Catherine L. Carpenter

DNA methylation analysis: a powerful new tool for lung cancer diagnosis

Carcinoma of the lung is the most common cause of cancer death worldwide. The estimated 5-year survival ranges from 6–16%, depending on the cell type. The best opportunity for improving survival of lung cancer patients is through early detection, when curative surgical resection is possible. Although the subjects at increased risk for developing carcinoma of the lung (long-term smokers) can be identified, only 10–20% of this group will ultimately develop the disease. Screening tests of long-term smokers employed to date (radiography and sputum cytology) have not been successful in reducing lung cancer mortality. The application of molecular markers specific for lung cancer offers new possibilities for early detection. Hypermethylation of CpG islands in the promoter regions of genes is a common phenomenon in lung cancer, as demonstrated by the analysis of the methylation status of over 40 genes from lung cancer tumors, cell lines, patient sputum and/or serum. Determination of the methylation patterns of multiple genes to obtain complex DNA methylation signatures promises to provide a highly sensitive and specific tool for lung cancer diagnosis. When combined with the development of non-invasive methods to detect such signatures, this may provide a viable method to screen subjects at risk for lung cancer.

Effect of family history, obesity and exercise on breast cancer risk among postmenopausal women

We examined effects of obesity and lifetime exercise patterns on postmenopausal breast cancer risk according to family history in a large population‐based case control study conducted in Los Angeles County, California, because we hypothesized that both factors would affect risk through similar mechanistic pathways, and that their effects would be stronger among women with a family history. We studied 1,883 postmenopausal breast cancer case subjects and 1,628 postmenopausal control subjects ranging in age from 55–72 years. Cases were diagnosed with incident breast cancer in the late 1980s and 1990s. Controls were individually matched to case subjects on age, ethnic origin and neighborhood. In‐person interviews determined known breast cancer risk factors including: height, weight, lifetime exercise, and family history of breast and other cancers. Breast cancer risk was raised among women who had at least 1 first‐degree relative with breast cancer (odds ratio [OR] = 1.68; 95% confidence interval [CI] = 1.36–2.08). Risk increased with increasing levels of body‐mass index (wt‐kg/ht‐m2) (p‐trend = 0.005). Breast cancer risk was reduced among women who maintained, on average, 17.6 metabolic equivalent of energy expenditure (MET)‐hr of activity/week from menarche onward (OR = 0.66; 95% CI = 0.48–0.90). Body‐mass index, adjusted for lifetime exercise, was strongly associated with breast cancer risk among women with a positive family history of breast cancer (p‐trend < 0.0001), but only weakly associated among women with no family history (p‐trend = 0.08; homogeneity of trends p = 0.0005). In contrast, the risk reduction associated with exercise activity, adjusting for body‐mass index, was limited to women without a family history of breast cancer (p‐trend = 0.001; homogeneity of trends p = 0.005). Body‐mass index and exercise activity, both modifiable risk factors for breast cancer, seem to have differential effects depending on a womans family history of breast cancer, and may impact risk through different biological mechanisms.

Lifetime exercise activity and breast cancer risk among post-menopausal women

SummaryLifetime exercise activity has been linked to breast cancer risk among young women. However, no study has specifically evaluated whether lifetime exercise activity is related to the breast cancer risk of post-menopausal women. We conducted a population-based case-control study of post-menopausal white women (1123 newly diagnosed cases and 904 healthy controls) aged 55–64 who lived in Los Angeles County, California, USA to evaluate this relationship. Although neither exercise activity from menarche to age 40 years, nor exercise after age 40 separately predicted breast cancer risk, risk was lower among women who had exercised each week for at least 17.6 MET-hours (metabolic equivalent of energy expenditure multiplied by hours of activity) since menarche than among inactive women (odds ratio (OR) = 0.55; 95% confidence interval (CI) 0.37–0.83). Exercise activity was not protective for women who gained considerable (> 17%) weight during adulthood. However, among women with more stable weight, breast cancer risk was substantially reduced for those who consistently exercised at high levels throughout their lifetime (OR = 0.42; 95% CI 0.24–0.75), those who exercised more than 4 h per week for at least 12 years (OR = 0.59; 95% CI 0.40–0.88), and those who exercised vigorously (24.5 MET-hours per week) during the most recent 10 years (OR = 0.52; 95% CI 0.32–0.85). Strenuous exercise appears to reduce breast cancer risk among post-menopausal women who do not gain sizable amounts of weight during adulthood.

