mTOR pathway candidate genes and physical activity interaction on breast cancer risk in black women from the women's circle of health study.

BACKGROUND: Physical activity has been shown to affect the mammalian target of rapamycin (mTOR) signaling pathway and consequently breast carcinogenesis. Given that Black women in the USA are less physically active, it is not well understood whether there are gene-environment interactions between mTOR pathway genes and physical activity in relation to breast cancer risk in Black women. METHODS: The study included 1398 Black women (567 incident breast cancer cases and 831 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with levels of vigorous physical activity in relation to breast cancer risk overall and by ER-defined subtypes using Wald test with 2-way interaction term and multivariable logistic regression. RESULTS: AKT1 rs10138227 (C > T) and AKT1 rs1130214 (C > A) were only associated with a decreased risk of ER + breast cancer among women with vigorous physical activity (odds ratio [OR] = 0.15, 95% confidence interval (CI) 0.04, 0.56, for each copy of the T allele, p-interaction = 0.007 and OR = 0.51, 95% CI 0.27, 0.96, for each copy of the A allele, p-interaction = 0.045, respectively). MTOR rs2295080 (G > T) was only associated with an increased risk of ER + breast cancer among women with vigorous physical activity (OR = 2.24, 95% CI 1.16, 4.34, for each copy of the G allele; p-interaction = 0.043). EIF4E rs141689493 (G > A) was only associated with an increased risk of ER- breast cancer among women with vigorous physical activity (OR = 20.54, 95% CI 2.29, 184.17, for each copy of the A allele; p-interaction = 0.003). These interactions became non-significant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: Our findings suggest that mTOR genetic variants may interact with physical activity in relation to breast cancer risk in Black women. Future studies should confirm these findings.

mTOR pathway candidate genes and obesity interaction on breast cancer risk in black women from the Women's Circle of Health Study.

BACKGROUND: Obesity is known to stimulate the mammalian target of rapamycin (mTOR) signaling pathway and both obesity and the mTOR signaling pathway are implicated in breast carcinogenesis. We investigated potential gene-environment interactions between mTOR pathway genes and obesity in relation to breast cancer risk among Black women. METHODS: The study included 1,655 Black women (821 incident breast cancer cases and 834 controls) from the Women's Circle of Health Study (WCHS). Obesity measures including body mass index (BMI); central obesity i.e., waist circumference (WC) and waist/hip ratio (WHR); and body fat distribution (fat mass, fat mass index and percent body fat) were obtained by trained research staff. We examined the associations of 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes with breast cancer risk using multivariable logistic regression. We next examined interactions between these SNPs and measures of obesity using Wald test with 2-way interaction term. RESULTS: The variant allele of BRAF (rs114729114 C > T) was associated with an increase in overall breast cancer risk [odds ratio (OR) = 1.81, 95% confidence interval (CI) 1.10-2.99, for each copy of the T allele] and the risk of estrogen receptor (ER)-defined subtypes (ER+ tumors: OR = 1.83, 95% CI 1.04,3.29, for each copy of the T allele; ER- tumors OR = 2.14, 95% CI 1.03,4.45, for each copy of the T allele). Genetic variants in AKT, AKT1, PGF, PRKAG2, RAPTOR, TSC2 showed suggestive associations with overall breast cancer risk and the risk of, ER+ and ER- tumors (range of p-values = 0.040-0.097). We also found interactions of several of the SNPs with BMI, WHR, WC, fat mass, fat mass index and percent body fat in relation to breast cancer risk. These associations and interactions, however, became nonsignificant after correction for multiple testing (FDR-adjusted p-value > 0.05). CONCLUSION: We found associations between mTOR genetic variants and breast cancer risk as well as gene and body fatness interactions in relation to breast cancer risk. However, these associations and interactions became nonsignificant after correction for multiple testing. Future studies with larger sample sizes are required to confirm and validate these findings.

mTOR pathway candidate genes and energy intake interaction on breast cancer risk in Black women from the Women's Circle of Health Study.

