Genetic variants in hormone-related genes and risk of breast cancer.

Sex hormones play a key role in the development of breast cancer. Certain polymorphic variants (SNPs and repeat polymorphisms) in hormone-related genes are associated with sex hormone levels. However, the relationship observed between these genetic variants and breast cancer risk has been inconsistent. We conducted a case-control study nested within two prospective cohorts to assess the relationship between specific genetic variants in hormone-related genes and breast cancer risk. In total, 1164 cases and 2111 individually-matched controls were included in the study. We did not observe an association between potential functional genetic polymorphisms in the estrogen pathway, SHBG rs6259, ESR1 rs2234693, CYP19 rs10046 and rs4775936, and UGT1A1 rs8175347, or the progesterone pathway, PGR rs1042838, with the risk of breast cancer. Our results suggest that these genetic variants do not have a strong effect on breast cancer risk.

Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer.

BACKGROUND: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. METHODS: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). RESULTS: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. CONCLUSION: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.

Mechanistic basis of resistance to PCBs in Atlantic tomcod from the Hudson River.

The mechanistic basis of resistance of vertebrate populations to contaminants, including Atlantic tomcod from the Hudson River (HR) to polychlorinated biphenyls (PCBs), is unknown. HR tomcod exhibited variants in the aryl hydrocarbon receptor 2 (AHR2) that were nearly absent elsewhere. In ligand-binding assays, AHR2-1 protein (common in the HR) was impaired as compared to widespread AHR2-2 in binding TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and in driving expression in reporter gene assays in AHR-deficient cells treated with TCDD or PCB126. We identified a six-base deletion in AHR2 as the basis of resistance and suggest that the HR population has undergone rapid evolution, probably due to contaminant exposure. This mechanistic basis of resistance in a vertebrate population provides evidence of evolutionary change due to selective pressure at a single locus.

DNA methylation in pre-diagnostic serum samples of breast cancer cases: results of a nested case-control study.

BACKGROUND: Promoter methylation of tumor suppressor genes is a frequent and early event in breast carcinogenesis. Paired tumor tissue and serum samples from women with breast cancer show that promoter methylation is detectable in both sample types, with good concordance. This suggests the potential for these serum markers to be used for breast cancer detection. METHODS: The current study was a case-control study nested within the prospective New York University Women's Health Study cohort aimed to assess the ability of promoter methylation in serum to detect pre-clinical disease. Cases were women with blood samples collected within the 6 months preceding breast cancer diagnosis (n=50). Each case was matched to 2 healthy cancer-free controls and 1 cancer-free control with a history of benign breast disease (BBD). RESULTS: Promoter methylation analysis of four cancer-related genes: -RASSF1A, GSTP1, APC and RARß2, - was conducted using quantitative methylation-specific PCR. Results showed that the frequency of methylation was lower than expected among cases and higher than expected among controls. Methylation was detected in the promoter region of: RASSF1A in 22.0%, 22.9% and 17.2% of cases, BBD controls and healthy controls respectively; GSTP1 in 4%, 10.4% and 7.1% respectively; APC in 2.0%, 4.4% and 4.2% respectively and RARß2 in 6.7%, 2.3% and 1.1% respectively. CONCLUSION: Methylation status of the four genes included in this study was unable to distinguish between cases and either control group. This study highlights some methodological issues to be addressed in planning prospective studies to evaluate methylation markers as diagnostic biomarkers.

Polymorphisms in XPC and ERCC2 genes, smoking and breast cancer risk.

To evaluate the associations of breast cancer risk with polymorphisms in the XPC and XPD/ERCC2 DNA nucleotide excision repair genes, a case-control study nested within a prospective cohort of 14,274 women was conducted. Genotypes were characterized for 612 incident, invasive breast cancer cases and their 1:1 matched controls. The homozygous variant of a poly(AT) insertion/deletion polymorphism in intron 9 of the XPC gene (XPC-PAT+/+), was associated with breast cancer risk [odds ratio (OR) = 1.45, 95% confidence interval: 1.07-1.97], after adjustment for other breast cancer risk factors. The breast cancer risk associated with XPC-PAT+/+ did not differ by age at diagnosis. There was an indication of an interaction (p = 0.08) between the XPC-PAT+/+ genotype and cigarette smoking. Ever smokers with the XPC-PAT+/+ genotype were at elevated risk of breast cancer (OR = 1.56, CI: 0.95-2.58), but no differences were observed among never smokers. Analyses of the ERCC2 Lys751Gln polymorphism did not show an association with breast cancer risk, either overall or at younger ages. The results suggest that breast cancer risk is related to the XPC haplotype tagged by the XPC-PAT+/+ insertion-deletion polymorphism in intron 9. Further study of the XPC haplotypes and their interactions with smoking in relation to breast cancer risk is needed.

Vitamin D receptor polymorphisms and risk of epithelial ovarian cancer.

The vitamin D receptor (VDR) is a critical mediator of the cellular effects of vitamin D. The associations between four common VDR polymorphisms (BSMI, APAI, TAQI, and FOKI) and risk of epithelial ovarian cancer (EOC) were assessed in a case-control study nested within two prospective cohorts. One hundred seventy incident cases of EOC and 323 individually matched controls were genotyped. Overall, no associations were observed in genotype analyses. Haplotypes combining three SNPs in high linkage disequilibrium (BSMI, APAI, and TAQI) were also not associated with risk. These observations do not support a role for BSMI, APAI, TAQI, and FOKI polymorphisms in epithelial ovarian cancer in a predominantly Caucasian population.

Biomarkers of benzene: urinary metabolites in relation to individual genotype and personal exposure.

This report is part of an extensive biomarker study conducted in a Chinese occupational population with benzene exposures ranging from 0.06 to 122 ppm (median exposure of 3.2 ppm). All urinary benzene metabolites measured in this study were significantly elevated after exposure to benzene at or above 5 ppm. Among these metabolites, however, only S-phenylmercapturic acid (S-PMA) and trans,trans-muconic acid (t,t-MA) showed a significant exposure-response trend over the exposure range from 0 to 1 ppm (for S-PMA, p<0.0001 and for t,t-MA, p=0.006). For benzene exposure monitoring, both S-PMA and t,t-MA were judged to be good and sensitive markers, which detected benzene exposure at around 0.1 and 1 ppm, respectively. Polymorphisms of the metabolic genes, including CYP2E1, quinone oxidoreductase (NQO1), GSTT1, and myeloperoxidase (MPO), were identified and did not show significant effects on the formation of metabolites, except GSTT1 on S-PMA. The production rate of S-PMA from benzene in exposed workers with GSTT1 null alleles (24.72+/-32.48 microg/g creatinine/ppm benzene) was significantly lower than that in subjects with the wild type of GSTT1 (59.84+/-47.66 microg/g creatinine/ppm benzene, p<0.0001). Further regression analysis of S-PMA production rate on GSTT1 genotype with adjustment of sex, age, benzene exposure, and cotinine levels indicated that the genotype of GSTT1 plays a critical role in determining the inter-individual variations of S-PMA formation from benzene exposure. Therefore, the individual genotype of GSTT1 needs to be identified and considered while using S-PMA as a marker to estimate the personal exposure levels of benzene in future population studies.