A new model for oncogenesis. From tumour immunology to a mathematical approach of oncogenesis

Around 1970 it was assumed that tumour cells are due to a single specific oncogenic mutation. This implied that daily many thousands of tumour cells would arise de novo and that most of these tumour cells were killed by immune surveillance or natural resistance mechanisms. Recent findings on immune surveillance and natural resistance implicate that tumour cells do not arise frequently, however. Given the fact that mutations occur at a frequency of about 2 X 20(-5) mutants per gene per generation, we calculated that transformation to a tumour cell probably requires 4 oncogenic mutations if a single tumour cell would arise de novo during lifetime. This four-mutation model of oncogenesis can explain many oncological data like the observed peak incidence of cancer in children, the hereditary aspects of some pediatric tumours and the usually non-hereditary cancer in adults, the occurrence of second tumours in children, and the data on the monoclonal and polyclonal origin of tumours.