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Redefining tumour suppressor genes: exceptions to the two-hit hypothesis

A J W Paige1

  • 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
PubMed

Insights

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.

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