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Polymorphisms in genes involved in the estrogen pathway and mammographic density.

ABSTRACT: Single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD), but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ER?, ER?), 17?-hydroxysteroid dehydrogenase 1 (HSD17B1), catechol-O-methyltransferase (COMT), cytochrome P450 1B1 (CYP1B1)) with premenopausal MD. Effect modification of four estrogen-related factors (parity, age at menarche, hormonal derivatives use and body mass index (BMI)) on this relation is also assessed.Polymorphisms were genotyped in 741 premenopausal Caucasian women whose MD was measured in absolute density (AD, cm²) and percent density using a computer-assisted method. Multivariate linear models were used to examine the associations (P(trend)) and interactions (Pi).None of the SNPs showed a statistically significant association with AD. However, each additional rare allele of rs1056836 CYP1B1 was associated with a reduction in AD among nulliparous women (P(trend) = 0.004), while no association was observed among parous women (P(trend) = 0.62; Pi = 0.02). An increase in the number of rare alleles of the HSD17B1 SNP (rs598126 and rs2010750) was associated with an increase in AD among women who never used hormonal derivatives (P(trend) = 0.06 and P(trend) = 0.04, respectively), but with a decrease in AD among past hormonal derivatives users (P(trend) = 0.04; Pi = 0.02 and P(trend) = 0.08; Pi = 0.01, respectively). Moreover, a negative association of rs598126 HSD17B1 SNP with AD was observed among women with higher BMI (>median) (P(trend) = 0.01; Pi = 0.02). A negative association between an increased number of rare alleles of COMT rs4680 SNP and AD was limited to women who never used hormonal derivatives (P(trend) = 0.02; Pi = 0.03) or with late age at menarche (>median) (P(trend) = 0.03; Pi = 0.02). No significant association was observed between polymorphisms in the ER? or ER? genes and AD. Similar results, although less significant, were observed when MD was assessed in percent density.SNPs located in CYP1B1, COMT or HSD17B1 genes seem to be associated with MD in some strata of estrogen-related factors. Our findings suggest that modifying effects of estrogen-related factors should be considered when evaluating associations of polymorphisms in estrogen-related genes with premenopausal mammographic density.

SUBMITTER: Dumas I

PROVIDER: S-EPMC3000407 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Polymorphisms in genes involved in the estrogen pathway and mammographic density.

Dumas Isabelle I Diorio Caroline C

BMC cancer 20101122

<h4>Background</h4>Single nucleotide polymorphisms (SNPs) in genes involved in the estrogen pathway appear to be associated with breast cancer risk and possibly with mammographic density (MD), but little is known of these associations among premenopausal women. This study examines the association of 11 polymorphisms in five estrogen-related genes (estrogen receptors alpha and beta (ERα, ERβ), 17β-hydroxysteroid dehydrogenase 1 (HSD17B1), catechol-O-methyltransferase (COMT), cytochrome P450 1B1 ( ...[more]

