Search

Aberrant DNA methylation patterns have been used for cancer detection. However, DNA hemi-methylation, present at about 10% CpG dinucleotides, has been less well studied. Here we show that a majority of differentially hemi-methylated regions (DHMRs) in liver tumor DNA or plasma cells free (cf) DNA do not overlap with differentially methylated regions (DMRs) of the same samples, indicating that DHMRs could serve as independent biomarkers. Furthermore, we analyzed the cfDNA methylomes of 215 samples from individuals with liver or brain cancer and individuals without cancer (controls), and trained machine learning models using DMRs, DHMRs or both. The models incorporated with both DMRs and DHMRs show a superior performance compared to models trained with DMRs or DHMRs, with AUROC being 0.978, 0.990, and 0.983 in distinguishing control, liver and brain cancer, respectively, in a validation cohort. This study supports the potential of utilizing both DMRs and DHMRs for multi-cancer detection. Alterations in DNA methylation patterns are known as predictors of cancer diagnosis. Here, the authors develop a method to analyze both symmetric- and hemi-methylated regions in plasma cell free DNA and show its utility in detecting both liver and brain cancer. [ABSTRACT FROM AUTHOR]

Purpose: Liver cancer incidence among American Indians/Alaska Natives has risen over the past 20 years. Peripheral blood DNA methylation may be associated with liver cancer and could be used as a biomarker for cancer risk. We evaluated the association of blood DNA methylation with risk of liver cancer. Methods: We conducted a prospective cohort study in 2324 American Indians, between age 45 and 75 years, from Arizona, Oklahoma, North Dakota and South Dakota who participated in the Strong Heart Study between 1989 and 1991. Liver cancer deaths (n = 21) were ascertained using death certificates obtained through 2017. The mean follow-up duration (SD) for non-cases was 25.1 (5.6) years and for cases, 11.0 (8.8) years. DNA methylation was assessed from blood samples collected at baseline using MethylationEPIC BeadChip 850 K arrays. We used Cox regression models adjusted for age, sex, center, body mass index, low-density lipoprotein cholesterol, smoking, alcohol consumption, and immune cell proportions to examine the associations. Results: We identified 9 CpG sites associated with liver cancer. cg16057201 annotated to MRFAP1) was hypermethylated among cases vs. non-cases (hazard ratio (HR) for one standard deviation increase in methylation was 1.25 (95% CI 1.14, 1.37). The other eight CpGs were hypomethylated and the corresponding HRs (95% CI) ranged from 0.58 (0.44, 0.75) for cg04967787 (annotated to PPRC1) to 0.77 (0.67, 0.88) for cg08550308. We also assessed 7 differentially methylated CpG sites associated with liver cancer in previous studies. The adjusted HR for cg15079934 (annotated to LPS1) was 1.93 (95% CI 1.10, 3.39). Conclusions: Blood DNA methylation may be associated with liver cancer mortality and may be altered during the development of liver cancer. [ABSTRACT FROM AUTHOR]

Purpose: To investigate how a healthy lifestyle index (HLI) is associated with breast cancer risk and survival in a population-based breast cancer study. Methods: The study included 1319 breast cancer cases and 1310 controls from the population-based Long Island Breast Cancer Study Project and its follow-up study where vital status was ascertained using the National Death Index (521 deaths, 210 from breast cancer; median follow-up 214.5 months). HLI scores were generated from body mass index, physical activity, intake of plant and animal foods, alcohol consumption, breastfeeding, and smoking, with higher values corresponding to healthier behaviors obtained from baseline questionnaire. Multivariable logistic and Cox regression models were used to estimate breast cancer odds ratios (ORs) and mortality hazards ratios (HRs), respectively. Results: Compared to women in the low HLI tertile, a significant reduction in risk of breast cancer was observed for women in the intermediate (OR = 0.78, 95% CI 0.64–0.93) and high (OR = 0.73, 95% CI 0.60–0.88) tertiles; a one-point increase in HLI score was associated with a 14% reduction in breast cancer risk (OR = 0.86, 95% CI 0.80–0.93). For survival, a significant reduction in all-cause mortality was also observed in women in the intermediate (HR = 0.68, 95% CI 0.56–0.84) and high (HR = 0.72, 95% CI 0.58–0.88) HLI tertiles with a 17% reduction in all-cause mortality (HR = 0.83, 95% CI 0.76–0.91) for one-point increase in HLI score. These inverse associations were more prominent among postmenopausal women. Conclusion: A healthy lifestyle is beneficial not only in reducing breast cancer risk but also in improving overall survival after breast cancer diagnosis, especially among postmenopausal women. [ABSTRACT FROM AUTHOR]

DNA repair phenotype can be measured in blood and may be a potential biomarker of cancer risk. We conducted a systematic review and meta-analysis of epidemiological studies of DNA repair phenotype and cancer through March 2021. We used random-effects models to calculate pooled odds ratios (ORs) of cancer risk for those with the lowest DNA repair capacity compared with those with the highest capacity. We included 55 case–control studies that evaluated 12 different cancers using 10 different DNA repair assays. The pooled OR of cancer risk (all cancer types combined) was 2.92 (95% Confidence Interval (CI) 2.49, 3.43) for the lowest DNA repair. Lower DNA repair was associated with all studied cancer types, and pooled ORs (95% CI) ranged from 2.02 (1.43, 2.85) for skin cancer to 7.60 (3.26, 17.72) for liver cancer. All assays, except the homologous recombination repair assay, showed statistically significant associations with cancer. The effect size ranged from 1.90 (1.00, 3.60) for the etoposide-induced double-strand break assay to 5.06 (3.67, 6.99) for the γ-H2AX assay. The consistency and strength of the associations support the use of these phenotypic biomarkers; however large-scale prospective studies will be important for understanding their use related to age and screening initiation. [ABSTRACT FROM AUTHOR]

