Faculty Bibliography

In the United States, the incidence of adenocarcinoma of the esophagus, including the esophagogastric (EG) junction, has been increasing rapidly over the past two decades. Except for an association with Barrett's esophagus, little is known about the etiology of these cancers. A population-based case-control interview study of 174 White men with adenocarcinoma of the esophagus and 750 controls living in three areas of the United States offered the opportunity to investigate the relationship of these cancers with smoking, alcohol drinking, socioeconomic factors, and history of ulcer. There were significantly elevated risks for men who smoked cigarettes (odds ratio [OR] = 2.1) or drank liquor (OR = 1.6). For both cigarette smoking and liquor drinking, there were significant dose gradients with amount consumed. No reduction in risk was observed following smoking cessation. Subjects who switched from nonfilter to filter cigarettes experienced half the risk of those who only smoked nonfilter cigarettes. Inverse risk gradients were seen with increasing recent annual income, with the highest risk (OR = 3.4) for the lowest category. The risk for a history of ulcer (OR = 1.7), especially of the duodenum (OR = 2.2), was also significantly elevated. These data suggest that tobacco and alcohol may be etiologic factors for adenocarcinoma of the esophagus and EG junction, but these factors do not appear to explain the rapid rise in incidence of these tumors. The associations with low social class and history of ulcer need to be explored in greater detail along with other factors that may account for the temporal trends in esophageal adenocarcinomas

Prostate cancer occurs more frequently in Blacks than Whites in the United States. A population-based case-control study which investigated the association between tobacco use and prostate cancer risk was carried out among 981 pathologically confirmed cases (479 Blacks, 502 Whites) of prostate cancer, diagnosed between 1 August 1986 and 30 April 1989, and 1,315 controls (594 Blacks, 721 Whites). Study subjects, aged 40 to 79 years, resided in Atlanta (GA), Detroit (MI), and 10 counties in New Jersey, geographic areas covered by three, population-based, cancer registries. No excesses in risk for prostate cancer were seen for former cigarette smokers, in Blacks (odds ratio [OR] = 1.1, 95 percent confidence interval [CI] = 0.7-1.5) and in Whites (OR = 1.2, CI = 0.9-1.6), or for current cigarette smokers, in Blacks (OR = 1.0, CI = 0.7-1.4) and in Whites (OR = 1.2, CI = 0.8-1.7). Increases in risk were noted for smokers of 40 or more cigarettes per day, among former (OR = 1.4, CI = 1.0-1.5) and current (OR = 1.5, CI = 1.0-2.4) smokers. Duration of cigarette use and cumulative amount of cigarette use (pack-years) were not associated with prostate cancer risk for Blacks or Whites. By age, only the youngest subjects, aged 40 to 59 years, showed excess risk associated with current (OR = 1.5, CI = 1.0-2.3) and former (OR = 1.7, CI = 1.1-2.6) use of cigarettes, but there were no consistent patterns in this group according to amount or duration of smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutations in the tumor suppressor gene p53 play an important role in carcinogenesis and tumor progression. To assess the status of p53 from genomic DNA from bladder cancer samples a two stage polymerase chain reaction was employed. The technique provided material for subsequent detection of mutations by Single Strand Conformation Polymorphism (SSCP) analysis followed by DNA sequence analysis. SSCP analysis of exons 5 to 9 of p53 was performed using fragments from PCR end-labeled with 32P followed by autoradiography using an electrophoresis system with temperature control. This SSCP method improved resolution of mutations in exons 5, 7, and 8 and the sharpness of bands in exons 6 and 9. Bands with altered migration patterns were excised from the dried SSCP gels, reamplified by PCR, and sequenced. Mutations in conserved exons 5, 6, 7, 8, and 9 of the p53 gene were analyzed from bladder tumor biopsies. Our results are consistent with the literature in that mutations in p53 are predominantly found in high grade bladder cancer (Odds Ratio = 4.05, Fisher Exact P = 0.104); however, the results were not statistically significant due to small numbers. Eight of 35 (23%) tumor samples examined showed mutations in p53 (including two double mutations). Six of 13 (46%) grade III and IV tumors had p53 mutations vs. 2 of 17 (12%) grade I and II tumors. Normal individuals carried no p53 mutations. We found no correlation between pack years of smoking and mutation in p53. The spectrum of mutations confirmed a high proportion of G:C C:G transversions as well as the occurrence of double mutations

