Linking toxicology to epidemiology: Biomarkers and new technologies—Special issue overview
Seymour Gartea, b, and Stefano Bonassic
aGenetics Research Institute, Milan, Italy
bSchool of Public Health, UMDNJ, 330 George St., New Brunswick, NJ 08903, USA
cUnit of Molecular Epidemiology, National Cancer Research Institute, Genoa, Italy
The papers in this special issue are the product of authors who presented their work at the ICT X Satellite Meeting: Linking Toxicology to Epidemiology – Biomarkers and New Technologies, held in summer 2004 in Haikko, Finland. The meeting was organized by an international panel of experts, and was chaired by Richard Hayes (NCI, Bethesda), Kirsti Husgafvel-Pursiainen (FIOH, Helsinki), and Harri Vainio (FIOH, Helsinki). The papers included in this issue have been chosen in order to provide a selection of high priority topics discussed during the conference.
The focus of the conference, and of this special issue is on recent biomarker research, especially as it relates to mechanisms of disease causation, risk assessment and prevention. Key areas of molecular epidemiologic investigation covered include strategies for exposure assessment, markers of intermediate effect, predictive markers of subsequent disease, and assessment of disease susceptibility. Important environmental risk factors such as air pollution, diesel exhaust, and metals are linked with epidemiology, human biomarker studies, and experimental toxicology.
Advances in the design of molecular epidemiologic studies, and associations between genetic polymorphisms and disease outcomes are discussed, and several interesting examples are provided. We believe that in sum, these papers contribute to a better understanding of gene-environment interactions in the etiology and development of human cancer and other diseases. The following is a brief summary of the 14 papers included in this special issue.
Hemminki and Bermejo point out that single nucleotide polymorphisms (SNPs) used for the identification of cancer susceptibility genes are inherited genetic factors, and therefore should be amenable to family history studies. Using the Swedish Family-Cancer Database in order to assess familial cancer risks, they conclude that the heritable component of cancer etiology is of relatively minor importance compared to environmental factors. Because of this the authors raise an important caution that successful applications of SNPs in gene-environment and cancer risk studies may be difficult.
Eyfjord and Bodvarsdottir discuss the complex interactions between different mechanistic pathways leading to cancer. These include cell cycle control and DNA repair. Such genes as ATM, ATR, FA-associated genes, NBS1 and BRCA1 and BRCA2 are part of networks that respond to DNA damage and prevent chromosomal aberrations. An understanding of chromosomal instability is providing new insights into carcinogenesis mechanisms.
The paper by Santella et al. deals with carcinogen-DNA adducts in humans as a marker of exposure and cancer risk. Methods such as ELISA and immunohistochemical assays and assays for DNA repair have been combined to analyze samples from two large sample repositories. The Long Island Breast Cancer Study Project, and the Metropolitan New York Registry of Breast Cancer Families, have provided blood and tumor tissue for the measurement of DNA adducts as biomarkers of exposure. The authors demonstrate that DNA repair capacity, determined by genotyping of DNA repair genes or by phenotyping methods, can influence risk from environmental exposure.
The interaction between exposure to asbestos and metabolic gene variants in the mEH, GSTM1, GSTT1, NAT2 and CYP1A1 genes in the etiology of malignant mesothelioma is the subject of the paper by Neri et al. A case-control study of 80 subjects with malignant mesothelioma (which represents a large fraction of the total Italian cases of this rare disease) was carried out. Functional variants in the mEH and NAT2 genes were associated with significantly increased risk of malignant mesothelioma. Both gene–environment and gene–gene interactions were observed. The precise role of these genes in mediating asbestos induced MM is not known, although mechanistic scenarios related to fiber type and exposure dose are plausible.
Raimondi et al. present an update from the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC) on the role of genetic susceptibility on lung cancer in non-smokers. By pooling the raw data from 21 case-control studies involving over 600 cases of lung cancer in non-smokers (a fairly rare disease) with information on metabolic gene genotypes, the authors found a significant association between lung cancer and CYP1A1Ile462Val polymorphism. Other effects were seen with specific combinations of genotypes. The results confirm the utility of the pooled analysis approach to investigate the effect of genetic variants in rare and specific categories of disease, and to test hypotheses that require higher power than is usually available in single smaller studies.