In the U.S., Hepatocellular carcinoma (HCC) incidence rates have increased. We aimed to determine whether environmental exposure plays a role in the high incidence of HCC observed in New York City. We conducted a hospital-based case only study to examine the prevalence of aflatoxin B1 (AFB1)- and polycyclic aromatic hydrocarbon (PAH)-albumin adducts and the distribution of adducts by different characteristics of HCC patients. Blood samples were collected from 155 HCC patients for biomarker analyses. We observed that about 46% and 49% of cases had detectable AFB1- and PAH-albumin adducts, respectively. There were significant differences between AFB1-albumin adducts and selected factors such as HCV infection status (p = 0.04), diabetes (p = 0.03) and Barcelona Clinic Liver Cancer stage (p = 0.02). Cases with detectable PAH-albumin adducts had a smoking history compared with those with nondetectable levels (p = 0.04). The level of AFB1-albumin adducts was positively correlated with plasma bilirubin (rs = 0.32, p < 0.0001) and adiponectin concentrations (rs = 0.28, p = 0.0005). The level of aflatoxin B1-albumin adducts was negatively associated with blood albumin concentration (rs = − 0.28, p = 0.0009) and plasma DNA LINE-1 methylation (rs = − 0.16, p = 0.04). Our study provides additional evidence that environmental exposures including to aflatoxin might drive the high incidence of HCC observed in the New York City. [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the prognostic ability of immunohistochemistry (IHC)-based vs. PAM50-based subtypes for breast cancer mortality in a population-based study of breast cancer. Methods: We included a total of 463 breast cancer cases from the population-based Long Island Breast Cancer Study Project (LIBCSP). IHC-based markers were abstracted from the medical records, while the PAM50-based intrinsic subtypes were assessed from tumor tissues using NanoString nCounter® Analysis System. Cox proportional hazards models were used to estimate hazards ratios (HRs) for breast cancer-specific mortality associated with subtypes. Results: For IHC-based hormone receptor-positive (HR+) tumors (n = 361), 68.7% were classified as luminal subtypes by PAM50; for HR− tumors (n = 102), 95.1% were classified as non-luminal subtypes. Compared to HR+/HER2− subtype, HR− patients had significantly higher breast cancer mortality (HR−/HER2+: HR = 2.84, 95% CI = 1.58–5.11; triple-negative breast cancer: HR = 2.42, 95% CI = 1.44–4.06). Compared to luminal A, a higher mortality rate was observed for all other PAM50-based subtypes: luminal B (HR = 4.03, 95% CI = 1.97–8.22), HER2-enriched (HR = 6.82, 95% CI = 3.29–14.14) and basal-like (HR = 4.71, 95% CI = 2.24–9.93). Additional subtyping of HR+ patients by PAM50 provided future risk stratification where luminal B patients in this group had significant higher mortality than luminal A patients (HR = 3.93, 95% CI = 1.92–8.03). Similar results were also observed among 291 HR+/HER2− patients, but not among the HR− patients. Conclusions: Our study suggests that for HR+ patients, especially HR+/HER2− patients, additional PAM50-based subtyping would provide better prognostic stratification and improve disease management. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) incidence is increasing around the globe, including in Taiwan, though the cause of the increasing incidence is less clear. We followed up 11,296 Taiwanese females who did not have BC at baseline, and ascertained new invasive BC (N = 351) through data linkage to the National Cancer Registry from 1991 to 2018 to examine whether reproductive, lifestyle and environmental risk factors including polycyclic aromatic hydrocarbons (PAH) were associated with BC risk. We conducted a nested case–control study using baseline blood available from a total of 305 women with BC and 598 women without BC matched on time in cohort. We examined the association of PAH-albumin adducts and BC risk using conditional logistic regression models. Age at menarche (HR 0.6 (95% CI 0.5–0.9) for ≥ 15 vs. < 13 years) and multiparity were associated with BC risk (HR 2.0 (95% CI 1.4–2.8), 2.8 (1.9–4.2), and 2.4 (1.0–5.0) for 3–4, 1–2 and 0 live birth, compared with women ≥ 5 births). PAH-albumin adducts were not associated with BC risk. Given the increasing BC incidence in Taiwan, there is a need to identify environmental factors that are important to this population. [ABSTRACT FROM AUTHOR]

Phthalates are commonly included as ingredients in personal care products such as cosmetics, shampoos and perfumes. Diethyl phthalate (DEP) has been found to be anti-androgenic and linked with adverse reproductive effects on males, but effects on females are poorly understood. We designed an integrative and translational study to experimentally examine the effects of DEP exposure at a human-equivalent dose on the mammary transcriptome in rats and to subsequently examine the DEP gene signature in breast tissues (both pre-malignant and tumor) from a population study. In Sprague-Dawley rats treated orally with DEP from birth to adulthood, we identified a signature panel of 107 genes predominantly down-regulated by DEP exposure. Univariate analysis of this 107 DEP gene signature in pre-malignant breast tissues revealed that six genes (P4HA1, MPZL3, TMC4, PLEKHA6, CA8, AREG) were inversely associated with monoethyl phthalate (MEP; the urinary metabolite of DEP) concentration (p < 0.05) among postmenopausal women; all six genes loaded on to one of seven factors identified by factor analysis. Transcription factor enrichment analysis revealed that genes in this factor were enriched for androgen receptor binding sites. These six genes were also significantly down-regulated in pre-malignant adjacent tissues compared to the corresponding tumor tissues in pair-wise analyses (p < 0.05). Results from our translational study indicate that low level exposure to diethyl phthalate results in measurable genomic changes in breast tissue with implications in breast carcinogenesis. [ABSTRACT FROM AUTHOR]

