Molecular Epidemiology and Biomarkers in Etiologic Cancer Research: The New in Light of the Old

Abstract

Th e purpose of this review is to evaluate progress in molecular epidemiology over the past 24 years in cancer etiology and prevention to draw lessons for future research incorporating the new generation of biomarkers. Molecular epidemiology was introduced in the study of cancer in the early 1980s, with the expectation that it would help overcome some major limitations of epidemiology and facilitate cancer prevention. Th e expectation was that biomarkers would improve exposure assessment, document early changes preceding disease, and identify subgroups in the population with greater susceptibility to cancer, thereby increasing the ability of epidemiologic studies to identify causes and elucidate mechanisms in carcinogenesis. Th e fi rst generation of biomarkers has indeed contributed to our understanding of risk and susceptibility related largely to genotoxic carcinogens. Consequently, interventions and policy changes have been mounted to reduce risk from several important environmental carcinogens. Several new and promising biomarkers are now becoming available for epidemiologic studies, thanks to the development of high-throughput technologies and theoretical advances in biology. Th ese include toxicogenomics, alterations in gene methylation and gene expression, proteomics, and metabonomics, which allow large-scale studies, including discovery-oriented as well as hypothesis-testing investigations. However, most of these newer biomarkers have not been adequately validated, and their role in the causal paradigm is not clear. Th ere is a need for their systematic validation using principles and criteria established over the past several decades in molecular cancer epidemiology. (Cancer Epidemiol Biomarkers Prev 2007;16(10):1954-65)

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…- 3 Number of subjects with high environmental exposure from residence in town, intense traffic and presence of industries near home (see Materials and Methods).- 4 Number of subjects with wood-or coal-based heating at home.- 5 Subjects with values higher than threshold limit of assay (0.01 mg/mmoles creatinine).-6 PAH exposure evaluated by urinary excretion of 1-pyrenol.-7 A value of 0.125 adducts/10 8 nucleotides was assigned to subjects with nondetectable adducts. DNA adduct preferentially binds to 5 0 -CpG sequences in the promoter region of p53, 41 which inhibits DNA methylation by DNMTs 42 in a dose-dependent manner, suggesting a direct role for anti-B[a]PDE on the p53 hypomethylation.…”

“…2 It has been proposed that DNA methylation, one of the best known epigenetic mechanisms, shares critical roles with DNA mutations in the theoretical continuum for exposure to cancer. 3,4 One potential mechanism for environmental factors is through hypermethylation or hypomethylation on somatic cells, leading to activation or silencing of key genes in critical pathways of cancer. 5,6 From some years, the disruption of DNA methylation status by exposure to genotoxic agents has been an issue in the literature, but the clear demonstration that such epigenetic alterations were caused by one or more specific agents in people has been demanding (for a review see Ref.…”

A review of the role of lymphoma markers and occupational and environmental exposures

“…Indeed, the study of how an environmental agent affects molecular targets, cellular function, tissue function, and survival ultimately informs us about the etiology, pathogenesis, and distribution of the disease (Vineis and Perera 2007).…”

“…The recently introduced ''meet in the middle approach'' has the potential to open new avenues for prevention by identifying the specific environmental factors involved in the disease process (Vineis and Perera 2007). In this approach, the relationship between putative intermediate markers and disease outcome is explored.…”

Lack of association of CYP1A1-MspI SNP and GSTM1 null genotypes with cancer in a Brazilian family with unusually high cancer incidence

“…One of the single nucleotide polymorphisms (SNPs) of the CYP1A1 gene most widely studied is the MspI restriction site (CYP1A1m1) in the 3'-non-coding region, a T→C transition that promotes an increase in the expression of the gene (Nakata et al, 2004). The high activity of this gene can be deleterious and contribute to the susceptibility to some diseases, including endometriosis (Nakata et al, 2004), cancers associated with tobacco (Cha et al, 2007), cardiovascular diseases, type 2 diabetes mellitus (Wang et al, 2002), and leukemia (Vineis and Perera, 2007).…”