BACKGROUND: Excessive energy intake has been shown to affect the mammalian target of the rapamycin (mTOR) signaling pathway and breast cancer risk. It is not well understood whether there are gene-environment interactions between mTOR pathway genes and energy intake in relation to breast cancer risk. METHODS: The study included 1642 Black women (809 incident breast cancer cases and 833 controls) from the Women's Circle of Health Study (WCHS). We examined interactions between 43 candidate single-nucleotide polymorphisms (SNPs) in 20 mTOR pathway genes and quartiles of energy intake in relation to breast cancer risk overall and by ER- defined subtypes using Wald test with a 2-way interaction term. RESULTS: AKT1 rs10138227 (C > T) was only associated with a decreased overall breast cancer risk among women in quartile (Q)2 of energy intake, odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.40, 0.91 (p-interaction = 0.042). Similar results were found in ER- tumors. AKT rs1130214 (C > A) was associated with decreased overall breast cancer risk in Q2 (OR = 0.63, 95% CI 0.44, 0.91) and Q3 (OR = 0.65, 95% CI 0.48, 0.89) (p-interaction = 0.026). HIF-1α C1772T rs11549465 (C > T) was associated with decreased overall breast cancer risk in Q4 (OR = 0.29, 95% CI 0.14, 0.59, p-interaction = 0.007); the results were similar in ER+ tumors. These interactions became non-significant after correction for multiple comparisons. CONCLUSION: Our findings suggest that mTOR genetic variants may interact with energy intake in relation to breast cancer risk, including the ER- subtype, in Black women. Future studies should confirm these findings.

Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear. OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study. METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined. RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities. CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

Associations between Plasma Choline Metabolites and Genetic Polymorphisms in One-Carbon Metabolism in Postmenopausal Women: The Women's Health Initiative Observational Study.

BACKGROUND: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites. OBJECTIVES: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites. METHODS: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined. RESULTS: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration. CONCLUSIONS: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women.

Urinary Concentrations of Triclosan, Bisphenol A, and Brominated Flame Retardants and the Association of Triclosan with Demographic Characteristics and Body Fatness among Women with Newly Diagnosed Breast Cancer.

Background: Triclosan, bisphenol A (BPA), and brominated flame retardants are environmental estrogenic endocrine-disrupting compounds that may influence the prognosis of breast cancer. We examined the urinary concentrations of these compounds and their associations with demographic characteristics and body fatness in a population of women with newly diagnosed breast cancer. Methods: Overnight urine collection and anthropometric measures were obtained from 302 participants. Triclosan, BPA, tetrabromobisphenol A (TBBPA), and tetrabromobenzoic acid (TBBA) concentrations were determined using ultra-performance liquid chromatography−tandem mass spectrometry. Regression analyses were conducted to examine associations of urinary compound concentration with age, menopause, race, ethnicity, educational level, estrogen receptor status, body size, and body composition. Results: Triclosan, BPA, and TBBA were detected in urine samples from 98.3%, 6.0%, and 0.3% of patients, respectively; TBBPA was undetectable. Among patients with quantifiable values, the geometric mean concentrations were 20.74 µg/L (27.04 µg/g creatinine) for triclosan and 0.82 µg/L (1.08 µg/g creatinine) for BPA. Body mass index ≥ 30 vs. <25 kg/m2 was associated with lower creatinine-corrected urinary concentrations of triclosan (−40.00, 95% confidence interval [CI] = −77.19 to −2.81; p = 0.0351). The observed association was predominantly in postmenopausal women (−66.57; 95% CI: −109.18% to −23.96%). Consistent results were found for associations between triclosan levels and fat mass variables. Conclusion: In this study population, women with newly diagnosed breast cancer had triclosan exposure. Assessments of the implications of urinary concentrations of triclosan for women should consider body fatness and menopausal status.

mTOR pathway gene expression in association with race and clinicopathological characteristics in Black and White breast cancer patients.

