title: Carcinogen-induced impairment of enzymes for replicative fidelity of DNA and the initiation of tumours.
abstract: Not all carcinogens are mutagens, and many mutagens are not carcinogens. Among related chemicals, small changes of structure can markedly influence carcinogenic potency. Many tumours are genetically unstable, but some, especially 'benign' types, rarely exhibit 'progression' or show other evidence of genetic instability. Cells of particular tumour types exhibit identifiable particular 'sets' of phenotypic abnormalities (e.g. rapid growth, uniform nuclei, little cytoplasm and occasionally production of adrenocorticotrophic hormone by anaplastic small-celled carcinoma of the bronchus). Tumour cells pass their abnormalities on to their daughter cells, indicating that a genomic alteration probably underlies tumour formation. A possible mechanism, which might explain these phenomena is carcinogen-induced reduction of fidelity of replication of DNA polymerase complexes during S phase of normal tissue stem cells. A single 'hit' by a reactive agent (chemical or physical) on one of the major enzymic sites (synthesis, proofreading, mismatch repair-MMR) could cause multiple sequence abnormalities in the length of DNA synthesized by one DNA polymerase complex. Because this length of DNA (half a replication 'bubble') averages 15 000-150 000 nucleotides, the affected DNA could include two or more significant genomic elements (genes, especially for tumour suppression, regulatory loci and other elements). The particular mutant elements in the affected DNA could then determine the 'set' of phenotypic abnormalities exhibited by a resulting tumour. Non-genotoxic carcinogenicity, non-carcinogenic mutagenicity, structure-dependent chemical carcinogenicity and the phenomenon of 'sets' of phenotypic abnormalities could thus be accommodated. In experimental studies, the 'hallmark pattern' of mutation caused by this mechanism would be multiple mainly point mutations clustered within the length of half a replication 'bubble'. Such a 'hallmark pattern' of mutation might be detectable in carcinogen-treated cell cultures by the use of cycle-synchronized cultures, single cell subculturing, restriction (endonuclease) fragment length analysis of the clones and nucleotide sequencing of abnormal bands for localization in the human genome. If the mechanism is important to carcinogenesis generally, then non-carcinogenic mutagens should not cause the 'hallmark pattern' of mutations in either in vitro or in vivo systems. In human tumour cells, the 'hallmark pattern' of mutations may be demonstrable in genetically stable human tumours, but might well be lost or obscured by secondary mutations in genetically unstable tumours. Among different cases of the same type of human tumour, the clustered point mutations might be tumour-type specific in their location in the genome, but vary case-to-case in the precise 'points' mutated in the cluster region. New assays for assessing the carcinogenic potential of environmental and synthetic substances for human and animal populations may result. The hypothesis is not put forward to the exclusion of some established mechanisms of carcinogenesis for particular human tumours: for example, the 'two-hit' mutational hypothesis for retinoblastoma, the 'multiple sequential mutational' hypothesis for UV-induced lesions of the epidermis, and the possibility of adduct-induced frameshift mutations by some chemical carcinogens for experimental tumours.
authors: Institute of Medical and Veterinary Science, Adelaide, South Australia and Department of Pathology, University of Adelaide, SA 5005, Australia. leon.bignold@adelaide.edu.au
authors: Leon P
authors: LP
authors: Bignold
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects*; D004259:DNA-Directed DNA Polymerase / Q000187:drug effects*; D006801:Humans; D009154:Mutation / Q000187:drug effects; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics
chemical_list: D002273:Carcinogens; D004259:DNA-Directed DNA Polymerase