Purpose: Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH-DNA adducts, methylation, and breast cancer are unknown. The objectives of this study were to (1) assess associations between PAH-DNA adducts, and breast cancer, stratified by DNA methylation markers and (2) examine interactions between adducts and DNA methylation in association with breast cancer and tumor subtype.Methods: In a population-based case-control study, promoter methylation of 13 breast cancer-related genes was measured in tumor tissue (n = 765-851 cases). Blood DNA from breast cancer cases (n = 873) and controls (n = 941) was used to assess PAH-DNA adducts and global methylation. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CI); and the ratio of the OR (ROR) was used to assess heterogeneity.Results: Women with detectable PAH-DNA adducts and methylated RARβ (ROR 2.69, 95% CI 1.02-7.12; p for interaction = 0.03) or APC (ROR 1.76, 95% CI 0.87-3.58; p for interaction = 0.09) genes were more likely to have hormone receptor-positive tumors than other subtypes. Interactions with other methylation markers were not apparent (p ≥ 0.10). The association between adducts and breast cancer did not vary by methylation status of the tumor nor did adducts associate with global methylation in the controls.Conclusions: Gene-specific methylation of RARβ, and perhaps APC, may interact with PAH-DNA adducts to increase risk of hormone receptor-positive breast cancer. There was little evidence that adducts were associated with or interacted with other methylation markers of interest. [ABSTRACT FROM AUTHOR]

Background: The impact of folate deficiency on global DNA methylation is uncertain. It also is unclear whether global DNA methylation is associated with outcome in HCC. LINE-1 methylation levels, as a surrogate marker of global methylation, may be influenced by folate deficiency. However, the interaction between LINE-1 methylation and folate level on overall survival (OS) in hepatocellular carcinoma (HCC) patients is unknown. We evaluated whether LINE-1 hypomethylation and folate deficiency are associated with HCC prognosis. Methods: We prospectively recruited 172 HCC patients between 2008 and 2012. LINE-1 methylation levels in plasma and white blood cells (WBC) were measured by pyrosequencing, and plasma folate levels by a radioprotein-binding assay. Results: Patients with plasma LINE-1 methylation <70.0% (hypomethylation) had significantly worse OS compared with those with ≥70.0% methylation (hypermethylation) [hazard ratio (HR) = 1.77; 95% confidence interval (CI) 1.12-2.79; P = 0.015]. HCC patients with lower plasma folate levels also had worse survival (<27.7 vs. ≥27.7 nmol/L; HR = 1.96; 95% CI, 1.24-3.09; P = 0.004). Furthermore, survival was poor in patients in whom both plasma LINE-1 methylation and folate levels were low compared with those patients in whom both levels were high (HR = 3.36; 95%CI, 1.77-6.40; P < 0.001). This interaction neared statistical significance ( P = 0.057). No significant association was found between WBC LINE-1 methylation levels and survival. Conclusions: These findings suggest that both lower plasma levels of LINE-1 methylation and folate are associated with worse survival in HCC patients. [ABSTRACT FROM AUTHOR]

Background:Most studies of environmental risk factors and breast cancer are conducted using average risk cohorts.Methods:We examined the association between polycyclic aromatic hydrocarbon (PAH)-albumin adducts in bloods from baseline and breast cancer risk in a prospective nested case-control study (New York site of the BCFR, 80 cases and 156 controls). We estimated the 10-year absolute breast cancer risk by a risk model that uses pedigree information (BOADICEA) and evaluated whether the increased risk from PAH differed by absolute risk.Results:Women with detectable levels of PAH had a twofold association with breast cancer risk (odds ratio (OR)=2.04; 95% CI=1.06-3.93) relative to women with non-detectable levels. The association increased with higher levels of PAH (⩾median) and by a higher level of absolute breast cancer risk (10-year risk ⩾3.4%: OR=4.09, 95% CI=1.38-12.13).Conclusions:These results support that family-based cohorts can be an efficient way to examine gene-environment interactions. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the poor breast cancer prognosis among obese women are unresolved. DNA methylation levels are linked to obesity and to breast cancer survival. We hypothesized that obesity may work in conjunction with the epigenome to alter prognosis. Using a population-based sample of women diagnosed with first primary breast cancer, we examined modification of the obesity-mortality association by DNA methylation. In-person interviews were conducted approximately 3 months after diagnosis. Weight and height were assessed [to estimate body mass index (BMI)], and blood samples collected. Promoter methylation of 13 breast cancer-related genes was assessed in archived tumor by methylation-specific PCR and Methyl Light. Global methylation in white blood cell DNA was assessed by analysis of long interspersed elements-1 (LINE-1) and with the luminometric methylation assay (LUMA). Vital status among 1308 patients (with any methylation biomarker and complete BMI assessment) was determined after approximately 15 years of follow-up ( N = 194/441 deaths due to breast cancer-specific/all-cause mortality). We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95 % confidence intervals (CIs) using two-sided p values of 0.05. Breast cancer-specific mortality was higher among obese (BMI ≥ 30) patients with promoter methylation in APC (HR = 2.47; 95 % CI = 1.43-4.27) and TWIST1 (HR = 4.25; 95 % CI = 1.43-12.70) in breast cancer tissue. Estimates were similar, but less pronounced, for all-cause mortality. Increased all-cause (HR = 1.81; 95 % CI = 1.19-2.74) and breast cancer-specific (HR = 2.61; 95 % CI = 1.45-4.69) mortality was observed among obese patients with the lowest LUMA levels. The poor breast cancer prognosis associated with obesity may depend on methylation profiles, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Purpose: Studies of vitamin D-pathway genetic variants in relation to cancer risk have been inconsistent. We examined the associations between vitamin D-related genetic polymorphisms, plasma 25-hydroxyvitamin D [25(OH)D], and breast cancer risk. Methods: In a population-based case-control study of 967 incident breast cancer cases and 993 controls, we genotyped 25 polymorphisms encoding the vitamin D receptor ( VDR) gene, 1α-hydroxylase ( CYP27B1), 24-hydroxylase ( CYP24A1), and vitamin D-binding protein ( GC) and measured plasma 25(OH)D. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and 95 % confidence intervals (CIs). Results: Among CYP24A1 polymorphisms, rs6068816 was associated with a 72 % reduction in breast cancer risk (TT vs. CC, OR 0.28, 95 % CI 0.10-0.76; p = 0.01), but for rs13038432, the 46 % decrease included the null value (GG vs. AA, OR 0.54, 95 % CI 0.17-1.67; p = 0.03). Increased risk that included the null value was noted for CYP24A1 rs3787557 (CC vs. TT, OR 1.34, 95 % CI 0.92-1.89). The VDR polymorphism, TaqI (rs731236), was associated with a 26 % risk reduction (TT vs. CC, OR 0.74, 95 % CI 0.56-0.98; p = 0.01). For other polymorphisms, ORs were weak and included the null value. The inverse association for plasma 25(OH)D with breast cancer was more pronounced (OR 0.43, 95 % CI 0.27-0.68) among women with the common allele for CYP24A1, rs927650 ( p for interaction on a multiplicative scale = 0.01). Conclusion: Breast cancer risk may be associated with specific vitamin D-related polymorphisms, particularly CYP24A1. Genetic variation in the vitamin D pathway should be considered when designing potential intervention strategies with vitamin D supplementation. [ABSTRACT FROM AUTHOR]

