Emanuela Taioli

Genetic metabolic polymorphisms and the risk of cancer: a review of the literature.

Abstract The purpose of this paper is to systematically analyse the design and results of epidemiological studies on the association between various types of cancer (lung, bladder, breast, colon, stomach) and four genetically-based metabolic polymorphisms, involved in the metabolism of several carcinogens (glutathione-S-transferase M1, debrisoquine hydroxylase, N acetyltransferase, aryl hydrocarbon hydroxylase). These inherited polymorphisms usually cause modifications in the quality or quantity of the relevant enzymes. Such enzymes are involved in the activation/inactivation of known carcinogens and seem to modify the extent to which carcinogens interact with DNA in target tissues. Two enzymes, debrisoquine hydroxylase and aryl hydrocarbon hydroxylase, activate procarcinogens to carcinogens (phase I enzymes). The other two, glutathione-S-transferase M1 and N-acetyltransferase, mainly detoxity carcinogenic substances (phase II enzymes). Because of their role as host factors (modulating the action of carcinogens), it has been hypothesized that subjects presenting a specific phenotype for such polymorphisms could be at a greater risk of developing various types of cancer. A number of epidemiological studies have investigated such associations, often with discordant results. We examine and discuss the design of the studies, and present a meta-analysis of the available data.

A Common Mutation in the Methylenetetrahydrofolate Reductase Gene (C677T) Increases the Risk for Deep-Vein Thrombosis in Patients With Mutant Factor V (Factor V:Q506)

Hyperhomocysteinemia is a frequent risk factor for deep-vein thrombosis. A common mutation (C677T) in the gene encoding for methylenetetrahydrofolate reductase (MTHFR) is responsible, in the homozygous state, for decreased enzyme activity and mild hyperhomocysteinemia and is associated with increased risk for cardiovascular disease. We studied the prevalence of C677T MTHFR in 77 patients with deep-vein thrombosis and in 154 age- and sex-matched healthy control subjects. In the same individuals, we also evaluated the frequency of the coexistence of C677T MTHFR with mutant factor V:Q506, a common risk factor for deep-vein thrombosis. Sixteen patients (20.8%) and 35 control subjects (22.7%) were homozygous for the C677T MTHFR mutation (odds ratio [OR] = 0.8, 95% confidence interval [CI] = 0.4-2.0). Sixteen patients (20.8%) and 4 control subjects (2.6%) had factor V:Q506; of them, 10 patients and 3 control subjects had isolated factor V:Q506 (adjusted OR = 6.3, 95% CI = 1.6-25.3) and 6 patients and 1 control subject also had C677T MTHFR (adjusted OR = 17.3, 95% CI = 2.0-152.9). The OR for the coexistence of the two mutations was 65% to 75% higher than the expected joint effect calculated by either an additive (OR = 6.0) or multiplicative (OR = 4.4) model. The homozygous C677T mutation of MTHFR per se is not a risk factor for deep-vein thrombosis but increases the risk associated with factor V:Q506. Due to the high prevalence of C677T MTHFR, it is likely that previous studies, which did not look for this mutation, overestimated the relative risk of thrombosis associated with factor V:Q506 alone.

Relationship between genotype and function of the human CYP1A1 gene

A comparative study of human CYP1A1 genotypes and enzymatic activity was performed in a racially diverse population in order to determine frequencies of CYP1A1 genetic polymorphisms and the relationship between CYP1A1 genotype and function. Restriction fragment length polymorphism analyses revealed significantly higher frequencies of a variant Msp1 polymorphism in Asians versus European-Americans, while African-American CYP1A1 genotypic frequencies more closely approximated those of Asians. Comparison of CYP1A1 genotypes at the Msp1 locus to a polymorphic site in exon 7 of the gene revealed a higher frequency of variant genotypes at the Msp1 site. Measurement of lymphocyte CYP1A1 enzyme activity by the ethoxyresorufin O-deethylase assay revealed significantly elevated levels of inducible enzyme activity among variant exon 7 genotypes when compared to wild-type genotypic individuals. These results demonstrate racially distinct patterns of CYP1A1 genotypes, and suggest a functional link between genotype and catalytic activity of the cytochrome P-450 protein responsible for the metabolism of many carcinogenic polycyclic aromatic hydrocarbons.