PMID: 21092186

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Project description:Single nucleotide polymorphisms (SNPs) involved in the estrogen pathway and SNPs in the estrogen receptor alpha gene (ESR1 6q25) have been linked to breast cancer development, and mammographic density is an established breast cancer risk factor. Whether there is an association between daily estradiol levels, SNPs in ESR1 and premenopausal mammographic density phenotypes is unknown.We assessed estradiol in daily saliva samples throughout an entire menstrual cycle in 202 healthy premenopausal women in the Norwegian Energy Balance and Breast Cancer Aspects I study. DNA was genotyped using the Illumina Golden Gate platform. Mammograms were taken between days 7 and 12 of the menstrual cycle, and digitized mammographic density was assessed using a computer-assisted method (Madena). Multivariable regression models were used to study the association between SNPs in ESR1, premenopausal mammographic density phenotypes and daily cycling estradiol.We observed inverse linear associations between the minor alleles of eight measured SNPs (rs3020364, rs2474148, rs12154178, rs2347867, rs6927072, rs2982712, rs3020407, rs9322335) and percent mammographic density (p-values: 0.002-0.026), these associations were strongest in lean women (BMI, ?23.6 kg/m2.). The odds of above-median percent mammographic density (>28.5 %) among women with major homozygous genotypes were 3-6 times higher than those of women with minor homozygous genotypes in seven SNPs. Women with rs3020364 major homozygous genotype had an OR of 6.46 for above-median percent mammographic density (OR: 6.46; 95 % Confidence Interval 1.61, 25.94) when compared to women with the minor homozygous genotype. These associations were not observed in relation to absolute mammographic density. No associations between SNPs and daily cycling estradiol were observed. However, we suggest, based on results of borderline significance (p values: 0.025-0.079) that the level of 17?-estradiol for women with the minor genotype for rs3020364, rs24744148 and rs2982712 were lower throughout the cycle in women with low (<28.5 %) percent mammographic density and higher in women with high (>28.5 %) percent mammographic density, when compared to women with the major genotype.Our results support an association between eight selected SNPs in the ESR1 gene and percent mammographic density. The results need to be confirmed in larger studies.

Project description:Introduction: Mammographic density (MD) is a strong biomarker of breast cancer risk. MD increases after women start estrogen plus progestin therapy (EPT) and decreases after women quit EPT. A large interindividual variation in EPT-associated MD change has been observed, but few studies have investigated genetic predictors of the EPT-associated MD change. Here, we evaluate the association between polymorphisms in hormone metabolism pathway genes and MD changes when women quit EPT.Methods: We collected mammograms before and after women quit EPT and genotyped 405 tagging single nucleotide polymorphisms (SNPs) in 30 hormone metabolism pathway genes in 284 non-Hispanic white participants of the California Teachers Study (CTS). Participants were ages 49 to 71 years at time of mammography taken after quitting EPT. We assessed percent MD using a computer-assisted method. MD change was calculated by subtracting MD of an 'off-EPT' mammogram from MD of an 'on-EPT' (that is baseline) mammogram. Linear regression analysis was used to investigate the SNP-MD change association, adjusting for the baseline 'on-EPT' MD, age and BMI at time of baseline mammogram, and time interval and BMI change between the two mammograms. An overall pathway and gene-level summary was obtained using the adaptive rank truncated product (ARTP) test. We calculated 'P values adjusted for correlated tests (P(ACT))' to account for multiple testing within a gene.Results: The strongest associations were observed for rs7489119 in SLCO1B1, and rs5933863 in ARSC. SLCO1B1 and ARSC are involved in excretion and activation of estrogen metabolites of EPT, respectively. MD change after quitting was 4.2% smaller per minor allele of rs7489119 (P?=?0.0008; P(ACT)?=?0.018) and 1.9% larger per minor allele of rs5933863 (P?=?0.013; P(ACT)?=?0.025). These individual SNP associations did not reach statistical significance when we further used Bonferroni correction to consider the number of tested genes. The pathway level summary ARTP P value was not statistically significant.Conclusions: Data from this longitudinal study of EPT quitters suggest that genetic variation in two hormone metabolism pathway genes, SLCO1B1 and ARSC, may be associated with change in MD after women stop using EPT. Larger longitudinal studies are needed to confirm our findings.

