Dataset Information

Melatonin pathway genes and breast cancer risk among Chinese women.

ABSTRACT: Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production or function. To address this question, we conducted a comprehensive evaluation of the association between common single nucleotide polymorphisms (SNPs) in the MTNR1a, MTNR1b, and AANAT genes and breast cancer risk among 2,073 cases and 2,083 controls, using a two-stage analysis of genome-wide association data among women of the Shanghai Breast Cancer Study. Results demonstrate two SNPs were consistently associated with breast cancer risk across both study stages. Compared with MTNR1b rs10765576 major allele carriers (GG or GA), a decreased risk of breast cancer was associated with the AA genotype (OR = 0.78, 95% CI = 0.62-0.97, P = 0.0281). Although no overall association was seen in the combined analysis, the effect of MTNR1a rs7665392 was found to vary by menopausal status (P-value for interaction = 0.001). Premenopausal women with the GG genotype were at increased risk for breast cancer compared with major allele carriers (TT or TG) (OR = 1.57, 95% CI = 1.07-2.31, P = 0.020), while postmenopausal women were at decreased risk (OR = 0.58, 95% 0.36-0.95, P = 0.030). No significant breast cancer associations were found for variants in the AANAT gene. These results suggest that common genetic variation in the MTNR1a and 1b genes may contribute to breast cancer susceptibility, and that associations may vary by menopausal status. Given that multiple variants in high linkage disequilibrium with MTNR1b rs76653292 have been associated with altered function or expression of insulin and glucose family members, further research may focus on clarifying this relationship.

SUBMITTER: Deming SL

PROVIDER: S-EPMC3777385 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Melatonin pathway genes and breast cancer risk among Chinese women.

Deming Sandra L SL Lu Wei W Beeghly-Fadiel Alicia A Zheng Ying Y Cai Qiuyin Q Long Jirong J Shu Xiao Ou XO Gao Yu-Tang YT Zheng Wei W

Breast cancer research and treatment 20111203 2

Previous studies suggest that melatonin may act on cancer growth through a variety of mechanisms, most notably by direct anti-proliferative effects on breast cancer cells and via interactions with the estrogen pathway. Three genes are largely responsible for mediating the downstream effects of melatonin: melatonin receptors 1a and 1b (MTNR1a and MTNR1b), and arylalkylamine N-acetyltransferase (AANAT). It is hypothesized that genetic variation in these genes may lead to altered protein production ...[more]

PMID: 22138747

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Project description:The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.

Project description:BackgroundGenetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.MethodsWe used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.ResultsProtein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.ConclusionsThe results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).

Project description:INTRODUCTION: Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese. METHODS: In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth). RESULTS: Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting (AUC: 0.637, 95% CI: 0.619 to 0.655; sensitivity = 62.16%, specificity = 60.03%) (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676) (sensitivity = 61.98%, specificity = 60.26%) was obtained for the combination of five marker SNPs, age at menarche and age at first live birth. CONCLUSIONS: This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment.

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Melatonin pathway genes and breast cancer risk among Chinese women.

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Melatonin pathway genes and breast cancer risk among Chinese women.

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