Purpose: We previously reported an inverse association between flavonoid intake and breast cancer incidence, which has been confirmed by others, but no studies have considered simultaneously potential interactions of flavonoids with multiple genetic polymorphisms involved in biologically relevant pathways (oxidative stress, carcinogen metabolism, DNA repair, and one-carbon metabolism). Methods: To estimate interaction effects between flavonoids and 13 polymorphisms in these four pathways on breast cancer risk, we used population-based data ( n = 875 cases and 903 controls) and several statistical approaches, including conventional logistic regression and semi-Bayesian hierarchical modeling (incorporating prior information on the possible biologic functions of genes), which also provides biologic pathway-specific effect estimates. Results: Compared to the standard multivariate model, the results from the hierarchical model indicate that gene-by-flavonoid interaction estimates are attenuated, but more precise. In the hierarchical model, the average effect of the deleterious versus beneficial gene, controlling for average flavonoid intake in the DNA repair pathway, and adjusted for the three other biologically relevant pathways (oxidative stress, carcinogen metabolism, and one-carbon metabolism), resulted in a 27 % increase risk for breast cancer [odds ratio = 1.27; 95 % confidence interval (CI) = 0.70, 2.29]. However, the CI was wide. Conclusions: Based on results from the semi-Bayesian model, breast cancer risk may be influenced jointly by flavonoid intake and genes involved in DNA repair, but our findings require confirmation. [ABSTRACT FROM AUTHOR]

Purpose: We previously observed that poor DNA repair phenotype is associated with increased breast cancer (BC) risk within families. Here, we examined whether genetic variation in double-strand break repair (DSBR) genes is associated with BC risk and if genotypes are related to phenotype in unaffected women. Methods: Using data from the New York site of the Breast Cancer Family Registry, we investigated 25 single-nucleotide polymorphism (SNPs) involved in DSBR using biospecimens from 337 BC cases and 410 unaffected sister controls. Results: Genotypes in XRCC4 were associated with BC risk, with ORs of 1.67 (95 % CI 1.01-2.76) for the combined GA/AA of rs1805377 and 1.69 (95 % CI 1.03-2.77) for rs1056503 TG/GG; these associations were no longer statistically significant in multivariable conditional logistic regression models. When examining the association of SNPs with phenotype, we found that genotypes of XRCC5 rs3834 and rs1051685, which were highly correlated with each other, were associated with end-joining (EJ) capacity; women with the XRCC5 rs3834 GA genotype had better DNA repair as measured by higher levels of EJ capacity (37.8 ± 14.1 % for GA vs. 27.9 ± 11.8 % for GG carriers p = 0.0006). Women with the AA genotype of BRCA1 rs799917 also had higher EJ capacity (35.1 ± 9.2 %) than those with GG (26.4 ± 10.1 %, p = 0.02). Conclusions: Overall, we found that selected DSBR genotypes were associated with phenotype, although they were not associated with BC risk itself, suggesting that phenotypic measures are influenced by endogenous and exogenous factors across the life course and may be better markers than genotypic measures for ascertaining BC risk. [ABSTRACT FROM AUTHOR]