Influence of exercise activity on quality of life in long-term breast cancer survivors

Background: Behavioral and lifestyle factors may influence quality of life (QOL) outcomes in breast cancer survivors. Methods: Information on QOL (Short Form-36, SF-36), lifestyle and survivorship was collected during telephone interviews with 374 breast cancer patients, diagnosed between 1983 and 1988 at ages 40 years or younger and interviewed, on average 13.2 years following diagnosis. These women previously participated in a case-control study soon after their diagnoses, providing information on breast cancer risk factors including exercise activity. We examined the impact of changes in exercise activity (comparing pre- to post-diagnosis levels) on the SF-36 mental and physical health summary scales using regression analyses. Results: A positive change in exercise activity was associated with a higher score on the SF-36 physical health summary scale at follow-up (p= 0.005). Change in exercise activity was not associated with the SF-36 mental health summary scale score. Patients who increased their activity levels did not differ from those who did not in terms of medical or demographic characteristics. Conclusion: This study provides one of the longest follow-up periods of breast cancer survivors to date among studies that focus on QOL and is unique in its focus on women diagnosed at a young age. Our results confirm high levels of functioning and well-being among long-term survivors and indicate that women whose exercise activity increased following diagnosis score higher on the SF-36 physical health summary scale. These findings suggest a potential role for exercise activity in maintaining well-being after a cancer diagnosis.

MENTHOLATED CIGARETTE SMOKING AND LUNG-CANCER RISK

PURPOSE Menthol smoking may lead to a greater increase in lung-cancer risk than smoking of nonmentholated cigarettes. Mentholation of cigarettes adds additional carcinogenic components to cigarette smoke and increases retention times for cigarette smoke in the lungs. Only two epidemiologic studies have been conducted on menthol smoking and lung cancer, and their results are conflicting. Of note, African American males have much higher rates of lung cancer than Caucasian males despite smoking fewer cigarettes per day. Because the consumption of menthol cigarettes is much more frequent among African Americans, it is of interest to examine the possible association between menthol smoking and lung-cancer risk in this population. METHODS We examined the association between menthol cigarette smoking and lung-cancer risk among smokers by comparing 337 incident cases of lung cancer with 478 population controls enrolled in a case-control study of lung cancer. Information on smoking history and other known and potential risk factors for lung cancer, including dietary intake, was obtained by in-person interviews. RESULTS The adjusted odds ratios did not differ appreciably between smokers of mentholated cigarettes versus exclusive nonmentholated cigarette smokers in the overall study group of smokers. The odds ratio (OR) for 32 pack-years or more of mentholated vs. nonmentholated cigarettes was 0.90 (95% confidence interval (CI) = 0.38-2.12) in African Americans and 1.06 (95% CI = 0.47-2.36) in Caucasians, and did not differ for either ethnic group (p = 0.98). CONCLUSIONS Our results suggest that the lung-cancer risk from smoking mentholated cigarettes resembles the risk from smoking non-mentholated cigarettes. Our data do not support the hypothesis that the increased risk of lung cancer among African Americans is due to the increased prevalence of menthol smoking.

Extreme obesity reduces bone mineral density: complementary evidence from mice and women.

Objective: To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women.

Phenolic acid concentrations in plasma and urine from men consuming green or black tea and potential chemopreventive properties for colon cancer

SCOPE Tea polyphenols are metabolized by the colonic microflora yielding phenolic metabolites, which may contribute to the health benefits of tea. We determined the serum and urine concentrations of phenolic acids, hippuric acid, and polyhydroxyphenyl-γ-valerolactones during green tea (GT) and black tea (BT) administration. The effects of (-)-epigallocatechin gallate (EGCG) and 3,4-dihydroxyphenylacetic acid (3,4-DHPAA) alone and in combination on bioavailability, intracellular metabolism, and antiproliferative activity were determined in HCT-116 colon cancer cells. METHODS AND RESULTS The concentration of phenolic metabolites was quantified by HPLC with electrochemical detection and MS. Urine concentrations of 4-hydroxyphenylacetic acid (4-HPAA), 3-hydroxyphenylacetic acid (3-HPAA), and polyhydroxy-γ-valerolactones were increased significantly in men drinking GT compared to control. Urine concentration of 3-O-methylgallic acid (3OMGA) was significantly increased in men drinking BT compared to control. Serum 3,4-DHPAA was significantly increased after consumption of GT and BT and 4-HPAA after GT consumption. In vitro treatment of HCT-116 colon cancer cells with 3,4-DHPAA and EGCG exhibited an additive antiproliferative effect, while methylation of 3,4-DHPAA was significantly decreased. 3OMGA exhibited the strongest antiproliferative activity among the phenolic acids. CONCLUSION The consumption of both, GT and BT, was associated with a significant increase in urinary and serum phenolic acids.

