IARC scientific publications最新文献

In this chapter, we apply the molecular epidemiological paradigm of biomarkers of exposure, early effect and susceptibility to causal models of leukaemia and lymphoma. The aim is to enhance the development of biomarkers for use in studying the causes of these haematopoeitic cancers in the general population. Two causal models of acute myeloid leukaemia are discussed in detail: chemotherapy-induced and benzene-induced acute myeloid leukaemia. Specific chromosomal changes found in acute myeloid leukaemia may serve as useful biomarkers of early effect in these models, and genetic variants in glutathione S-transferases, NQO1 and DNA-repair enzymes may serve as useful biomarkers of susceptibility. Several causal models of lymphoma exist in which biomarkers could be developed and validated. These include human immunodeficiency virus (HIV) immunosuppression, families with inherited disorders and workers exposed to petroleum products, pesticides or organochlorines. Biomarkers of early effect could include markers of DNA double-strand breaks and aberrant V(D)J recombination, and susceptibility may be related to polymorphisms in genes controlling DNA repair and immunological status. We predict that biomarkers of susceptibility will continue to be studied in the case-control format, perhaps in large pooled studies, but that for biomarkers of early effect, there will be a move away from the study of diseased populations to the study of individuals 'at risk' in the causal models described above.

This chapter will review a variety of issues related to the use of biomarkers in molecular epidemiological studies. It will draw upon experience gained from related mechanistic research in toxicological studies. This includes important methodological issues that impact on the type of assays that can be used and how these issues affect the selection of the method and the biological sample. It will also address issues affecting the use of biomarkers as measures of exposure and effect, and discuss inferences for causality and the selection of target organ versus surrogate tissues. Combining information from toxicological studies can also aid in the interpretation of epidemiological studies, such as tissues with and without strong biological plausibility and relationships between observed DNA adducts and those that arise from endogenous processes. Finally, it will discuss issues related to important pathways of metabolism and implications of genetic polymorphisms. These critical issues affect both the design and interpretation of molecular epidemiological studies.

Rodent models are often used as surrogates for humans in toxicology and cancer research. Transgenic mice have been useful for studying gene function by loss of function or gain of function through mutation or overexpression. Thus, transgenic or genetically altered mouse models could play an important role in understanding environment-gene interactions. Wild-type Trp53 protein is critical for cell function and maintaining integrity of the genome, which suppresses cancer in humans and rodents. Mice heterozygous for a Trp53 null and a wild-type allele are p53 haplo-insufficient. This reduction in p53 protein results in deficiencies in cell cycle check-point control and induction of apoptosis. p53 Haplo-insufficient mice do not immediately develop neoplasia as a result of this signalling dysregulation. However, exposure to mutagenic carcinogens induces neoplasia during the period in which unexposed, co-isogenic haplo-insufficient and homozygous wild-type mice are free from neoplasia. These observations provide a basis for evaluation of p53 haplo-insufficient mice for mechanism-based identification of carcinogens. Maximum tolerated doses (MTD) determined and used for 2-year NCI/NTP cancer bioassays and/or by 28-day toxicokinetic studies to predict MTD for subchronic studies were, generally, effective in inducing neoplasia with reduced latency in 26-week exposure studies in p53 haplo-insufficient mice. The latency of tumour development may be shortened by requiring only an additional genetic alteration (or alterations) in p53 (mutation or loss of heterozygosity (LOH) involving the Trp53 locus) or in other tumour-suppressor genes by mutation or inactivation. LOH is a loss of genetic loci through chromosomal aberrations and reduction to homozygosity that often results in loss of tumour-suppressor genes. Interspecies extrapolation between rodents and humans is difficult owing to the possibility of species differences, but demonstration of an operational mechanism, such as mutation or loss of p53 function through LOH, may help in reducing uncertainty and, thus, lead to identification of carcinogens of presumed risk to humans.

Cytogenetic biomarkers in peripheral blood lymphocytes such as chromosomal aberrations, sister chromatid exchanges and micronuclei have long been applied in surveillance of human genotoxic exposure and early effects of genotoxic carcinogens. The use of these biomarker assays is based on the fact that most established human carcinogens are genotoxic in short-term tests and capable of inducing chromosomal damage. The relevance of chromosomal aberrations as a biomarker has been further emphasized by epidemiological studies suggesting that a high frequency of chromosomal aberrations is predictive of an increased risk of cancer. Structural and numerical chromosomal aberrations are typical of cancer cells, probably as a manifestation of genetic instability of such cells, but may also represent mechanisms leading to such instability. The frequency of all three biomarkers increases with age, and this effect is particularly clear for micronuclei in women. Tobacco smoking is known to increase the level of sister chromatid exchanges and chromosomal aberrations, but its effect on micronuclei is unclear. Several studies have recently examined the influence of genetic polymorphisms of xenobiotic metabolizing enzymes on cytogenetic biomarkers. The lack of glutathione S-transferase M1 (GSTM1 null genotype) appears to be associated with increased sensitivity to genotoxicity of tobacco smoking. N-Acetyltransferase (NAT2) slow acetylation genotypes seem to elevate baseline level of chromosomal aberrations, whereas deletion of glutathione S-transferase T1 gene (GSTT1 null genotype) has been found to yield an increase in baseline sister chromatid exchange frequency. These findings may be explained by reduced detoxification capacity rendered by the altered gene and may be linked with exposure to, for example, heterocyclic amines in the case of NAT2 and endogenously formed ethylene oxide in the case of GSTT1. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects, but, as yet, there is very little information about the significance of these polymorphisms or about their impact on cytogenetic biomarkers.

The biological model of gastric carcinogenesis can be described as a series of sequential phases. The first consists of a chronic active inflammatory response to Helicobacter pylori infection. Infiltration of the gastric mucosa by mucosa-associated lymphoid tissue and polymorphonuclear neutrophils, as well as damage to the epithelial cells, characterize this phase. The second phase is dominated by alterations of the epithelial cell cycle, especially increased rates of apoptosis and cell proliferation. These changes may be responsible for the multifocal atrophy that characterizes the type of gastritis associated with an increased risk of cancer. The third, more advanced phase of the model displays nuclear and architectural abnormalities, which may represent progressive mutational events as expected in classical molecular models of carcinogenesis. The importance of a comprehensive view of the biological model is stressed.