Project description:INTRODUCTION:Increased mammographic breast density is one of the strongest risk factors for breast cancer. While two-thirds of the variation in mammographic density appears to be genetically influenced, few variants have been identified. We examined the association of inherited variation in genes from pathways that mediate cell division with percent mammographic density (PMD) adjusted for age, body mass index (BMI) and postmenopausal hormones, in two studies of healthy postmenopausal women. METHODS:We investigated 2,058 single nucleotide polymorphisms (SNPs) in 378 genes involved in regulation of mitosis for associations with adjusted PMD among 484 unaffected postmenopausal controls (without breast cancer) from the Mayo Clinic Breast Cancer Study (MCBCS) and replicated the findings in postmenopausal controls (n = 726) from the Singapore and Sweden Breast Cancer Study (SASBAC) study. PMD was assessed in both studies by a computer-thresholding method (Cumulus) and linear regression approaches were used to assess the association of SNPs and PMD, adjusted for age, BMI and postmenopausal hormones. A P-value threshold of 4.2 × 10-5 based on a Bonferroni correction of effective number of independent tests was used for statistical significance. Further, a pathway-level analysis was conducted of all 378 genes using the self-contained gene-set analysis method GLOSSI. RESULTS:A variant in PRPF4, rs10733604, was significantly associated with adjusted PMD in the MCBCS (P = 2.7 × 10-7), otherwise, no single SNP was associated with PMD. Additionally, the pathway analysis provided no evidence of enrichment in the number of associations observed between SNPs in the mitotic genes and PMD (P = 0.60). We evaluated rs10733604 (PRPF4), and 73 other SNPs at P < 0.05 from 51 genes in the SASBAC study. There was no evidence of an association of rs10733604 (PRPF4) with adjusted PMD in SASBAC (P = 0.23). There were, however, consistent associations (P < 0.05) of variants at the putative locus, LOC375190, Aurora B kinase (AURKB), and Mini-chromosome maintenance complex component 3 (MCM3) with adjusted PMD, although these were not statistically significant. CONCLUSIONS:Our findings do not support a role of inherited variation in genes involved in regulation of cell division and adjusted percent mammographic density in postmenopausal women.

Project description:BackgroundObesity and elevated breast density are common risk factors for breast cancer, and their effects may vary by estrogen receptor (ER) subtype. However, their joint effects on ER subtype-specific risk are unknown. Understanding this relationship could enhance risk stratification for screening and prevention. Thus, we assessed the association between breast density and ER subtype according to body mass index (BMI) and menopausal status.MethodsWe conducted a case-control study nested within two mammography screening cohorts, the Mayo Mammography Health Study and the San Francisco Bay Area Breast Cancer SPORE/San Francisco Mammography Registry. Our pooled analysis contained 1538 ER-positive and 285 ER-negative invasive breast cancer cases and 4720 controls matched on age, menopausal status at time of mammogram, and year of mammogram. Percent density was measured on digitized film mammograms using computer-assisted techniques. We used polytomous logistic regression to evaluate the association between percent density and ER subtype by BMI subgroup (normal/underweight, < 25 kg/m2 versus overweight/obese, ≥ 25 kg/m2). We used Wald chi-squared tests to assess for interactions between percent density and BMI. Our analysis was stratified by menopausal status and hormone therapy usage at the time of index mammogram.ResultsPercent density was associated with increased risk of overall breast cancer regardless of menopausal status or BMI. However, when analyzing breast cancer across ER subtype, we found a statistically significant (p = 0.008) interaction between percent density and BMI in premenopausal women only. Specifically, elevated percent density was associated with a higher risk of ER-negative than ER-positive cancer in overweight/obese premenopausal women [OR per standard deviation increment 2.17 (95% CI 1.50-3.16) vs 1.33 (95% CI 1.11-1.61) respectively, Pheterogeneity = 0.01]. In postmenopausal women, elevated percent density was associated with similar risk of ER-positive and ER-negative cancers, and no substantive differences were seen after accounting for BMI or hormone therapy usage.ConclusionsThe combination of overweight/obesity and elevated breast density in premenopausal women is associated with a higher risk of ER-negative compared with ER-positive cancer. Eighteen percent of premenopausal women in the USA have elevated BMI and breast density and may benefit from lifestyle modifications involving weight loss and exercise.

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Polymorphisms in genes involved in the estrogen pathway and mammographic density.

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Polymorphisms in genes involved in the estrogen pathway and mammographic density.

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