A controlled trial of protein enrichment of meal replacements for weight reduction with retention of lean body mass

BackgroundWhile high protein diets have been shown to improve satiety and retention of lean body mass (LBM), this study was designed to determine effects of a protein-enriched meal replacement (MR) on weight loss and LBM retention by comparison to an isocaloric carbohydrate-enriched MR within customized diet plans utilizing MR to achieve high protein or standard protein intakes.MethodsSingle blind, placebo-controlled, randomized outpatient weight loss trial in 100 obese men and women comparing two isocaloric meal plans utilizing a standard MR to which was added supplementary protein or carbohydrate powder. MR was used twice daily (one meal, one snack). One additional meal was included in the meal plan designed to achieve individualized protein intakes of either 1) 2.2 g protein/kg of LBM per day [high protein diet (HP)] or 2) 1.1 g protein/kg LBM/day standard protein diet (SP). LBM was determined using bioelectrical impedance analysis (BIA). Body weight, body composition, and lipid profiles were measured at baseline and 12 weeks.ResultsEighty-five subjects completed the study. Both HP and SP MR were well tolerated, with no adverse effects. There were no differences in weight loss at 12 weeks (-4.19 ± 0.5 kg for HP group and -3.72 ± 0.7 kg for SP group, p > 0.1). Subjects in the HP group lost significantly more fat weight than the SP group (HP = -1.65 ± 0.63 kg; SP = -0.64 ± 0.79 kg, P = 0.05) as estimated by BIA. There were no significant differences in lipids nor fasting blood glucose between groups, but within the HP group a significant decrease in cholesterol and LDL cholesterol was noted at 12 weeks. This was not seen in the SP group.ConclusionHigher protein MR within a higher protein diet resulted in similar overall weight loss as the standard protein MR plan over 12 weeks. However, there was significantly more fat loss in the HP group but no significant difference in lean body mass. In this trial, subject compliance with both the standard and protein-enriched MR strategy for weight loss may have obscured any effect of increased protein on weight loss demonstrated in prior weight loss studies using whole food diets.

Epigenetic effects of green tea polyphenols in cancer

Epigenetics describes heritable alterations of gene expression and chromatin organization without changes in DNA sequence. Both hypermethylation and hypomethylation of DNA can affect gene expression and the multistep process of carcinogenesis. Epigenetic changes are reversible and may be targeted by dietary interventions. Bioactive compounds from green tea (GT) such as (-)-epigallocatechin gallate have been shown to alter DNA methyltransferase activity in studies of esophageal, oral, skin, Tregs, lung, breast and prostate cancer cells, which may contribute to the chemopreventive effect of GT. Three out of four mouse model studies have confirmed the inhibitory effect of (-)-epigallocatechin gallate on DNA methylation. A human study demonstrated that decreased methylation of CDX2 and BMP-2 in gastric carcinoma was associated with higher GT consumption. It is the goal of this review to summarize our current knowledge of the potential of GT to alter epigenetic processes, which may be useful in chemoprevention.

Lung cancer risk in relation to the CYP2E1 Rsa I genetic polymorphism among African-Americans and Caucasians in Los Angeles County.

Genetic polymorphisms in the activation or detoxication of carcinogens, such as those in tobacco smoke, may produce differences in individual susceptibility to lung cancer. The cytochrome P450 CYP2E1 is an enzyme involved in the metabolism of nitrosamines in tobacco smoke. A polymorphism of CYP2E1 detectable by the restriction enzyme Rsa I may be functionally important because it is located in a putative binding site for the transcription factor HNF-1 and has been associated with higher levels of CYP2E1 transcription. It is conceivable that this CYP2E1 Rsa I polymorphism might contribute to differences in susceptibility to lung cancer. We conducted a case-control study of patients with incident lung cancer and population controls in Los Angeles County to examine the association between the CYP2E1 Rsa I polymorphism and lung cancer risk among African-Americans and Caucasians. Samples of white blood cell DNA sufficient for determination of the CYP2E1 Rsa I genotype by a polymerase chain reaction-based assay were obtained from 341 cases and 706 controls with data on lifetime smoking history. No subjects were homozygous for the CYP2E1 Rsa I rare c2 allele. The rare c2 allele was not associated with an increased risk of lung cancer (adjusted odds ratio, OR 0.72; 95% confidence interval, CI = 0.35-1.46). Among the population controls the percentage of subjects carrying the rare c2 allele was lower (p = 0.002) among African-Americans (2%) compared with Caucasians (8%). However, the association between the CYP2E1 Rsa I genotype and lung cancer risk did not differ between ethnic groups. There was no important association between the CYP2E1 Rsa I genotype and lung cancer risk in analyses stratified by cell-type, smoking history, gender, occupational asbestos exposure, and dietary intake of antioxidants vitamin C, vitamin E or beta carotene. Due to the low frequency of the c2 allele in these populations, larger studies would be necessary to rule out a modest association between the CYP2E1 Rsa I polymorphism and lung cancer risk.