Purpose: The mechanisms driving the physical activity-breast cancer association are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Given the paradoxical effects of physical activity, the oxidative stress pathway is of interest. Genetic variation in CAT or antioxidant-related polymorphisms may mediate the physical activity-breast cancer association.Methods: We investigated the main and joint effects of three previously unreported polymorphisms in CAT on breast cancer risk. We also estimated interactions between recreational physical activity (RPA) and 13 polymorphisms in oxidative stress-related genes. Data were from the Long Island Breast Cancer Study Project, with interview and biomarker data available on 1,053 cases and 1,102 controls.Results: Women with ≥1 variant allele in CAT rs4756146 had a 23 % reduced risk of postmenopausal breast cancer compared with women with the common TT genotype (OR = 0.77; 95 % CI = 0.59-0.99). We observed two statistical interactions between RPA and genes in the antioxidant pathway (p = 0.043 and 0.006 for CAT and GSTP1, respectively). Highly active women harboring variant alleles in CAT rs1001179 were at increased risk of breast cancer compared with women with the common CC genotype (OR = 1.61; 95 % CI, 1.06-2.45). Risk reductions were observed among moderately active women carrying variant alleles in GSTP1 compared with women homozygous for the major allele (OR = 0.56; 95 % CI, 0.38-0.84).Conclusions: Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation. [ABSTRACT FROM AUTHOR]

The impact of genetic variants in telomere pathway genes on telomere length and breast cancer survival remains unclear. We hypothesized that telomere length and genetic variants of telomere pathway genes are associated with survival among breast cancer patients. A population-based cohort study of 1,026 women diagnosed with a first primary breast cancer was conducted to examine telomere length and 52 genetic variants of 9 telomere pathway genes. Adjusted Cox regression analysis was employed to examine associations between telomere length, genetic variants and all-cause and breast cancer-specific mortality. Longer telomere length was significantly correlated with all-cause mortality in the subgroup with HER-2/neu negative tumors (HR = 1.90, 95 % CI: 1.12-3.22). Carrying the PINX1- 33 (rs2277130) G-allele was significantly associated with increased all-cause mortality (HR = 1.45, 95 % CI: 1.06-1.98). Three SNPs ( TERF2- 03 rs35439397, TERT- 14 rs2853677, and TERT- 67 rs2853669) were significantly associated with reduced all-cause mortality. A similar reduced trend for breast cancer-specific mortality was observed for carrying the TERT- 14 (rs2853677) T-allele (HR = 0.57, 95 % CI: 0.39-0.84), while carrying the POT1- 18 (rs1034794) T-allele significantly increased breast cancer-specific mortality (HR = 1.48, 95 % CI: 1.00-2.19). However, none of the associations remained significant after correction for multiple tests. A significant dose-response effect was observed with increased number of unfavorable alleles/genotypes ( PINX1- 33 G-allele, POT1- 18 T-allele, TERF2- 03 GG, TERT- 14 CC, and TERT- 67 TT genotypes) and decreased survival. These data suggest that unfavorable genetic variants in telomere pathway genes may help to predict breast cancer survival. [ABSTRACT FROM AUTHOR]

The association between promoter methylation status and survival was investigated in a large cohort of women with breast cancer, participants in the Long Island Breast Cancer Study Project. Archived tumor tissues ( n = 839) were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997. Vital status was followed through the end of 2005 with a mean follow-up time of 8 years. Promoter methylation of eight breast cancer-related genes was assessed by MethyLight. The frequencies of methylation for HIN1, RASSF1A, DAPK1, GSTP1, CyclinD2, TWIST, CDH1 and RARβ were 62.9, 85.2, 14.1, 27.8, 19.6, 15.3, 5.8 and 27.6%, respectively. Since survival rates of in situ and invasive breast cancers are substantially different, survival analyses were conducted within 670 invasive cases with complete data on all genes. Age-adjusted Cox proportional hazards models revealed that GSTP1, TWIST and RARβ methylation was significantly associated with higher breast cancer-specific mortality. Methylation of GSTP1 and RARβ was significantly associated with higher all-cause mortality. To investigate the relationship between the number of methylated genes and breast cancer-specific mortality, we included previously published MethyLight data on p16 and APC methylation status. Breast cancer-specific mortality increased in a dose-dependent manner with increasing number of methylated genes ( P = 0.002), although confidence intervals were wide. Our results suggest that promoter methylation, particularly for a panel of genes, has the potential to be used as a biomarker for predicting prognosis in breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown.Methods: These questions were investigated in a case-control study nested within the prostate cancer prevention trial (PCPT) with 1,798 biopsy-proven prostate cancer cases and 1,798 matched controls.Results: Among men on placebo, no relationship of serum estrogens with risk of prostate cancer was found. Among those on finasteride, those in the highest quartile of baseline estrogen levels had a moderately increased risk of Gleason score < 7 prostate cancer (for estrone, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.06-2.15; for estradiol, OR = 1.50, 95% CI = 1.03-2.18). Finasteride treatment increased serum estrogen concentrations; however, these changes were not associated with prostate cancer risk.Conclusion: Our findings confirm those from previous studies that there are no associations of serum estrogen with prostate cancer risk in untreated men. In addition, finasteride results in a modest increase in serum estrogen levels, which are not related to prostate cancer risk. Whether finasteride is less effective in men with high serum estrogens, or finasteride interacts with estrogen to increase cancer risk, is uncertain and warrants further investigation. [ABSTRACT FROM AUTHOR]

mong obstetricians and neonatologists in administrative roles in New York City hospitals, a survey was initiated to compare the physicians' definitions of live birth and fetal death, the gestational age at which they consider infants viable, and the resuscitation practices of the neonatologists. The target survey population was 34 neonatologists, and 39 obstetricians representing 41 of the City's 43 maternity hospitals. A telephone survey was used to gather qualitative data from the physicians regarding their definitions of live birth, fetal death, and viability, and their practices regarding extremely premature births. Surveys were completed for 58 physicians, a response rate of 79% (94% for neonatologists and 67% for obstetricians). Physicians' definitions of live birth and fetal death varied, with almost a third (29%) of physicians including gestational age as part of their live birth criteria. Most of the physicians (90%) consider infants born at ≥23 weeks gestation viable. Most neonatologists (97%) said they always resuscitate infants born at ≥23 weeks gestation, and most (94%) said they would never resuscitate infants born at <20 weeks gestation. For infants born at 20-22 weeks gestation, there were differences in resuscitation practices. There is a gap between clinical practices and reporting requirements for live birth and fetal death. Whereas reporting requirements are based on definitions of live birth and fetal death, physicians make resuscitation and other clinical decisions regarding extremely premature infants based on definitions of viability. [ABSTRACT FROM AUTHOR]

