The Role of Genotypes That Modify the Toxicity of Chemical Mutagens in the Risk for Myeloproliferative Neoplasms

Background: The etiology of myeloproliferative neoplasms (MPN) (polycythemia vera; essential thrombocythemia; primary myelofibrosis) is unknown, however they are associated with a somatic mutation—JAK2 V617F—suggesting a potential role for environmental mutagens. Methods: We conducted a population-based case-control study in three rural Pennsylvania counties of persons born 1921–1968 and residing in the area between 2000–2008. Twenty seven MPN cases and 292 controls were recruited through random digit dialing. Subjects were genotyped and odds ratios estimated for a select set of polymorphisms in environmentally sensitive genes that might implicate specific environmental mutagens if found to be associated with a disease. Results: The presence of NAT2 slow acetylator genotype, and CYP1A2, GSTA1, and GSTM3 variants were associated with an average 3–5 fold increased risk. Conclusions: Exposures, such as to aromatic compounds, whose toxicity is modified by genotypes associated with outcome in our analysis may play a role in the environmental etiology of MPNs

Variants in estrogen-biosynthesis genes CYP17 and CYP19 and breast cancer risk: a family-based genetic association study

BACKGROUND: Case-control studies have reported inconsistent results concerning breast cancer risk and polymorphisms in genes that control endogenous estrogen biosynthesis. We report findings from the first family-based association study examining associations between female breast cancer risk and polymorphisms in two key estrogen-biosynthesis genes CYP17 (T→C promoter polymorphism) and CYP19 (TTTA repeat polymorphism). METHODS: We conducted the study among 278 nuclear families containing one or more daughters with breast cancer, with a total of 1123 family members (702 with available constitutional DNA and questionnaire data and 421 without them). These nuclear families were selected from breast cancer families participating in the Metropolitan New York Registry, one of the six centers of the National Cancer Institute's Breast Cancer Family Registry. We used likelihood-based statistical methods to examine allelic associations. RESULTS: We found the CYP19 allele with 11 TTTA repeats to be associated with breast cancer risk in these families. We also found that maternal (but not paternal) carrier status of CYP19 alleles with 11 repeats tended to be associated with breast cancer risk in daughters (independently of the daughters' own genotype), suggesting a possible in utero effect of CYP19. We found no association of a woman's breast cancer risk either with her own or with her mother's CYP17 genotype. CONCLUSION: This family-based study indicates that a woman's personal and maternal carrier status of CYP19 11 TTTA repeat allele might be related to increased breast cancer risk. However, because this is the first study to report an association between CYP19 11 TTTA repeat allele and breast cancer, and because multiple comparisons have been made, the associations should be interpreted with caution and need confirmation in future family-based studies

Genetic polymorphisms of phase I metabolizing enzyme genes, their interaction with lifetime grilled and smoked meat intake, and breast cancer incidence

To examine associations between 22 CYP single nucleotide polymorphisms (SNPs) and breast cancer incidence and their interactions with grilled–smoked meat intake, a source of polycyclic aromatic hydrocarbons

Integrative epigenomic and genomic filtering for methylation markers in hepatocellular carcinomas

Background: Epigenome-wide studies in hepatocellular carcinoma (HCC) have identified numerous genes with aberrant DNA methylation. However, methods for triaging functional candidate genes as useful biomarkers for epidemiological study have not yet been developed. Methods: We conducted targeted next-generation bisulfite sequencing (bis-seq) to investigate associations of DNA methylation and mRNA expression in HCC. Integrative analyses of epigenetic profiles with DNA copy number analysis were used to pinpoint functional genes regulated mainly by altered DNA methylation. Results: Significant differences between HCC tumor and adjacent non-tumor tissue were observed for 28 bis-seq amplicons, with methylation differences varying from 12% to 43%. Available mRNA expression data in Oncomine were evaluated. Two candidate genes (GRASP and TSPYL5) were significantly under-expressed in HCC tumors in comparison with precursor and normal liver tissues. The expression levels in tumor tissues were, respectively, 1.828 and − 0.148, significantly lower than those in both precursor and normal liver tissue. Validations in an additional 42 paired tissues showed consistent under-expression in tumor tissue for GRASP (−7.49) and TSPYL5 (−9.71). A highly consistent DNA hypermethylation and mRNA repression pattern was obtained for both GRASP (69%) and TSPYL5 (73%), suggesting that their biological function is regulated by DNA methylation. Another two genes (RGS17 and NR2E1) at Chr6q showed significantly decreased DNA methylation in tumors with loss of DNA copy number compared to those without, suggesting alternative roles of DNA copy number losses and hypermethylation in the regulation of RGS17 and NR2E1. Conclusions: These results suggest that integrative analyses of epigenomic and genomic data provide an efficient way to filter functional biomarkers for future epidemiological studies in human cancers

