Implications of results of molecular epidemiology on DNA adducts, their repair and mutations for mechanisms of human cancer.
This review covers human data on DNA adducts, their repair and induced mutations. The new data on human studies in vivo challenge some widely held notions relating to cancer and ageing. These data collected from humans of different ages show no age-dependent change in levels of diverse DNA adducts in peripheral lymphocytes, no deterioration of global DNA excision repair in skin in situ and no change in mutation rate, because the HPRT mutant fraction increases linearly by age. These molecular epidemiological results argue against earlier animal and in-vitro data, but are in line with multistage models for cancer. A further application of DNA adducts as an intermediary tool for genotyping studies, for both metabolic enzyme and DNA repair system genotypes, is recommended. As the common polymorphisms are likely to cause at most moderate increases in the risk of cancer, the intermediary adduct end-point is a necessary proof of causal relationships. The mechanistic data on the mutational spectra induced by important human DNA adducts may be helpful in the characterization, not only of carcinogenic exposures, but also of protective factors, such as dietary ingredients. Examples are shown of the application of mutational spectra on the von Hippel Lindau (VHL) gene in kidney cancer in relation to dietary intake. Some fruit and vegetables provide protection against mutations and the effect is stronger among smokers who have both endogenous and exogenous mutagenic exposures.
Hemminki
Kari
K
Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden. kari.hemminki@cnt.ki.se
Thilly
William G
WG
D000375:Aging; D002273:Carcinogens / Q000378:metabolism*; D018736:DNA Adducts / Q000032:analysis*; D004260:DNA Repair; D005838:Genotype; D006801:Humans; D017720:Molecular Epidemiology; D009154:Mutation; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics*; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D002273:Carcinogens; D018736:DNA Adducts; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human