Mortality was investigated for the years 1950-1980 for 1,009 male members of a New York jewelry workers union, and for the years 1984-1989 among 919 men and 605 women identified as jewelry workers on death certificates from 24 states. Malignant neoplasms were excessive for male union members (proportional mortality ratio [PMR] = 1.17; 95% confidence interval [CI]: 1.02-1.33) and female jeweler deaths from the 24 states (PMR = 1.24; 95% CI: 1.07-1.42). Deaths due to nonmalignant causes were not unusual, except for excesses, in union males, of the circulatory system (PMR = 1.10; 95% CI: 1.02-1.19), including arteriosclerotic heart disease (PMR = 1.25; 95% CI: 1.14-1.37) and rheumatic heart disease (PMR = 3.02; 95% CI: 1.94-4.50). Cancers of the digestive tract were proportionally elevated among union males (proportional cancer mortality rate [PMR] = 1.13; 95% CI: 0.89-1.41) and among deaths from the 24 states (PCMR = 1.22; 95% CI: 1.01-1.47). For the 24 states, excesses for digestive cancer were found for both males (PCMR = 1.19; 95% CI: 0.90-1.54) and females (PCMR = 1.26; 95% CI: 0.96-1.62). Regarding specific sites in the digestive tract, colon cancer excesses were found in union males (PCMR = 1.53: 95% CI: 1.05-2.15), and for men (PCMR = 1.27; 95% CI: 0.82-1.88) and women (PCMR = 1.36; 95% CI: 0.92-3.27) in 24 states.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors previously reported results from the largest cohort mortality study of ethylene oxide-exposed workers that has been conducted to date. Here they extend their previous work by quantitatively examining the relation between cancer mortality and ethylene oxide exposure. This study included workers from 13 of the 14 geographically distinct facilities that were included in the previous investigation. These facilities began regularly using ethylene oxide to sterilize medical supplies or spices sometime between 1938 and 1969. Workers were followed from first exposure through December 31, 1987. Historical exposures to ethylene oxide were estimated using a regression model. Standard life-table analysis was used to examine cancer mortality in three categories of cumulative exposure to ethylene oxide. The Cox proportional hazards model was also used to examine cumulative and other measures of ethylene oxide exposure as predictors of cancer mortality. In both the life-table analysis and the Cox model, a positive trend was observed in all lymphatic and hematopoietic cancer mortality for cumulative ethylene oxide exposure. This trend was strengthened when ethylene oxide exposures 10 years prior to death were discounted (lagged) and when the analysis was restricted to neoplasms of lymphoid cell origin. Despite limitations discussed in this paper, the authors believe that these findings provide some support for the hypothesis that exposure to ethylene oxide increases the risk of mortality from lymphatic and hematopoietic neoplasms. The authors intend to continue follow-up of this relatively young cohort, which may allow more definitive conclusions to be drawn in the future

Eighty-four healthy Chinese male control subjects derived from an occupation-based case-control study of bladder cancer were evaluated for hepatic N-acetyltransferase activity by dapsone and for NAT2 genotype using allele-specific amplification of peripheral leukocyte DNA by the polymerase chain reaction. Fifty-nine percent of the overall variation in acetylation activity was explained by genotype (p < 0.0001). The remaining variation in acetylation was not associated with dapsone N-hydroxylation activity, age, current smoking status, or weight in the study population, or within any genotype subgroup. Although acetylation activity in the homozygous mutant group did not overlap with the other genotype categories, there was moderate overlap in acetylation between the heterozygous mutant and wildtype groups, and substantial variation in acetylation within them. Considering all subjects with the identical NAT2 genotype as phenotypically similar and all subjects with differing NAT2 genotypes as phenotypically distinct may result in misclassification of metabolic risk factors in epidemiological investigations. As such, it would seem prudent, where possible, to collect both acetylation phenotype and NAT2 genotype data, since the advantages and limitations of these two sources of information complement, and serve to assess the accuracy of each other