To better understand breast cancer etiology and progression, we explored the association between promoter methylation status of three breast cancer-related genes ( BRCA1, APC, and p16) and survival in a large cohort of women with breast cancer. About 800 archived tumor tissues were collected from women diagnosed with a first primary invasive or in situ breast cancer in 1996–1997. The vital status of the participants was followed through the end of year 2005 with a mean follow-up time of 8.0 years. Promoter methylation was assessed by methylation-specific PCR (for BRCA1) and MethyLight (for APC and p16). The association of promoter methylation and breast cancer mortality was evaluated by Cox-proportional hazards models. Methylated promoters were found in 59.0, 48.4, and 3.6% of the tumor samples for BRCA1, APC, and p16, respectively. Breast cancer-specific mortality was strongly associated with promoter methylation of p16 [HR and 95% CI: 3.53 (1.83–6.78)], whereas the associations with of BRCA1 and APC were less pronounced [HR and 95% CI: 1.81 (1.18–2.78) and 1.46 (0.98–2.17), respectively]. Similar associations were observed with all-cause mortality. As the number of methylated genes increased, the risk of breast cancer-specific mortality also increased in a dose-dependent manner ( P, trend = 0.01). Importantly, even with our results stratified by hormone receptor status, promoter methylation of the three genes remained predictive of mortality. Our results suggest that promoter methylation could be promising epigenetic markers to be considered for breast cancer survival. [ABSTRACT FROM AUTHOR]

Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin ( LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. A modest increase in risk of developing breast cancer was associated with the LEP −2548AA genotype when compared to the LEP −2548GG genotype (age-adjusted OR = 1.30; 95% CI = 1.01–1.66). This association was stronger among postmenopausal women who were obese (OR = 1.86; 95% CI = 0.95–3.64) although the interaction was of borderline statistical significance ( P = 0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time = 66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis. [ABSTRACT FROM AUTHOR]

The Breast Cancer Family Registry is a resource for interdisciplinary and translational studies of the genetic epidemiology of breast cancer. This resource is available to researchers worldwide for collaborative studies. Herein, we report the results of testing for germline mutations in BRCA1 and BRCA2. We have tested 4,531 probands for mutations in BRCA1 and 4,084 in BRCA2. Deleterious mutations in BRCA1 and BRCA2 were identified for 9.8% of probands tested [233/4,531 (5.1%) for BRCA1 and 193/4,084 (4.7%) for BRCA2]. Of 1,385 Ashkenazi Jewish women tested for only the three founder mutations, 17.4% carried a deleterious mutation. In total, from the proband and subsequent family testing, 1,360 female mutation carriers (788 in BRCA1, 566 in BRCA2, 6 in both BRCA1 and BRCA2) have been identified. The value of the resource has been greatly enhanced by determining the germline BRCA1 and BRCA2 mutation statuses of nearly 6,000 probands. [ABSTRACT FROM AUTHOR]

Promoter-CpG island hypermethylation has been proposed as an alternative mechanism to inactivate BRCA1 in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996–1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers ( P = 0.02) and among premenopausal cases ( P = 0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05–2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02–2.18). Neither dietary methyl intakes in the year prior to the baseline interview nor the functional polymorphisms in one-carbon metabolism were associated with BRCA1 methylation status. Our study is the first epidemiological investigation on the prognostic value of BRCA1 promoter methylation in a large population-based cohort of breast cancer patients. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival. [ABSTRACT FROM AUTHOR]

Excessive oxidative stress may induce and promote breast carcinogenesis. Manganese superoxide dismutase (MnSOD) is critical to management of oxidative stress by catalyzing the formation of hydrogen peroxide from two superoxide anions. To examine the relationship between MnSOD Val-9Ala polymorphism, breast cancer and potential modifiers, we analyzed data from a large population-based case-control study. Study participants completed an in-home interviewer-administered questionnaire, and self-completed a Block food frequency questionnaire. Age-adjusted unconditional logistic models included 1034 cases and 1084 controls. As compared with Val/Val genotype, we found no association between MnSOD Ala/Val (OR = 0.98, 95% CI: 0.79-1.21) and Ala/Ala (OR = 1.00, 95% CI: 0.79-1.28) genotypes and breast cancer. Results did not differ by menopausal status, stage of tumor, or estrogen and progesterone receptor status. No discernable patterns of interaction were found between this MnSOD variant and anti-oxidative exposures, including fruit and vegetable intake or NSAID use, or pro-oxidant exposures, including smoking and alcohol. This study provides little evidence that variation in Val-9Ala polymorphism of MnSOD alone or through substantial interaction with key exposures believed to be pro- or anti-oxidant properties influences breast cancer risk. [ABSTRACT FROM AUTHOR]

