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2 Oncogenes and tumor suppressor genes
Molecular genetic analysis of tumorigenesis has revealed two fundamental mechanisms of
neoplasia: 1) the activation of dominant oncogenes or 2) the inactivation of recessive tumor
suppressor genes (anti-oncogenes). Accumulating evidence suggests that the progression of
many tumors to full malignancy requires both types of changes in the tumor cell genome.
2.1 Oncogenes
First evidence for the existence of oncogenes came from the induction of sarcomas by the
Rous sarcoma retrovirus, containing the V-Sf'C oncogene (Martin, 1970). Later, other
retroviral oncogenes (v-olle) and their human homologues (c-olle) were discovered in various
cancers. Also the dissection of chromosomal translocations, tumor associated DNA
amplifications and the use of gene-transfer have resulted in the identification of more
oncogenes. Until now 100 or more of them have been isolated. Under normal conditions
proto-oncogenes are thought to be involved in the regulation of cell proliferation. They act
as growth factors or their receptors. Within the cell, they function as downstream modulators
in signal transduction pathways. Furthermore, the nuclear (proto-)oncoproteins may regulate
gene transcription in response to these signals (Hunter, 1991). Different mechanisms (point
mutation, amplification or translocation) are involved in the activation of a proto-oncogene
into an oncogene. Mutations in the proto-oncogenes occur in one of the two alleles of the
gene and they act in a dominant way relative to the wild-type allele. Therefore, they are
called 'gain of function' mutations that give normal cells neoplastic properties (Weinberg,
1989).
2.2 Tumor suppressor genes
Three lines of evidence support the existence of growth-constraining tumor suppressor genes:
1) somatic cell hybrids 2) familial cancer and 3) loss of heterozygosity in tumors.
The first evidence that tumor suppressor genes are involved in neoplastic
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