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Redefining tumour suppressor genes: exceptions to the two-hit hypothesis.
1University of Edinburgh Cancer Research Centre, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, United Kingdom. adam.paige@cancer.org.uk
Cellular and Molecular Life Sciences : CMLS
|November 18, 2003
Summary
Knudson's two-hit model requires two gene mutations for tumors. However, this review explores exceptions like haploinsufficient and epigenetically silenced tumor suppressor genes, proposing a revised definition.
Area of Science:
- Oncology
- Genetics
- Epigenetics
Background:
- Knudson's two-hit model is the established theory for tumor suppressor gene inactivation.
- This model posits that two mutations, one in each allele, are necessary for tumor development.
- Numerous cancer genes have been identified that fit this biallelic disruption model.
Purpose of the Study:
- To review exceptions to Knudson's two-hit model for tumor suppressor genes.
- To discuss candidate tumor suppressors inactivated by mechanisms other than biallelic mutation.
- To propose a revised definition of tumor suppressor genes.
Main Methods:
- Literature review of recent findings on tumor suppressor gene inactivation.
- Analysis of cases involving haploinsufficient tumor suppressor genes.
- Examination of tumor suppressor genes inactivated by epigenetic mechanisms like hypermethylation.
Main Results:
- Identified candidate tumor suppressors that deviate from the two-hit model.
- Highlighted haploinsufficient genes requiring only one allele inactivation.
- Discussed genes inactivated by epigenetic silencing, such as hypermethylation.
Conclusions:
- The traditional two-hit model does not encompass all tumor suppressor genes.
- A broader definition is needed to include haploinsufficient and epigenetically silenced genes.
- A revised definition will aid in identifying novel tumor suppressor loci.