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1.  Prognostic significance of gene-specific promoter hypermethylation in breast cancer patients 
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 8 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 were 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 (Ptrend = 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.
doi:10.1007/s10549-011-1712-y
PMCID: PMC3576848  PMID: 21837480
Promoter methylation; Tumor suppressor gene; Breast cancer; Mortality
2.  Aberrant Promoter Hypermethylation and Genomic Hypomethylation in Tumor, Adjacent Normal Tissues and Blood from Breast Cancer Patients 
Anticancer research  2010;30(7):2489-2496.
Background
Promoter hypermethylation and global hypomethylation in the human genome are hallmarks of most cancers. Detection of aberrant methylation in white blood cells (WBC) has been suggested as a marker for cancer development, but has not been extensively investigated. This study was carried out to determine whether aberrant methylation in WBC DNA can be used as a surrogate biomarker for breast cancer risk.
Patients and Methods
Promoter hypermethylation of 8 tumor suppressor genes (RASSF1A, APC, HIN1, BRCA1, cyclinD1, RARβ, CDH1 and TWIST1) and DNA methylation for three repetitive elements (LINE1, Sat2M1 and AluM2) were analyzed in invasive ductal carcinoma of the breast, paired adjacent normal tissue and WBC from 40 breast cancer patients by the MethyLight assay. Methylation in WBC from 40 controls was also analyzed.
Results
Tumor and adjacent tissues showed frequent hypermethylation for all genes tested, while WBC DNA was rarely hypermethylated. For HIN1, RASSF1A, APC and TWIST1 there was agreement between hypermethylation in tumor and adjacent tissues (P=0.04, P=0.02, P=0.005 and P<0.0001, respectively). DNA methylation for the three repetitive elements was lower in tumor compared to adjacent tissue and WBC DNA. Significant correlations in the methylation of Sat2M1 between tumor and adjacent tissues and WBC DNA were found (P<0.0001 and P=0.046, respectively). There was also a significant difference in methylation of Sat2M1 between cases and controls (P=0.01).
Conclusion
These results suggest that further studies of WBC methylation, including prospective studies, may provide biomarkers of breast cancer risk.
PMCID: PMC3568974  PMID: 20682973
Breast cancer; promoter hypermethylation; genomic methylation; tumor suppressor genes; repetitive elements; WBC DNA
3.  Prenatal Smoke Exposure and Genomic DNA Methylation in a Multiethnic Birth Cohort 
Background
Exposure to prenatal tobacco smoke (PTS) has been associated with a number of health outcomes in the offspring, including some childhood cancers. Lower levels of genomic DNA methylation have also been associated with several types of cancers. We investigated whether PTS was associated with global DNA methylation levels in the offspring.
Methods
Our sample was drawn from a birth cohort of women born between 1959 and 1963 in New York City (n = 90). We measured methylation of repetitive elements (Sat2, Alu, LINE-1) from peripheral blood granulocytes. We combined prospectively collected data on PTS with adult epidemiologic data and blood samples collected in 2001 to 2007 (mean age, 43 years). We used linear regression to assess the association between PTS and repetitive element methylation.
Results
Thirty-six percent of mothers smoked during pregnancy. We observed an inverse association between PTS and Sat2 methylation. This inverse association remained even after adjustment for potential mediators including child environmental tobacco smoke exposure, birth size, postnatal weight and height changes, and adult smoking status and alcohol intake (β = −0.22, 95% confidence interval = −0.40 to −0.03 for ever exposed to PTS vs. never exposed using models of log-transformed methylation levels). PTS exposure was not statistically significantly associated with LINE-1 or Alu methylation.
Conclusions
PTS exposure, measured at the time of pregnancy and not retrospectively reported, was associated with a decrease in Sat2 methylation but not LINE-1 or Alu methylation.
Impact
If replicated in larger studies, this study supports a persistent effect of PTS on DNA methylation levels, as measured by Sat2, in adulthood.
doi:10.1158/1055-9965.EPI-11-0553
PMCID: PMC3559183  PMID: 21994404
4.  Early life socioeconomic factors and genomic DNA methylation in mid-life 
Epigenetics  2013;8(1):23-27.
Epigenetic modifications may be one mechanism linking early life factors, including parental socioeconomic status (SES), to adult onset disease risk. However, SES influences on DNA methylation patterns remain largely unknown. In a US birth cohort of women, we examined whether indicators of early life and adult SES were associated with white blood cell methylation of repetitive elements (Sat2, Alu and LINE-1) in adulthood. Low family income at birth was associated with higher Sat2 methylation (β = 19.7, 95% CI: 0.4, 39.0 for lowest vs. highest income quartile) and single parent family was associated with higher Alu methylation (β = 23.5, 95% CI: 2.6, 44.4), after adjusting for other early life factors. Lower adult education was associated with lower Sat2 methylation (β = -16.7, 95% CI: -29.0, -4.5). There were no associations between early life SES and LINE-1 methylation. Overall, our preliminary results suggest possible influences of SES across the life-course on genomic DNA methylation in adult women. However, these preliminary associations need to be replicated in larger prospective studies.
doi:10.4161/epi.22989
PMCID: PMC3549876  PMID: 23196856
birth cohort; early life; socioeconomic status; adult genomic DNA methylation; lifecourse
5.  Significant differences in global genomic DNA methylation by gender and race/ethnicity in peripheral blood 
Epigenetics  2011;6(5):623-629.
