Is the initial event in carcinogenesis an enhancement of the mutation rate?
The age-specific incidence rates of adult cancer indicate that the carcinogenic process is a power function of elapsed time. If the malignant clone arises by a series of mutations, and each mutation is regarded as an independent event with a small instantaneous probability of occurrence, then the slope of the age-specific incidence gives an indication of the number of genes involved. In most cases, the epidemiological data exhibit an age-specific incidence the slope of which is between a fourth and a seventh power of age. Assuming that the mutations involved are deletions and must occur in otherwise viable and proliferative cells, the mutation rate required to generate enough mutant cells to fit the cancer incidence data must be remarkably high in the pre-malignant cell population. The initiation process may thus be an event that results in a raised mutation rate in the affected cell and its progeny. It is proposed that the process of induction involves one or more mutations that induce a metabolic lesion that has the effect of increasing the subsequent mutation rate in the affected clone. A possible mechanism involving free radical generation is suggested and some of the biological implications of the proposal examined.
Riley
P A
PA
Dept Chemical Pathology, UCM School of Medicine, London, UK.
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004249:DNA Damage; D005609:Free Radicals; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D016296:Mutagenesis; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics; D011230:Precancerous Conditions / Q000235:genetics; D011336:Probability
D005609:Free Radicals