / Folkerd, Elizabeth / Novik, Karen L / Kelemen, Livia / Ogata, Saeko / Pharoah, Paul D P / Easton, Douglas F / Day, N E / Ponder, Bruce A J

Journal of the National Cancer Institute

2004 Volume 96, Issue 12, Page(s) 936–945

Abstract: Background: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide ... ...

Abstract	Background: Reports suggest a relationship between circulating sex hormone levels and breast cancer risk, but genetic association studies have been inconclusive. We investigated the association between levels of sex hormones and single nucleotide polymorphisms (SNPs) in genes coding for the enzymes that regulate them. Methods: We assayed circulating levels of estradiol, testosterone, estrone, androstenedione, 17alpha-hydroxyprogesterone, and sex hormone-binding globulin (SHBG) in 1975 normal postmenopausal women. Fifteen SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were genotyped in these postmenopausal women and in a breast cancer case-control study. Associations of genotypes with breast cancer risk were evaluated in the case-control study and with hormone levels in the postmenopausal women using multiple linear regression with assay batch, body mass index, parity, peri- or postmenopausal status, and age band as covariates. Results: CYP19 SNPs (rs10046 and [TCT]+/-) were associated with differences in estradiol level (P =.0006 and P =.0003, respectively) and the estradiol : testosterone ratio (P =.000001() and P =.002). SNP rs10046 explained 1.6% of the variance (r2) in the estradiol : testosterone ratio. SHBG SNPs (5' untranslated region [5'UTR] g-a and D356N) were associated with both SHBG levels (P<10(-6) and P =.005) and the estradiol : SHBG ratio (P =().000008() and P =.01). These SNPs explained 2.4% and 0.6% of the variance in SHBG levels, respectively. SNPs in the other genes were not associated with differences in any hormone levels, and none were statistically significantly associated with breast cancer risk. Conclusion: Genetic variation in CYP19 and SHBG contributes to variance in circulating hormone levels between postmenopausal women, but low r2 values may explain why these genes have given inconclusive results in breast cancer case-control studies.
MeSH term(s)	17-alpha-Hydroxyprogesterone/blood ; Aged ; Androstenedione/blood ; Aromatase/genetics ; Aryl Hydrocarbon Hydroxylases/genetics ; Breast Neoplasms/blood ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Case-Control Studies ; Catechol O-Methyltransferase/genetics ; Cytochrome P-450 CYP1B1 ; England ; Estradiol/blood ; Estrone/blood ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Gonadal Steroid Hormones/blood ; Gonadal Steroid Hormones/metabolism ; Humans ; Linear Models ; Middle Aged ; Odds Ratio ; Polymorphism, Single Nucleotide ; Postmenopause/blood ; Postmenopause/genetics ; Sex Hormone-Binding Globulin/genetics ; Sex Hormone-Binding Globulin/metabolism ; Steroid 17-alpha-Hydroxylase/genetics ; Testosterone/blood
Chemical Substances	Gonadal Steroid Hormones ; Sex Hormone-Binding Globulin ; Estrone (2DI9HA706A) ; Testosterone (3XMK78S47O) ; Androstenedione (409J2J96VR) ; Estradiol (4TI98Z838E) ; 17-alpha-Hydroxyprogesterone (68-96-2) ; Aromatase (EC 1.14.14.1) ; Aryl Hydrocarbon Hydroxylases (EC 1.14.14.1) ; CYP1B1 protein, human (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; Steroid 17-alpha-Hydroxylase (EC 1.14.14.19) ; Catechol O-Methyltransferase (EC 2.1.1.6)
Language	English
Publishing date	2004-05-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djh167
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