Tumour suppressor genes Flashcards
What is a tumour suppressor gene?
A gene that normally acts to inhibit cell proliferation and tumour development
In general terms, how do tumour suppressor genes result in malignancy?
If these genes are lost/inactivated, negative regulation of cell proliferation is lost - this contributes to abnormal proliferation of tumour cells
Is loss of one allele of a TSG enough to promote tumour development?
No - both TSG alleles must be inactivated to promote tumour development
What are some of the ways inactivation of the second copy of a TSG can occur?
Mutation, deletion, silencing by methylation, loss of heterozygosity
What is ‘Knudson’s two hit hypothesis’?
Explains the difference between hereditary and sporadic forms of retinoblastoma that both require ‘two hits’:
Hereditary = a mutant LoF allele is inherited (most are de novo) and a subsequent later somatic mutation inactivates the normal allele - leads to variable penetrance and an apparently dominant MOI (one hit kinetics)
Sporadic = two somatic mutation events must occur - second event must occur in the descendants of cell with first mutation (two hit kinetics)
What are the main categories of TSG?
- Gatekeeper genes - encode proteins that control the cell cycle and regulate cell proliferation (e.g. p53, Rb, APC)
- Caretaker genes - maintain and protect the integrity of the genome. Involved in DNA repair and help to prevent the accumulation of mutations (e.g. MLH1, MLH2)
Proposed third = landscaper genes - help create ‘environments’ that control cell growth (e.g. PTEN)
Give two roles of p53/TP53 as a TSG
- Controlling progression within cell cycle
- Stimulating cell death in cells deviating from normal growth
What are the four main examples of TSGs
- Rb (retinoblastoma)
- p53
- CDKN2A
- microRNAs (e.g. let-7, miR-34)
What is retinoblastoma?
Aggressive childhood cancer of the eye that is usually diagnosed <5yrs
Presenting sign is leukocoria (whitening of the pupil)
Two forms: hereditary (~33%) and sporadic (~66%) - links to Knudson’s two hit hypothesis
Outline the mutation spectrum seen in retinoblastoma
- Large structural changes (~10-20%)
- Single base substitutions (~50-60%)
- Small insertions/deletions (~30%)
60-70% of tumours exhibit LoH with a mutation in the remaining copy
~10% of tumours have promoter hypermethylation (inhibits levels of rb protein made by the cell)
Is the type of mutation seen in Rb thought to correlate with phenotype?
Yes.
PTC/truncating mutations are most often associated with full penetrance and bilateral retinoblastoma.
Milder disease with VE/RP usually found in families with missense mutations, some splice site changes, small in-frame dels and promoter region mutations.
What is the nickname for p53?
The guardian of the genome
What is the role of p53 in normal cells?
p53 levels are downregulated via binding of proteins such as E3 ubiquitin ligase and MDM2 - causes migration to cytoplasm and degradation by the ubiquitin/proteasome pathway.
These genes are actually upregulated by p53, leading to a regulation loop that keeps p53 levels very low.
What is the role of p53 in ‘stressed’ cells?
p53 becomes phosphorylated and acetylated - no longer interacts with MDM2.
Levels of p53 activity rise leading to transcriptional activation of genes involved in various pathways (apoptosis, angiogenesis/metastasis and arrest/repair).
What are the three main mechanisms for loss of p53 function?
- Mutations in genes upstream of p53 that prevent its activation (e.g. ATM kinase and CHK2)
- Mutations in p53 - somatic p53 mutations found in more tumour types than any other gene. p53 mutations also cause Li-Fraumeni syndrome.
- Mutations in downstream mediators of p53 function (e.g. PTEN)