To elucidate the potential factors modulating exposure to aflatoxin B1 (AFB1) in three Chinese populations, an epidemiologic study was conducted in Fusui County and Nanning City of Guangxi Province and Chengdu City of Sichuan Province. The incidence rates of hepatocelluar carcinoma (HCC) for males in these three regions were 92-97 per 100,000, 32-47 per 100,000, and 21 per 100,000, respectively. Eighty-nine residents from Fusui, 196 residents from Nanning, and 118 residents from Chengdu were screened for AFB1-albumin adduct (AAA) levels and hepatitis virus (HBV, HCV, HDV, HEV, and HGV) infections, as well as liver biochemistry (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], y-glutamyl transpeptidase [GGT], 5'-nucleotidase, globulin [GLO], direct bilirubin, indirect bilirubin, and bile acid levels). At least one marker of hepatitis virus (HV) infection was present in 47.2% (42/89) of subjects from Fusui, while in Nanning and Chengdu the values were 15.8% (31/196) and 22.0% (26/118), respectively. In contrast to females, a higher level of AAA was observed in males; the difference was statistically significant in both the Nanning (P = 0.023) and the Chengdu (P = 0.026) subjects. In the Chengdu group, there was a significantly higher level of AAA in cases with HV infection (P = 0.041). There was a close association between AAA level and BMI in the adults without HV infection (r = 0.148, P = 0.044). Also, AAA was closely associated with DBIL and GGT in non-HV-infected minors (P < 0.05), closely associated with ALB, GLO, and GGT in HV-infected minors (P < 0.05), and closely associated with IBIL, GLO, TBA, and AST in non-HV-infected adults (P < 0.01). The co-effect of HV infection and AFB1 exposure may be responsible for the high risk of HCC in the Fusui region, whereas age, gender, BMI, and HV infection may modify individual aflatoxin levels. The relationship between AAA level and liver biochemistry indicates injury induced by aflatoxin to both hepatic parenchyma and biliary tract. But the associations vary with age and HV infection status. [ABSTRACT FROM AUTHOR]

This paper describes findings from a recently completed study of polycyclic aromatic hydrocarbon (PAH) exposure among city dwellers of Dhaka, Bangladesh. We measured PAH-DNA adducts in white blood cells (WBCs) as a marker of environmental and occupational PAH exposure in 46 rickshaw drivers (who pedal commercial unshielded three-wheelers for passenger transport) and 48 non-rickshaw drivers (comparison group) in Dhaka city. We performed enzyme-linked immunosorbent assay (ELISA) to quantify immunologically the WBC PAH-DNA adducts. Rickshaw drivers had a significantly higher WBC PAH-DNA adducts level than the non-rickshaw drivers. Among rickshaw drivers, adduct levels tended to be positively associated with the duration of residence in the city and cigarette smoking. No such trends were observed among non-rickshaw drivers. In conclusion, the results suggest that urban residents who are occupationally exposed to traffic pollution in Dhaka are at potentially higher risk of health effects from exposure to carcinogenic PAH compounds. [ABSTRACT FROM AUTHOR]

The Long Island Breast Cancer Study Project is a federally mandated, population-based case-control study to determine whether breast cancer risk among women in the counties of Nassau and Suffolk, NY, is associated with selected environmental exposures, assessed by blood samples, self-reports, and environmental home samples. This report describes the collaborative project's background, rationale, methods, participation rates, and distributions of known risk factors for breast cancer by case-control status, by blood donation, and by availability of environmental home samples. Interview response rates among eligible cases and controls were 82.1% ( n, = 1,508) and 62.8% ( n = 1,556), respectively. Among case and control respondents who completed the interviewer-administered questionnaire, 98.2 and 97.6% self-completed the food frequency questionnaire; 73.0 and 73.3% donated a blood sample; and 93.0 and 83.3% donated a urine sample. Among a random sample of case and control respondents who are long-term residents, samples of dust (83.6 and 83.0%); soil (93.5 and 89.7%); and water (94.3 and 93.9%) were collected. Established risk factors for breast cancer that were found to increase risk among Long Island women include lower parity, late age at first birth, little or no breast feeding, and family history of breast cancer. Factors that were found to be associated with a decreased likelihood that a respondent would donate blood include increasing age and past smoking; factors associated with an increased probability include white or other race, alcohol use, ever breastfed, ever use of hormone replacement therapy, ever use of oral contraceptives, and ever had a mammogram. Long-term residents (defined as 15+ years in the interview home) with environmental home samples did not differ from other long-term residents, although there were a number of differences in risk factor distributions between long-term residents and other participants, as anticipated. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Several previous studies have shown that malignant progression in Barrett’s metaplasia (BM) occurs even in patients treated with fundoplication or acid suppression therapy (AST). The aim of this study was to test the hypothesis that AST may not alter malignant progression in BM if key genes involved in DNA repair and cell cycle control, particularly p53, are defective.METHODS:Initial and follow-up biopsies from 21 patients with BM treated with AST and observed for 1–13 yr were entered in the study. All biopsies were graded for dysplasia and evaluated for p53 protein accumulation and oxidative DNA damage by immunohiostochemistry, using antibodies to p53 and to 8-hydroxydeoxyguanosine, respectively. DNA ploidy was determined using image analysis. Statistical analysis was performed using Kaplan-Meier curves, log rank test, and multivariate regression.RESULTS:Patients with p53 positive initial biopsies were more likely to have progression in dysplasia grade (p = 0.022) and DNA ploidy status (p = 0.023) than those with p53 negative biopsies. In eight patients AST resulted in significant reduction in oxidative DNA damage in the five patients with p53-negative initial biopsies, but not the three with p53 positive ones (p = 0.0007).CONCLUSIONS:We conclude that failure of AST to alter malignant progression in BM may be due, at least in part, to defects in DNA repair and cell cycle control resulting from p53 gene mutation, present before AST treatment. Although AST may be effective in preventing further DNA damage, it is unlikely to alter progression in genetically unstable cells. [Copyright &y& Elsevier]