BACKGROUND: Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway has been linked to obesity and endocrine therapy resistance, factors that may contribute to Black-White disparities in breast cancer outcomes. We evaluated associations of race and clinicopathological characteristics with mRNA expression of key mTOR pathway genes in breast tumors. METHODS: Surgical tumor tissue blocks were collected from 367 newly diagnosed breast cancer patients (190 Black and 177 White). Gene expression of AKT1, EIF4EBP1, MTOR, RPS6KB2, and TSC1 were quantified by NanoString nCounter. Differential gene expression was assessed using linear regression on log2-transformed values. Gene expression and DNA methylation data from TCGA were used for validation and investigation of race-related differences. RESULTS: Compared to White women, Black women had relative under-expression of AKT1 (log2 fold-change = - 0.31, 95% CI - 0.44, - 0.18) and RPS6KB2 (log2 fold-change = - 0.11, 95% CI - 0.19, - 0.03). Higher vs. lower tumor grade was associated with relative over-expression of EIF4EBP1 and RPS6KB2, but with lower expression of TSC1. Compared to luminal tumors, triple-negative tumors had relative under-expression of TSC1 (log2 fold-change = - 0.42, 95% CI - 0.22, - 0.01). The results were similar in the TCGA breast cancer dataset. Post-hoc analyses identified differential CpG methylation within the AKT1 and RPS6KB2 locus between Black and White women. CONCLUSIONS: Over-expression of RPS6KB2 and EIF4EBP1 and under-expression of TSC1 might be indicators of more aggressive breast cancer phenotypes. Differential expression of AKT1 and RPS6KB2 by race warrants further investigation to elucidate their roles in racial disparities of treatment resistance and outcomes between Black and White women with breast cancer.

Change in Pattern of Secondary Cancers After Kaposi Sarcoma in the Era of Antiretroviral Therapy.

IMPORTANCE: Studies performed in the 1980s and early 1990s have shown that people who develop Kaposi sarcoma (KS) are at higher risk of developing other cancers. The demographics of those affected with human immunodeficiency virus (HIV)/AIDS and KS have changed, and individuals with HIV/AIDS and KS now live longer. OBJECTIVES: To test the hypothesis that the secondary cancers developing in patients with KS have changed in recent years and to assess the risk of secondary cancers after KS in different periods. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal data from 9 cancer registries in the Surveillance, Epidemiology, and End Results (SEER) database were used to identify cases of KS diagnosed from January 1973 to December 2013. The dates of the analysis were November 2016 to February 2017. MAIN OUTCOMES AND MEASURES: The primary outcome was the development of secondary cancers in individuals with KS. Secondary cancers were considered only if diagnosed 2 months after a diagnosis of KS. Standardized incidence ratios (SIRs) were calculated for the development of new secondary cancers in the pre-AIDS era (1973-1979), pre-highly active antiretroviral therapy (HAART) era (1980-1995), and HAART era (1996-2013). Stratified analysis was then performed on a subset of the cases diagnosed from 1996 to 2013 based on age at diagnosis (<65 and ≥65 years), latency period between KS and the development of secondary cancers (1 year, 2-5 years, >5 to 10 years, and >10 years), and registries with higher vs lower reported rates of HIV/AIDS. RESULTS: Among 14 905 individuals with diagnosed KS, 13 721 (92.1%) were younger than 65 years at the time of diagnosis, and 14 356 (96.3%) were male. From 1980 to 1995, SIRs were 2.01 (95% CI, 1.00-3.60) for cancer of the rectum, 49.70 (95% CI, 33.53-70.94) for cancer of the anus, 4.98 (95% CI, 2.79-8.22) for cancer of the liver, 13.70 (95% CI, 2.82-40.03) for cancer of the cervix, 6.40 (95% CI, 2.76-12.60) for Hodgkin lymphoma, and 48.97 (95% CI, 44.85-53.36) for non-Hodgkin lymphoma. From 1996 to 2013, cancer of the anus, Hodgkin lymphoma, non-Hodgkin lymphoma, and cancer of the liver remained associated with KS, with the addition of the following significant SIRs: 6.99 (95% CI, 3.20-13.27) for cancer of the tongue, 10.28 (95% CI, 1.24-37.13) for cancer of the penis, and 17.62 (95% CI, 3.63-51.49) for acute lymphocytic leukemia. The SIR of developing any tumor after KS decreased significantly from 3.36 to 1.94 from the pre-HAART era to the HAART era. CONCLUSIONS AND RELEVANCE: There has been a significant decline in the overall risk of secondary cancers after KS. Certain cancers, including acute lymphocytic leukemia, cancer of the tongue, and cancer of the penis, are increasingly becoming more common in the HAART era compared with the pre-HAART era. Close monitoring and screening for these secondary cancers is desirable in patients with KS.