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Association between breast cancer susceptibility loci and mammographic density: the Multiethnic Cohort.

ABSTRACT: Mammographic density is a strong risk factor for breast cancer. Our objective was to examine its association with polymorphisms identifying breast cancer susceptibility loci that were ascertained in recent genome-wide association studies.Subjects were 825 women who participated in previous case-control studies of mammographic density and genetic factors nested within the Multiethnic Cohort study and were from three ethnic groups (White, Japanese American, Native Hawaiian). Eight polymorphisms (rs2981582 in FGFR2, rs3803662 and rs12443621in TOX3, rs3817198 in LSP1, rs981782 and rs10941679 near HCN1/MRPS30, rs889312 in MAP3K1, and rs13387042 at 2q) were examined. Mammographic density was quantified with a computer-assisted method as the percent dense area: the area of radiologically dense fibroglandular tissue relative to the total breast area that also includes radiologically lucent fatty tissue.The polymorphism rs12443621 in TOX3 was associated with percent dense area; women with at least one G allele (previously associated with increased breast cancer risk) had 3% to 4% higher densities than women with two A alleles. The polymorphism rs10941679 near HCN1/MRPS30 was also associated with percent dense area; women who were homozygous for the G allele (previously associated with increased breast cancer risk) had 4% to 5% lower densities than women with at least one A allele. The other polymorphisms were not associated with percent dense area.The available data suggest that the effects of most of these polymorphisms on breast cancer are not mediated by mammographic density. Some effects may have been too small to be detected. The association with rs12443621 may provide clues as to how variation in TOX3 influences breast cancer risk.

SUBMITTER: Woolcott CG

PROVIDER: S-EPMC2687715 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Association between breast cancer susceptibility loci and mammographic density: the Multiethnic Cohort.

Woolcott Christy G CG Maskarinec Gertraud G Haiman Christopher A CA Verheus Martijn M Pagano Ian S IS Le Marchand Loïc L Henderson Brian E BE Kolonel Laurence N LN

Breast cancer research : BCR 20090221 1

<h4>Introduction</h4>Mammographic density is a strong risk factor for breast cancer. Our objective was to examine its association with polymorphisms identifying breast cancer susceptibility loci that were ascertained in recent genome-wide association studies.<h4>Methods</h4>Subjects were 825 women who participated in previous case-control studies of mammographic density and genetic factors nested within the Multiethnic Cohort study and were from three ethnic groups (White, Japanese American, Nat ...[more]

PMID: 19232126

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Project description:BackgroundMenopausal hormone therapy (MHT) is a risk factor for breast cancer (BC). Evidence suggests that its effect on BC risk could be partly mediated by mammographic density. The aim of this study was to investigate the relationship between MHT, mammographic density and BC risk using data from a prospective study.MethodsWe used data from a case-control study nested within the French cohort E3N including 453 cases and 453 matched controls. Measures of mammographic density, history of MHT use during follow-up and information on potential confounders were available for all women. The association between MHT and mammographic density was evaluated by linear regression models. We applied mediation modelling techniques to estimate, under the hypothesis of a causal model, the proportion of the effect of MHT on BC risk mediated by percent mammographic density (PMD) for BC overall and by hormone receptor status.ResultsAmong MHT users, 4.2% used exclusively oestrogen alone compared with 68.3% who used exclusively oestrogens plus progestogens. Mammographic density was higher in current users (for a 60-year-old woman, mean PMD 33%; 95% CI 31 to 35%) than in past (29%; 27 to 31%) and never users (24%; 22 to 26%). No statistically significant association was observed between duration of MHT and mammographic density. In past MHT users, mammographic density was negatively associated with time since last use; values similar to those of never users were observed in women who had stopped MHT at least 8 years earlier. The odds ratio of BC for current versus never MHT users, adjusted for age, year of birth, menopausal status at baseline and BMI, was 1.67 (95% CI, 1.04 to 2.68). The proportion of effect mediated by PMD was 34% for any BC and became 48% when the correlation between BMI and PMD was accounted for. These effects were limited to hormone receptor-positive BC.ConclusionsOur results suggest that, under a causal model, nearly half of the effect of MHT on hormone receptor-positive BC risk is mediated by mammographic density, which appears to be modified by MHT for up to 8 years after MHT termination.

Project description:BACKGROUND:The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species. METHODS:To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study. RESULTS:We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk (P = 0.017, q = 0.102). In mtSNP-subset analysis, the gene MT-CO2 (P = 0.001, q = 0.09) in Complex IV (cytochrome c oxidase) and MT-ND2 (P = 0.004, q = 0.19) in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk. CONCLUSIONS:In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.

Project description:Breast density and microcalcifications are strongly associated with the risk of breast cancer. However, few studies have evaluated the combined association between these two factors and breast cancer risk. We investigated the association between breast density, microcalcifications, and risk of breast cancer. This cohort study included 3,910,815 women aged 40-74 years who were screened for breast cancer between 2009 and 2010 and followed up until 2020. The National Health Insurance Service database includes national health-screening results from the national breast cancer screening program, which is an organized screening program provided every 2 years for all women aged 40 years or older. Breast density was assessed based on the Breast Imaging Reporting and Data System (BI-RADS) 4th edition, mostly through visual assessment by radiologists. The presence or absence of microcalcifications was obtained from the mammographic results. Cox proportional hazard regression for breast cancer risk was used to estimate hazard ratios (aHRs) adjusted for breast cancer risk factors. A total of 58,315 women developed breast cancer during a median follow-up of 10.8 years. Women with breast cancer had a higher proportion of microcalcifications than women without breast cancer (0.9% vs. 0.3%). After adjusting for breast density, women with microcalcification had a 3.07-fold (95% confidence interval [CI] 2.82-3.35) increased risk of breast cancer compared to women without microcalcification. The combined association between microcalcification and breast density dramatically increased the risk of breast cancer, corresponding to a higher level of breast density. Among postmenopausal women, the highest risk group was women with BI-RADS 4 and microcalcification. These women had more than a sevenfold higher risk than women with BI-RADS 1 and non-microcalcification (aHR, 7.26; 95% CI 5.01-10.53). Microcalcification is an independent risk factor for breast cancer, and its risk is elevated when combined with breast density.

Dataset Information

Association between breast cancer susceptibility loci and mammographic density: the Multiethnic Cohort.

Publications

Association between breast cancer susceptibility loci and mammographic density: the Multiethnic Cohort.

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