Although arsenic is a well-established human carcinogen, the underlying carcinogenic mechanism(s) is not known. Using the human-hamster hybrid (AL) cell mutagenic assay that is sensitive in detecting mutagens that induce predominately multilocus deletions, we showed previously that arsenite is indeed a potent gene and chromosomal mutagen and that oxyradicals may be involved in the mutagenic process. In the present study, the effects of free radical scavenging enzymes on the cytotoxic and mutagenic potential of arsenic were examined using the AL cells. Concurrent treatment of cells with either superoxide dismutase or catalase reduced both the cytotoxicity and mutagenicity of arsenite by an average of 2–3 fold, respectively. Using immunoperoxidase staining with a monoclonal antibody specific for 8-hydroxy-2′-deoxyguanosine (8-OHdG), we demonstrated that arsenic induced oxidative DNA damage in AL cells. This induction was significantly reduced in the presence of the antioxidant enzymes. Furthermore, reducing the intracellular levels of non-protein sulfhydryls (mainly glutathione) using buthionine S-R-Sulfoximine increased the total mutant yield by more than 3-fold as well as the proportion of mutants with multilocus deletions. Taken together, our data provide clear evidence that reactive oxygen species play an important causal role in the genotoxicity of arsenic in mammalian cells. [ABSTRACT FROM AUTHOR]

Objective: To conduct timely epidemiologic investigations of molecular/genetic markers that may contribute to the development of prostate, lung, colorectal, or other cancers within the Selenium and Vitamin E Cancer Prevention Trial (SELECT), and to evaluate interactions between these markers and the study interventions.Methods: The epidemiologic studies within SELECT will be based on 32,400 men aged 55 years or older (age 50 or older for the African-American men) enrolled into an intergroup, randomized, placebo-controlled, double-blind, phase III prevention trial of supplemental selenium and vitamin E developed and funded by the National Cancer Institute, and coordinated by the Southwest Oncology Group. During the 12-year study period approximately 1500-2000 cases of prostate cancer, 800 lung cancers, and 500 colon cancers are estimated to be diagnosed, based on data from the ongoing Prostate Cancer Prevention Trial of finasteride. A modified fasting blood sample will be processed to collect plasma for analysis of micronutrients, hormones, cytokines, and other proteins. Buffy-coat derived white blood cells collected at baseline will be used for isolation of DNA and establishment of immortalized cell lines. Red blood cells will be stored for analysis of hemoglobin adducts and other components.Results: Specific results anticipated from these molecular studies will provide information on factors hypothesized to contribute to prostate cancer risk and that may modify the efficacy of either trial supplement, including: steroid sex hormones and several polymorphic genes that encode proteins affecting androgenic stimulation of the prostate, including the androgen receptor, steroid 5alpha-reductase type II, CYP17, and beta-hydroxysteroid dehydrogenase; polymorphisms of DNA repair genes and carcinogen metabolism genes, including those involved in the activation of chemical carcinogens to reactive intermediates (e.g., CYP1A1) or the detoxification of reactive intermediates (e.g., glutathione S-transferase M1); DNA and protein adducts; and insulin-like growth factors and leptin.Conclusion: SELECT offers an excellent opportunity to conduct molecular epidemiologic investigations to assess gene-environment interactions and their role in prostate, lung, and colon carcinogenesis. [ABSTRACT FROM AUTHOR]

Cdc25 phosphatases activate cyclin-dependent kinases (Cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. Several types of studies indicate that Cdc25s can enhance cell proliferation and oncogenesis. Furthermore, overexpression of Cdc25A and/or B have been detected in several types of primary human cancers, including breast cancers. To further assess the oncogenic capacity of Cdc25B in vivo, we have generated transgenic mice that overexpress Cdc25B in the mammary epithelium, driven by the MMTV – LTR promoter. Although these mice are grossly normal for up to 18 months, the ectopic expression of Cdc25B in their mammary glands increases the susceptibility of these mice to induction of mammary tumors by the carcinogen 9,10-dimethyl-1,2-benzanthracene (DMBA). [ABSTRACT FROM AUTHOR]

Mutations in the PTEN/MMAC1 gene have been identified in several types of human cancers and cancer cell lines, including brain, endometrial, prostate, breast, thyroid, and melanoma. In this study, we screened a total of 96 hepatocellular carcinoma (HCC) samples from Taiwan, where HCC is the leading cancer in males and third leading cancer in females, for mutations in the PTEN/MMAC1 gene. Complete sequence analysis of these samples demonstrated a missense mutation in exon 5 (K144I) and exon 7 (V255A) from HCC samples B6-21 and B6-2, respectively. A putative splice site mutation was also detected in intron 3 from sample B6-2. Both B6-21 and B6-2 were previously shown to contain missense mutations in the coding sequences of the p53 gene. Functional studies with the two missense mutations demonstrated that while mutation V255A in exon 7 resulted in a loss of phosphatase activity, mutation K144I in exon 5 retained its phosphatase activity. Additionally, we identified a silent mutation (P96P) in exon 5 of the PTEN/MMAC1 gene from HCC sample B6-22. These data provide the first evidence that the PTEN/MMAC1 gene is mutated in a subset of HCC samples. [ABSTRACT FROM AUTHOR]