We investigated estrogen (estrone and estradiol) levels in serum and in nipple aspirates of breast fluid in relation to reproductive and menopausal characteristics in 104 normal women. In general, breast fluid and serum estrogen levels were not correlated and breast fluid estrogen levels were approximately 5 to 45 times higher than serum levels. Serum estrogen levels were lower in post-menopausal than in pre-menopausal women. In contrast, breast fluid estrogen levels were approximately the same in pre- and post-menopausal women. Breast fluid estrogen mean levels were lower in pre-menopausal parous women than in nulligravidous or nulliparous women whereas serum estrogen levels did not differ in these 3 groups. Breast fluid estrogen levels were positively correlated with months since last birth or since last breast-feeding. Estrogen levels were low in nipple aspirates of breast milk but gradually increased in breast fluid of non-lactating women over a period of several years after cessation of lactation. Serum estrogen levels did not increase with months since last breast-feeding. We were unable to evaluate the post-partum effect of pregnancy without lactation due to the small numbers of these subjects. The high concentrations of estrogen in breast fluid and the absence of a relationship to serum estrogen levels may explain why prior serum studies have failed to link variations in serum estrogens with breast cancer risk. The prolonged low levels of breast fluid estrogens following full-term birth and lactation may, in part, provide a mechanism by which parity reduces breast cancer risk.
Epigenome-wide DNA methylation association studies have identified highly replicable genomic loci sensitive to maternal smoking during gestation. The role of inter-individual genetic variation in influencing DNA methylation, leading to the possibility of confounding or bias of such associations, has not been assessed. We investigated whether the DNA methylation levels at the top 10 CpG sites previously associated with exposure to maternal smoking during gestation were associated with individual genetic variation at the genome-wide level. Genome-wide association tests between DNA methylation at the top 10 candidate CpG and genome-wide SNPs were performed in 736 case and control participants of the California Childhood Leukemia Study. Three of the strongest maternal-smoking sensitive CpG sites in newborns were significantly associated with SNPs located proximal to each gene: cg18146737 in the GFI1 gene with rs141819830 (P D 8.2£10¡44 ), cg05575921 in the AHRR gene with rs148405299 (P D 5.3£10 ¡10), and cg12803068 in the MYO1G gene with rs61087368 (P D 1.3£10 ¡18). For the GFI1 CpG cg18146737, the underlying genetic variation at rs141819830 confounded the association between maternal smoking and DNA methylation in our data (the regression coefficient changed from ¡0.02 [P D 0.139] to ¡0.03 [P D 0.015] after including the genotype). Our results suggest that further studies using DNA methylation at cg18146737, cg05575921, or cg12803068 that aim to assess exposure to maternal smoking during gestation should include genotype at the corresponding SNP. New methods are required for adequate and routine inclusion of genotypic influence on DNA methylation in epigenome-wide association studies to control for potential confounding.
Family histories of male patients with histologically confirmed malignant gliomas were compared to family histories of controls (wives). Included were 77 case families with 892 relatives and 77 control families with 719 relatives. Cases had significantly more siblings than controls (P = 0.02), although cases were not preferentially the oldest or the youngest sibs. Odds ratios of two or more were found for mental retardation, Parkinson's disease, and meningitis for the relatives of cases versus controls, but none were statistically significant. The excesses of Parkinson's disease and meningitis were explained by the family of one particularly interesting case containing three relatives with meningitis and two relatives with Parkinson's disease. Noteworthy age-adjusted odds ratios for cancer among relatives of cases compared to relatives of controls were 1.6 (95% confidence interval (CI) = 1.0-2.3) for cancer of any site, 2.4 (95% CI = 0.8-6.1) for breast cancer, and 4.0 (95% CI = 0.6-10.7) for lung cancer. Only the odds ratio for cancer of any site was statistically significant. Overall, 6 of 77 (8%) of cases came from families that included two or more relatives with breast or lung cancer in addition to the proband with malignant glioma. These three cancer sites may form familial clusters worthy of further evaluation in future studies by pedigree and genetic linkage analyses.
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