Accumulation of mutations

The development of a malignant cell requires several mutations. Examples exist in model organisms and humans where a series of mutations or inactivations of genes that lead to malignancy have been identified. In mice the series of molecular events that lead to a Friend Virus-induced Erythroleukemia are known. In humans, analysis of the DNA from cells in different stages of development of colorectal cancer has lead to a model for the mutational events that cumulatively produce metastatic colorectal tumors.

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Friend Virus-Induced Erythroleukemia in a Model Organism

The mouse provides a model system where an intitiating event (infection with virus) can be controlled and the infected cells can be monitored for genetic and cellular changes. The following progression of events leads to erythroleukemia. The process is shown diagrammatically below the outlined steps.

1. Injection of mice with Friend retrovirus.
2. The Friend retrovirus binds to the Epo receptor, stimulating erythroid precursor cell proliferation.
3. Friend retrovirus inserts near the Spi gene, activating it. (= Spi⁺ mutation).
4. There is a clonal expansion (proliferation) of cells containing the Spi⁺ mutation.
5. Mutations occur in both copies of the p53 gene in one of the Spi⁺ mutant cells.
6. Further proliferation of subclones with the inactivated p53 genes results in overt erythroleukemia.
   
   

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A Genetic Model for Human Colorectal Tumorigenesis

Several mutational events that are common to tumor cells in colorectal cancer have been identified. While it is not known if the accumulation of these mutations has occurred in a specific order, stages in the development of the disease do correlate with the presence of particular mutations.

	Cell Differentiation
	Mutations Affecting Cellular Processes
	Accumulation of Mutations in Cancer
	Cell Proliferation
	Genomic Instability
	Familial Cancers