Faculty Bibliography

Chronic exposure to inorganic arsenic is known to cause non-melanocytic skin and internal cancers in humans. An estimated 50-70 million people in Bangladesh have been chronically exposed to arsenic from drinking water and are at risk of skin and other cancers. We undertook the first study to examine whether genetic susceptibility, as determined by the codon 751 SNP (A-->C) of the DNA repair gene XPD, influences the risk of arsenic-induced hyperkeratotic skin lesions, precursors of skin cancer, in a case-control study of 29 hyperkeratosis cases and 105 healthy controls from the same community in an area of Bangladesh. As expected, there was a monotonic increase in risk of hyperkeratosis in relation to urinary arsenic measures but the XPD genotype was not independently associated with the risk. However, the increase in hyperkeratosis risk in relation to urinary arsenic measures genotype was borderline significant for urinary total arsenic (P for trend=0.06) and statistically significant for urinary creatinine adjusted arsenic (P for trend=0.01) among subjects with the XPD A allele (AA) but not among subjects with the other XPD genotypes. Among AA carriers, the risk for the highest arsenic exposed group compared with the lowest was more than 7-fold for urinary total arsenic and about 11-fold for urinary creatinine adjusted arsenic. In conclusion, our findings suggest that the DNA repair gene XPD may influence the risk of arsenic-induced premalignant hyperkeratotic skin lesions. Future larger studies are needed to confirm this novel finding and investigate how combinations of different candidate genes and/or other host and environmental factors may influence the risk of arsenic induced skin and other cancers

PURPOSE: To test whether differences in smoking-related lung cancer risks in blacks and whites can explain why lung cancer incidence is greater in black males than in white males but about equal in black and white females, given that a greater proportion of blacks are smokers, but smoke far fewer cigarettes per day than do whites. METHODS: A hospital-based case-control study was conducted between 1984 and 1998 that included interviews with 1,710 white male and 1,321 white female cases of histologically confirmed lung cancer, 254 black male and 163 black female cases, and 8,151 controls. Relative risks were estimated via odds ratios using logistic regression, adjusted for age, education, and body mass index. RESULTS. We confirmed prior reports that smoking prevalence is higher but overall dosage is lower among blacks. Overall ORs were similar for blacks and whites, except among the heaviest smoking males (21+ cigarettes per day or 37.5 pack-years), in whom ORs for blacks were considerably greater than for whites. Long-term benefits of cessation were similar for white and black ex-smokers. Smokers of menthol flavored cigarettes were at no greater risk for lung cancer than were smokers of unflavored brands. CONCLUSIONS. Lung cancer risks were similar for whites and blacks with similar smoking habits, except possibly for blacks who were very heavy smokers; this sub-group is unusual in the general population of African American smokers. Explanations of racial disparities in lung cancer risk may need to account for modifying factors including type of cigarette (yield, mentholation), diet, occupation, and host factors such as ability to metabolize mainstream smoke carcinogens

O(6)-methylguanine-DNA methyltransferase (MGMT) is a repair protein that specifically removes promutagenic alkyl groups from the O(6) position of guanine in DNA. MGMT is transcriptionally silenced by promoter hypermethylation in several human cancers. Methylation-specific PCR (MSP) was used to analyze the MGMT promoter methylation status of 83 hepatocellular carcinomas (HCC) and 2 HCC cell lines (HepG2 and Hep3B). Hypermethylation was detected in 32 of 83 (39%) HCC tissues, but it was not found in either HCC cell line. We also analyzed MGMT expression by immunohistochemical analysis of HCC tissue samples. The presence of aberrant hypermethylation was associated with loss of MGMT protein. The relationship between methylation status and risk factors and tumor markers including environmental exposure to aflatoxin B(1) (AFB(1)), measured as DNA adducts, and status of tumor suppressor gene p53 was also investigated. A statistically significant association was found between MGMT promoter hypermethylation and high level of AFB(1)-DNA adducts in tumor tissues (OR = 5.05, 95% CI = 1.29-19.73). A significant association was also found between methylation and p53 mutation status (OR = 2.97, 95% CI = 1.09-8.11). These results suggest that epigenetic inactivation of MGMT plays an important role in the development of HCC and exposure to environmental carcinogens may be related to altered methylation of genes involved in cancer development. The role of chemical carcinogens in hypermethylation needs further investigation

The regulation of signaling pathways by feedback inhibitors has become an emerging theme in the control of pattern formation during development. Nodal and Lefty proteins belong to divergent subfamilies of the TGF-beta family. Nodal signals promote mesendoderm induction in vertebrates, and Lefty proteins antagonize it. In zebrafish, Squint functions as a long-range Nodal signal during mesoderm induction. We report that the range over which Squint induces mesoderm is reduced by Lefty proteins. In contrast, the activity range of the short-range Nodal signal Cyclops is not regulated by Lefty activity. We present three lines of evidence that Lefty proteins diminish the range of Squint signaling by acting not only as antagonists of Squint autoregulation but also as long-range inhibitors of Squint activity. First, Lefty can block Nodal signaling at a distance. Second, Lefty regulates the range of Squint signaling before regulating squint expression. Third, Lefty restricts the range of Squint activity in squint mutant embryos, in which the endogenous gene is not subject to autoregulation. We also find that Lefty restricts the response to both high and low levels of Nodal signaling. These results indicate that Lefty proteins restrict the activity range of Nodal signals by dampening Nodal signaling in surrounding cells

