The multiple mutation theory on cancer involves three different parts;
1) primary cancer evolves from one initial cancerous cell having been multiplied in some way or other above a critical number
2) initial cancer cells are produced from normal ones by means of genetic mutations
3) not one but a number (five to seven) of different mutations in the same cell are required for the production of a cancerous cell. This theory is supported by the following facts;
1) the correlation between mutagens and carcinogens
2) the correlation between cell proliferation and cancer incidence
3) the kind of mathematical relation between cancer frequency and age in man, and 4) the stepwise increase of the malignancy of tumours.
From this compelling simplicity, an increasingly complicated picture has emerged as more than 100 oncogenes and 30 tumor suppressor genes have been identified.
There is increasing evidence that in eukaryotic cells, DNA undergoes continuous damage, repair and resynthesis. A homeostatic equilibrium exists in which extensive DNA damage is counterbalanced by multiple pathways for DNA repair. In normal cells, most DNA damage is repaired without error. However, in tumor cells this equilibrium may be skewed, resulting in the accumulation of multiple mutations. Among genes mutated are those that function in guaranteeing the stability of the genome. Loss of this stability results in a mutator phenotype. Evidence for a mutator phenotype in human cancers includes the frequent occurrence of gene amplification, microsatellite instability, chromosomal aberrations and aneuploidy. Current experiments have centered on two mechanisms for the generation of genomic instability, one focused on mutations in mismatch repair genes resulting in microsatellite instability, and one focused on mutations in genes that are required for chromosomal segregation resulting in chromosomal aberrations. This dichotomy may reflect only the ease by which these manifestations can be identified. Underlying both pathways may be a more general phenomenon involving the selection for mutator genes during tumor progression. During carcinogenesis there is selection for cells harboring mutations that can overcome adverse conditions that limit tumor growth. These mutations are produced by direct DNA damage as well as secondarily as a result of mutations in genes that cause a mutator phenotype. Thus, as tumor progression selects for cells with specific mutations, it also selects for cancer cells harboring mutations in genes that normally function in maintaining genetic instability.
Multiple-hit hypothesis proposed that a single cell must receive a series of mutational events in order to become malignant or cancerous.
It has been long understood that mutation distribution is not completely random across genomic space and in time. Indeed, recent surprising discoveries identified multiple simultaneous mutations occurring in tiny regions within chromosomes while the rest of the genome remains relatively mutation-free. Mechanistic elucidation of these phenomena, called mutation showers, mutation clusters, or kataegis, in parallel with findings of abundant clustered mutagenesis in cancer genomes, is ongoing. So far, the combination of factors most important for clustered mutagenesis is the induction of DNA lesions within unusually long and persistent single-strand DNA intermediates.