Reduced levels of global DNA methylation are associated with genomic instability and are independent predictors of cancer risk. Little is known about the environmental determinants of global DNA methylation in peripheral blood. We examined the association between demographic and lifestyle factors and levels of global leukocyte DNA methylation in 161 cancer-free subjects enrolled in the North Texas Healthy Heart Study aged 45–75 years in 2008. We used in-person interviews for demographics and lifestyle factors, a self-administrated Block food frequency questionnaire for diet, and bioelectrical impedance analysis and CT-scan for body composition. We measured genomic DNA methylation using bisulfite conversion of DNA and pyrosequencing for LINE-1. Body composition measures including body mass index, waist circumference, areas of subcutaneous fat and visceral fat, percent of fat mass and fat-free mass were not associated with global genomic DNA methylation after controlling the effect of age, gender and race/ethnicity. Instead, female gender was significantly associated with a reduced level of global methylation (β = −2.77, 95% CI: −4.33, −1.22). Compared to non-Hispanic whites, non-Hispanic blacks (β = −2.02, 95% CI: −3.55, −0.50) had significantly lower levels of global methylation. No association was found with age, cigarette smoking, alcohol drinking and dietary intake of nutrients in one-carbon metabolism. Global leukocyte DNA methylation differs by gender and race/ethnicity, suggesting these variables need to be taken into consideration in studies of global DNA methylation as an epigenetic marker for cancer.
doi:10.4161/epi.6.5.15335
PMCID: PMC3230547  PMID: 21739720
gender; race/ethnicity; DNA methylation
6.  Physical activity and global genomic DNA methylation in a cancer-free population 
Epigenetics  2011;6(3):293-299.
Changes in DNA methylation may represent an intermediate step between the environment and human diseases. Little is known on whether behavioral risk factors may modify gene expression through DNA methylation. To assess whether DNA methylation is associated with different levels of physical activity, we measured global genomic DNA methylation using bisulfite-converted DNA and real-time PCR (MethyLight) for LINE-1 in peripheral blood of 161 participants aged 45–75 years enrolled in the North Texas Healthy Heart Study and levels of physical activity using an accelerometer (Actigraph GT1M Monitor). We found that individuals with physical activity 26–30 min/day had a significantly higher level of global genomic DNA methylation compared to those with physical activity ≤10 min/day (β = 2.52, 95% CI: 0.70, 4.35). However, the association was attenuated and became statistically insignificant after multivariate adjustment (β = 1.24, 95% CI: −0.93, 3.40). There were some suggestions of a positive association between physical activity and global genomic DNA methylation in non-Hispanics (β = 1.50, 95% CI: −0.08, 3.08) that warrants further investigation.
doi:10.4161/epi.6.3.14378
PMCID: PMC3092677  PMID: 21178401
DNA methylation; physical activity; peripheral blood
7.  DNA Methylation Changes Correlate with Gleason Score and Tumor Stage in Prostate Cancer 
DNA and Cell Biology  2012;31(2):187-192.
DNA methylation, a widely used epigenetic mark, has been associated with many tumors. However, few studies have addressed the role of cell-free plasma DNA methylation in discriminating aggressive prostate cancer (PCa) from indolent cases. We conducted a case series and a case–control study among histologically confirmed stage II/III cases and matched controls recruited at Columbia University Medical Center. The aim of this study was to investigate whether plasma DNA methylation levels are appropriate surrogate biomarker of PCa tumor tissue levels and whether these markers are associated with worse clinicopathological tumor characteristics, which correlate with poorer prognosis. Quantitative pyrosequencing was used to detect methylation levels of p16 (CDKN4A), APC, GSTP1, and LINE-1 in 24 pairs of prostate tumor and adjacent tissues, as well as 27 plasma samples of PCa patients and 24 of controls. DNA methylation levels were significantly higher in tumor tissue than in adjacent nontumor tissue for p16 (CDKN4A), GSTP1, and APC; GSTP1 had a higher average percentage methylation in tumor tissue (38.9%) compared with p16 (CDKN4A) (5.9%) and APC (14.5%). GSTP1, p16 (CDKN4A), and APC methylation in tumor tissue was statistically significantly higher for cases with Gleason score ≥7 compared with those with Gleason score <7 [49.0% vs. 21.9% (p=0.01), 6.6% vs. 4.5% (p=0.04), and 19.1% vs. 7.4% (p=0.02), respectively]. Plasma LINE-1 methylation levels were higher in those with higher Gleason (67.6%) than in those with Gleason's below 7 (64.6%, p=0.03). Significant plasma–tissue correlations were observed for GSTP1 and LINE-1 methylation. These data, although preliminary, suggest that aberrant methylation may be a useful marker to identify PCa patients with clinically aggressive disease.
doi:10.1089/dna.2011.1311
PMCID: PMC3272239  PMID: 21830905
8.  Global DNA methylation levels in girls with and without a family history of breast cancer 
Epigenetics  2011;6(1):29-33.
Lower levels of global DNA methylation in white blood cell (WBC) DNA have been associated with adult cancers. It is unknown whether individuals with a family history of cancer also have lower levels of global DNA methylation early in life. We examined global DNA methylation in WBC (measured in three repetitive elements, LINE1, Sat2 and Alu, by MethyLight and in LINE1 by pyrosequencing) in 51 girls aged 6–17 years. Compared to girls without a family history of breast cancer, methylation levels were lower for all assays in girls with a family history of breast cancer and statistically significantly lower for Alu and LINE1 pyrosequencing. After adjusting for age, body mass index (BMI) and Tanner stage, only methylation in Alu was associated with family history of breast cancer. If these findings are replicated in larger studies, they suggest that lower levels of global WBC DNA methylation observed later in life in adults with cancer may also be present early in life in children with a family history of cancer.
doi:10.4161/epi.6.1.13393
PMCID: PMC3052913  PMID: 20930546
Alu; DNA global methylation; early life exposure; epigenetics; LINE1; methylight; pyrosequencing; Sat2

Results 1-8 (8)