The effect of low-level exposure to formaldehyde on oral, nasal, and lymphoycte biological markers was studied prospectively in a group of 29 mortician students who were about to take a course in embalming. During the 85-day study period, the subjects performed an average of 6.9 embalmings and had average cumulative formaldehyde exposures of 14.8 ppm-h, with an average air concentration of 1.4 ppm during embalming. Since the average time spent embalming was 125 min, formaldehyde exposures calculated as an 8-h time-weighted average were 0.33 ppm on days when embalmings were done, which was less than the Occupational Safety and Health Administration permissible exposure limit of 0.75 ppm. Epithelial cells from the buccal area of the mouth showed a 12-fold increase in micronucleus frequency during the study period, from 0.046 +/- 0.17/1000 cells preexposure to 0.60 +/- 1.27/1000 cells at the end of the course (P < 0.05). Nasal epithelial micronuclei increased 22%, from 0.41 +/- 0.52/1000 cells to 0.50 +/- 0.67/1000 cells (P = 0.26). In blood cells, the frequency of micronucleated lymphocytes increased 28%, from 4.95 +/- 1.72/1000 cells to 6.36 +/- 2.03/1000 cells (P < 0.05), while sister chromatid exchanges decreased 7.5% (P < 0.05). A dose-response relationship was observed between cumulative exposure to formaldehyde and increases in buccal micronuclei in the 22 male subjects but not in the 7 female subjects. We conclude that low-level exposure to formaldehyde is associated with cytogenetic changes in epithelial cells of the mouth and in blood lymphocytes. These cytogenetic effects may be useful as markers of biologically effective dose

A multiple-site case-control study of 15 cancers (stomach; colon; rectum; larynx; lung; melanoma; skin; female breast; male breast; cervix; ovary; uterus; prostate; testis; and bladder) was conducted to evaluate their association with occupational physical activity and socioeconomic status (SES). A hospital-based study population (3,486 male cases and 379 female cases, and 2,127 male and 244 female controls) was established in an oncological treatment center in Istanbul, Turkey, from 1979-84. Assessment of physical activity and SES was based on job titles held by the study subjects. Two measures of physical activity were developed based on energy expenditure and 'sitting time' during working hours. Observed risks were adjusted for age, smoking, and SES. Elevated risks were observed among workers who held sedentary jobs for cancers of the colon (odds ratio [OR] = 1.6), rectum (OR = 1.3), melanoma (OR = 1.9), male breast (OR = 1.4), prostate (OR = 5.0), and ovary (OR = 2.0). Cancers of the cervix and uterus showed significantly decreasing risks with decreased activity. Risks of cancers of the colon, rectum, larynx, ovary, and melanoma were enhanced after risks for physical activity indices were adjusted for SES, while the associations between physical activity and cancers of the prostate, cervix, and uterus were weakened after SES adjustment. Risks of melanoma rose significantly with both activity indices after SES adjustment.(ABSTRACT TRUNCATED AT 250 WORDS)

Phenotype and genotype markers of genetic susceptibility are of increasing interest in case-control studies of cancer. It is well established that bias to the odds ratio is caused by less-than-perfect assay sensitivity and specificity and varies with risk factor prevalence. As such, the observed variation in odds ratio between studies of genetic markers and cancer risk may be real, or may be attributed, in part, to variation in assay accuracy or in risk factor prevalence (e.g., prevalence differences between racial groups). The latter can be a particular concern when the prevalence of the 'at risk' polymorphism in one or more populations is either very high (e.g., > 85%) or very low (e.g., < 15%). For example, even very high sensitivity (e.g., 98%) can produce substantial bias to the odds ratio when the risk factor prevalence is high. Under some prevalence conditions, however, assays with only moderate accuracy are sufficient and result in minimal bias to the odds ratio. Understanding misclassification in the context of marker prevalence may help to explain disparate findings in the literature and should assist investigators in selecting markers that are appropriate for future studies