The complexities of the role of metabolic genes in cancer susceptibility is illustrarted by the paper of Seow et al. These authors report that the GST genes have high affinity for Isothiocyanates (ITCs), chemical anticarcinogens found in cruciferous vegetables. The protective effect of cruciferous vegetable/ITC intake is enhanced in people who lack the GSTM1 or T1 gene. This effect is especially seen for lung cancer in current smokers. Thus, while GST deletion has been postulated to be a risk factor for cancer, because of the putative accumulation of carcinogenic metabolites that cannot be conjugated and removed, this paper points out that genetic polymorphism in this category of genes is often a two edged sword, and that a balance between positive and negative effects are sometimes necessary in order to understand the entirety of their role in human carcinogenesis.
The paper by Weston et al. is an elegant use of epidemiological evidence and computational chemistry to understand the interactions between exposure to beryllium and HLA-DPB1 gene variants in human beryllium sensitization and chronic beryllium disease. The authors found that molecular epidemiological studies suggest that some HLA-DPB1*E69 variants convey low, intermediate or high risk of chronic beryllium disease. Molecular modeling was then used to discover a strong correlation between the risk of disease associated with alleles and the predicted negative surface charge of the proteins coded for by these genetic variants.
Pardo and Van Duijn review the current understanding of the genetics of Alzheimer‘s disease (AD) and Parkinson‘s disease (PD). A number of high penetrant genes have been discovered for both of these diseases, however, they explain only a small proportion of cases. The only common gene found to increase the risk of early and late onset AD is APOE. The authors discuss the common disease/common variant and common disease/rare variant hypotheses as related to the discovery of new genes associated with common forms of neurodegeneration and other complex diseases.
Costa et al. discuss some fundamental aspects of nickel carcinogenesis. They describe how uptake of insoluble nickel into the nucleus leads to silencing of genes placed near heterochromatin. Gene silencing is an epigenetic effect, whose mechanism was furthered investigated by the authors. Nickel exposure leads to blockage of iron uptake, which results in effects on iron-dependent enzymes. Among the consequences of these effects are activation of hypoxic signaling, a decrease in histone acetylation, and an increase in methylation of histones, all of which are associated with gene silencing.
The example of the GSEC study discussed in the paper by Raimondi et al. (above) is followed by Hung et al, who discuss the initial stages of formation of two new collaborative consortia devoted to pooled analysis studies – INHANCE – the International Head and Neck Cancer Epidemiology Consortium and ILCCO – the International Lung Cancer Consortium.
Risom et al. review the evidence that particulate matter (PM) -induced health effects involve inflammation and oxidative stress. This includes evidence that exposure to diesel exhaust particles causes oxidative DNA damage. Both surface area and chemical composition are important determinants of effect depending on particle size. Some studies of human biomonitoring to ambient air have found a correlation between guanine oxidation in DNA and exposure to ultrafine particles.
Kang et al. selected three examples of cross-sectional biomarker studies to exemplify the major issues in the design of such studies. These include a study of urinary PAH metabolites and environmental particulate exposure, an analysis of the relationship between urinary PAH metabolites and oxidative stress, and an evaluation of the effect of genetic polymorphisms of GSTM1 on the association of metabolites of green tea in shipyard workers. With these studies as guides, the authors discuss issues related to selection of appropriate biomarkers, validity of assays, and application of selected biomarkers to specific populations.
The paper by Hayes et al. is focused on large-scale cohort studies which have become so important for research on disease etiology. The authors describe a cohort from the Etiology and Early Marker Study (EEMS), which is part of the Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) screening trial. The cohort includes 155,000 volunteers among whom 77,000 subjects are providing blood samples and risk factor data collected six times. Buccal cells are also being collected. The project will allow for etiologic studies on environmental and genetic risk factors, and biologic markers for early detection of disease.
Schulte‘s paper deals with the uses of biomarkers in medical surveillance and screening. The author lays out the necessary conditions under which biomarkers can serve as indicators of early disease or exposure, in the identification of people for further diagnostic confirmation and early treatment, and the effectiveness of prevention strategies. Among these conditions is the requirement that the biomarker provides value added information not otherwise obtainable, and that evidenced-based knowledge of biomarker usage and limitations has been developed.
The field of molecular epidemiology and biomarker research is reaching maturity and is developing closer interactions with many related fields of biomedical research, including molecular biology, toxicology and related disciplines. The papers in this issue demonstrate the close ties that bind current progress in this field to that of research scientists working in many areas to find solutions to the problem of prevention, management and understanding of human disease. The organizers and editors are appreciative for the financial and organizational support provided by the FIOH, and for the contributions of other sponsors, including the Work Environment Fund, Finland; the Academy of Finland; the National Institute of Environmental Health Sciences, USA; the Environmental Protection Agency, USA; the Health Effects Institute, USA; the National Institute for Occupational Health, USA; and the European Association for Cancer Research