Validation and Calibration of a Model Used to Reconstruct Historical Exposure to Polycyclic Aromatic Hydrocarbons for Use in Epidemiologic Studies

OBJECTIVES: We previously developed a historical reconstruction model to estimate exposure to airborne polycyclic aromatic hydrocarbons (PAHs) from traffic back to 1960 for use in case–control studies of breast cancer risk. Here we report the results of four exercises to validate and calibrate the model. METHODS: Model predictions of benzo[a]pyrene (BaP) concentration in soil and carpet dust were tested against measurements collected at subjects’ homes at interview. In addition, predictions of air intake of BaP were compared with blood PAH–DNA adducts. These same soil, carpet, and blood measurements were used for model optimization. In a separate test of the meteorological dispersion part of the model, predictions of hourly concentrations of carbon monoxide from traffic were compared with data collected at a U.S. Environmental Protection Agency monitoring station. RESULTS: The data for soil, PAH–DNA adducts, and carbon monoxide concentrations were all consistent with model predictions. The carpet dust data were inconsistent, suggesting possible spatial confounding with PAH-containing contamination tracked in from outdoors or unmodeled cooking sources. BaP was found proportional to other PAHs in our soil and dust data, making it reasonable to use BaP historical data as a surrogate for other PAHs. Road intersections contributed 40–80% of both total emissions and average exposures, suggesting that the repertoire of simple markers of exposure, such as traffic counts and/or distance to nearest road, needs to be expanded to include distance to nearest intersection

Environmental Tobacco Smoke Exposure and Survival Following Breast Cancer

Environmental tobacco smoke (ETS) exposure is hypothesized to influence survival after breast cancer, but few studies have examined this association

Genome-Wide Expression of MicroRNAs Is Regulated by DNA Methylation in Hepatocarcinogenesis

Background. Previous studies, including ours, have examined the regulation of microRNAs (miRNAs) by DNA methylation, but whether this regulation occurs at a genome-wide level in hepatocellular carcinoma (HCC) is unclear. Subjects/Methods. Using a two-phase study design, we conducted genome-wide screening for DNA methylation and miRNA expression to explore the potential role of methylation alterations in miRNAs regulation. Results. We found that expressions of 25 miRNAs were statistically significantly different between tumor and nontumor tissues and perfectly differentiated HCC tumor from nontumor. Six miRNAs were overexpressed, and 19 were repressed in tumors. Among 133 miRNAs with inverse correlations between methylation and expression, 8 miRNAs (6%) showed statistically significant differences in expression between tumor and nontumor tissues. Six miRNAs were validated in 56 additional paired HCC tissues, and significant inverse correlations were observed for miR-125b and miR-199a, which is consistent with the inactive chromatin pattern found in HepG2 cells. Conclusion. These data suggest that the expressions of miR-125b and miR-199a are dramatically regulated by DNA hypermethylation that plays a key role in hepatocarcinogenesis

Circulating growth factor concentrations and breast cancer risk: a nested case-control study of IGF-1, IGFBP-3, and breast cancer in a family-based cohort

Background Insulin-like growth factor 1 (IGF-1) and binding protein 3 (IGFBP-3) are associated with breast cancer in women at average risk of cancer. Less is known whether these biomarkers also predict risk in women with breast cancer family history. Methods We conducted a nested case-control study within the New York site of the Breast Cancer Family Registry (BCFR, n = 80 cases, 156 controls), a cohort enriched for breast cancer family history. Using conditional logistic regression, we estimated the association between IGF-1 and IGFBP-3 levels and breast cancer risk and examined whether this risk differed by predicted absolute breast cancer risk based on pedigree models. Results The overall association between IGF-1 or IGFBP-3 elevation (≥ median in controls) and breast cancer risk was elevated, but not statistically significant (IGF-1 OR = 1.37, 95% CI = 0.66–2.85; IGFBP-3 OR = 1.62, 95% CI = 0.81–3.24). Women with elevated predicted absolute 10-year risk ≥ 3.4% and elevated IGFBP-3 (≥ median) had more than a 3-fold increased risk compared to women with lower predicted absolute 10-year risk (< 3.4%) and low IGFBP-3 (OR = 3.47 95% CI = 1.04–11.6). Conclusions These data offer some support that the overall magnitude of the associations between IGF-1 and IGFBP3 seen in average risk cohorts may be similar in women enriched with a strong breast cancer family history

Polycyclic aromatic hydrocarbons and postmenopausal breast cancer: An evaluation of effect measure modification by body mass index and weight change

Polycyclic aromatic hydrocarbons (PAHs) have been linked to breast cancer in many, but not all, previous studies. PAHs are lipophilic and stored in fat tissue, which we hypothesized may result in constant low-dose exposure to these carcinogens. No previous studies have evaluated whether obesity modifies associations between multiple measures of PAHs and breast cancer incidence