Occupational exposure to Cr(VI): comparison between chromium levels in lymphocytes, erythrocytes, and urine

The relationships between chromium (Cr) levels in lymphocytes, erythrocytes, urine, and ambient air were compared among 14 chrome-platers from a metallurgic plant in Bulgaria and two groups of local controls, one from the same heavily polluted industrial town as the chrome-platers (n=11) and one from a seaside resort town 100 km away (n=6). Among the chrome-platers, the Cr concentration in peripheral lymphocytes was positively correlated with total Cr and Cr(VI) levels in ambient air and with Cr excretion in urine. As compared to the controls, the chromeplaters had mean Cr levels in lymphocytes twice as high, in erythrocytes ninefold higher, and in urine fourfold to eightfold higher. Although Cr levels in urine and lymphocytes were similar between the two control groups, levels in erythrocytes were 3 times higher among subjects from the industrial area than among those from the seaside town. The study suggests that lymphocyte Cr could be a good indicator of the Cr body burden caused by high exposures to Cr(VI), such as in electroplating operations. In these conditions, erythrocyte Cr may be less useful, possibly owing to increased toxicity due to the high affinity of erythrocytes for Cr. However, when exposure is lower, such as in most environmental situations, erythrocyte Cr should provide a better and more sensitive index than lymphocyte Cr. By contrast, urinary Cr, which provides information on total Cr exposure, including Cr(III) from dietary and environmental sources, does not seem to be of value for studying occupational exposure to Cr(VI).

Preliminary report on a simple new assay for DNA-protein cross-links as a biomarker of exposures experienced by welders.

A method originally developed to detect topoisomerase DNA complexes has been adapted to determine DNA-protein cross-links formed in cells following their exposure in vitro and in vivo to cross-linking agents. A preliminary study on welders and controls has been carried out to assess the feasibility of this assay to detect human exposure to chromium (Cr) and nickel (Ni) that are associated with increased DNA-protein cross-links. The percentage of cross-link was significantly higher among welders (1.85% +/- 1.14) than among controls (1.17% +/- 0.46; p = .01) Cross-links were not affected by age, weight, or smoking status. The assay developed has substantial advantages over previous methods, being considerably more simple, inexpensive, and sensitive.

Reduced IL-6 Levels among Individuals in Hudson County, New Jersey, an Area Contaminated with Chromium

Hudson County, New Jersey, was a major center for the processing of chromium ore. After processing, some of the ore residue that contained low concentrations of chromium became distributed in population centers throughout the county. There now exists concern in the county about possible health effects from chromium exposure. Our previous research suggested that immune-function assays would make useful biomarkers for chromate exposure in humans. Blood samples were drawn from 46 individuals who lived and/or worked in Hudson County and from 47 controls. Only one of the immune-associated assays performed on these samples showed any statistically significant differences between the Hudson County and control groups. The mean level of IL-6 produced by pokeweed mitogen-stimulated mononuclear cells isolated from the Hudson County group was 64% of the control value--a highly significant decrease (p<.001). There was also a significant correlation between the proliferative responses of the mononuclear cells to pokeweed mitogen and the levels of IL-6 produced by these cells. No differences were detected in the IL-6 responses that resulted from age, gender, or smoking status. The reliability of the IL-6 assay was found to be 90%. To our knowledge, there have been no reports, until now, that describe reduced production of any cytokine in individuals who are exposed to chromate.

Development of biomarkers of human exposure to carcinogens: the example of DNA-protein cross-links

Biomarkers are considered to be more biologically informative than traditional methods and less prone to misclassification bias. However, new biomarkers are conceived in experimental laboratories and normally undergo extensive experimental in vitro and in vivo testing, usually without regard as to their potential use in humans. Whereas the epidemiologist had no role in the original development of the basic research idea leading to the initial formulation of a biomarker, the new biomarker or technical modification of an existing one are the product of observations in humans. The results of our field studies on DNA-protein cross-links (DPX) among chromate workers illustrates inherent difficulties in the process of development and validation of biomarkers.

Enhanced Risk of Lung and Prostate Adenocarcinoma in African-American Smokers Carrying a Novel Cypiai Gene Polymorphism

Abstract The CYPlA1 gene codes for aromatic hydrocarbon hydroxlase (AHH), a critical enzyme in the metabolism of carcinogenic polycyclic aromatic hydrocarbons. Polymorphisms in this gene have been implicated in aberrant gene function, and in increased risk of cancer from exposure to hydrocarbons such as those found in tobacco smoke. We have discovered a novel restriction polymorphism (“AA RFLP”) in this gene that is found only in people of African descent. African Americans suffer a disproportionate high incidence of lung and prostate cancer. This is not due to increased smoking, but may be related to either environmental or genetic factors. We have examined the possibility that the African American specific CYPlA1 RFLP may be associated with higher risk for tobacco related carcinogenesis. The incidence of the AA polymorphism in the healthy African-American population was 14.5%. In African-Americans with adenocarcinoma of the lung the incidence of the polymorphism was doubled. We observed no difference be...

Applying management strategies in molecular epidemiology field studies.

In conducting field studies of human exposure, we have encountered significant methodological challenges. The management strategy our group developed to conduct two recent studies of environmental health utilizes a collaborative study design process and innovative protocol management tools, and emphasizes community outreach. We present here the phases of planning, development and realization of two studies--one conducted in an environmentally contaminated area, and another in an occupational setting. We show how the use of this management strategy increases the efficiency of field operations and improves variability assessment.