Epigenetic changes in gene expression due to extensive CpG island methylation is now accepted as the main cause of inactivation of the p16 gene. More recently, it has been suggested that the human ras association domain family (RASSF) 1 gene, cloned from the lung tumor-suppressor locus 3p21.3, also may be inactivated by methylation. It consists of two major alternative transcripts, RASSF1A and RASSF1C. Epigenetic inactivation of isoform A was observed in several carcinomas and tumor cell lines. In this study, promoter hypermethylation of RASSF1A and p16 was investigated in 83 hepatocellular carcinoma (HCC) tissue samples from Taiwan and in two HCC cell lines (Hep3B and HepG2). High frequencies (85% and 47%, respectively) of methylation of the CpG island promoters of RASSF1A and p16 were found in the HCC tissues. The methylation of RASSF1A also was detected in Hep3B cells but not in HepG2 cells; p16 was not methylated in either cell line. Methylation status was determined in 12 normal control liver tissues and 10 adjacent nontumor tissues. No methylation was found in normal liver control tissues for both RASSF1A and p16; methylation was detected in one of 10 and seven of 10 adjacent nontumor tissue sampless for p16 and RASSF1A, respectively, in subjects with positive tumors. These data indicate that aberrant methylation of the CpG island promoters of both genes is a frequent occurrence in hepatocarcinogenesis. The high frequency of RASSF1A methylation in adjacent tissues suggests that this may be an early event. The relationship between methylation status and clinical parameters and tumor markers, including DNA damage resulting from aflatoxin B(1) (AFB(1)), an environmental carcinogen, and p53 status, also was analyzed. A statistically significant association was found between RASSF1A methylation status and the level of AFB(1)-DNA adducts in tumor tissues. No association was found between methylation status and p53 status. These results suggest the hypothesis that exposure to environmental carcinogens may be involved in altered methylation of genes involved in cancer development

Rates of lung cancer in American men have greatly exceeded those in Japanese men for several decades despite the higher smoking prevalence in Japanese men. It is not known whether the relative risk of lung cancer associated with cigarette smoking is lower in Japanese men than American men and whether these risks vary by the amount and duration of smoking. To estimate smoking-specific relative risks for lung cancer in men, a multicentric case-control study was carried out in New York City, Washington, DC, and Nagoya, Japan from 1992 to 1998. A total of 371 cases and 373 age-matched controls were interviewed in United States hospitals and 410 cases and 252 hospital controls in Japanese hospitals; 411 Japanese age-matched healthy controls were also randomly selected from electoral rolls. The odds ratio (OR) for lung cancer in current United States smokers relative to nonsmokers was 40.4 [95% confidence interval (CI) = 21.8-79.6], which was >10 times higher than the OR of 3.5 for current smokers in Japanese relative to hospital controls (95% CI = 1.6-7.5) and six times higher than in Japanese relative to community controls (OR = 6.3; 95% CI = 3.7-10.9). There were no substantial differences in the mean number of years of smoking or average daily number of cigarettes smoked between United States and Japanese cases or between United States and Japanese controls, but American cases began smoking on average 2.5 years earlier than Japanese cases. The risk of lung cancer associated with cigarette smoking was substantially higher in United States than in Japanese males, consistent with population-based statistics on smoking prevalence and lung cancer incidence. Possible explanations for this difference in risk include a more toxic cigarette formulation of American manufactured cigarettes as evidenced by higher concentrations of tobacco-specific nitrosamines in both tobacco and mainstream smoke, the much wider use of activated charcoal in the filters of Japanese than in American cigarettes, as well as documented differences in genetic susceptibility and lifestyle factors other than smoking

The purpose of this study is to perform a cost-effectiveness analysis of long-term moderate exercise training (ET) in patients with stable chronic heart failure. In particular, the study focuses on the survival analysis and cost savings from the reduction in the hospitalization rate in the exercise group. In the past 10 years, ET has been shown to be beneficial for patients with stable class II and III heart failure in many randomized clinical trials. However, the cost-effectiveness of a long-term ET program has not been addressed for outcomes related to morbidity/mortality end points or health care utilization. We examined the cost-effectiveness of a 14-month long-term training in patients with stable chronic heart failure. The estimated increment cost for the training group, $3,227/patient, was calculated by subtracting the averted hospitalization cost, $1,336/patient, from the cost of ET and wage lost due to ET, estimated at $4,563/patient. For patients receiving ET, the estimated increment in life expectancy was 1.82 years/person in a time period of 15.5 years, compared with patients in the control group. The cost-effectiveness ratio for long-term ET in patients with stable heart failure was thus determined at $1,773/life-year saved, at a 3% discount rate. Long-term ET in patients with stable chronic heart failure is cost-effective and prolongs survival by an additional 1.82 years at a low cost of $1,773 per/life-year saved