As introduced earlier, whereas the proteins encoded by proto- oncogenes promote cancer when activated or overexpressed, mutations in TSGs contribute to malignancy by a different mechanism— namely, the loss of function of both alleles of the gene. The products of many TSGs have now been isolated and characterized, some of which are presented in Table 1.

Table1. Selected Tumor Suppressor Genes

The existence of TSG mutations leading to cancer was proposed by Alfred Knudson some five decades ago to explain why certain tumors can occur in either hereditary or sporadic forms (Fig. 1) (see discussion in next section). It was suggested that the hereditary form of the childhood cancer retinoblastoma (see next section) might be initiated when a retinal cell in a person heterozygous for a germline pathogenic variant in the retinoblastoma TSG (now known to be RB1), required to prevent the development of the cancer, undergoes a second somatic event that inactivates the other RB1 allele. As a consequence of this second somatic event, the cell loses function of both alleles, giving rise to a tumor. In the sporadic form of retinoblastoma, both alleles are also inactivated, but in this case the inactivation results from two somatic events occurring in the same cell.

Fig1. Comparison of mendelian and sporadic forms of cancers such as retinoblastoma and familial adenomatous polyposis of the colon. See text for discussion.

This so- called Knudson two- hit model is now widely accepted as the explanation for many hereditary cancers in addition to retinoblastoma, including cancers arising in familial adenomatous polyposis (FAP), hereditary breast cancer, neurofibromatosis type 1 (NF1), Lynch syndrome (LS), and Li- Fraumeni syndrome (LFS).

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المزيد

مواضيع ذات صلة

RNA Interference Causes Gene Inactivation by Destroying the Corresponding mRNA

Linkage Studies Can Map Disease Genes with a Resolution of About 1 Centimorgan

DNA Polymorphisms Are Used as Markers for Linkage Mapping of Human Mutations

DNA Microarrays Can Be Used to Evaluate the Expression of Many Genes at One Time

Hybridization Techniques Permit Detection of Specific DNA Fragments and mRNAs

Cloned DNA Molecules Can Be Sequenced Rapidly by Methods Based on PCR

Cellular and Molecular Mechanisms in Development: Gene Regulation by Transcription Factors

Transcriptional Control of Megakaryocytopoiesis: GATA Family Transcription Factors

The Polymerase Chain Reaction Amplifies a Specific DNA Sequence from a Complex Mixture

Role of Developmentally Important Neutrophil-Specific Genes in Disease

Genes Can Be Identified by Their Map Position on the Chromosome

Homologous Recombination Can Repair DNA Damage and Generate Genetic Diversity