Oncogenes And Tumour Suppressor Genes Flashcards
Function of a proto-oncogene?
Control differentiation and proliferation to regulate homeostasis
What are Ras - tumour suppressor or oncogenes?
Oncogenes
How are Ras genes activated and what do they cause?
Ras are G-proteins which are activated by the GPCR tyrosine kinase
Activation of Ras activates the MAPK(kinase) pathway causing cell proliferation and growth
What happens if there is a mutation to the Ras protein?
Switched on all the time causing constant proliferation. Doesn’t need the tyrosine kinase receptor to activate it.
Why are Ras mutations easy to detect?
Only nine bases can be changed
What kind of cancers are Ras mutations common in?
Epithelial cancers such as
- colon
- bladder
- lung
Where can mutations be found for Ras?
Codons 12, 13 and 61
How can the type of Ras mutation be an indicator of prognosis in colorectal cancer?
Eg there are two mutations which are highly significantly associated with a high risk of recurrence and a lower two year survival rate than other mutations
What is insertional mutagenesis?
When a DNA virus incorporates a viral oncogene into the host DNA.
What can cause insertional mutagenesis?
HPV 16 and 18 - cervical cancer
Hep B - hepatocellular cancer
What is a chromosomal translocation?
When a fragment of one chromosome attaches to another non-homologous chromosome
Give some examples of chromosome translocations that can lead to cancer
9;22 - chronic myeloid leukaemia leading to abnormal tyrosine kinase activity (Philadelphia chromosome)
8;14 - burkitt’s lymphoma leading to constitutive MYC expression
What is an example of gene amplification and in which cancer is it seen?
Human epidermal growth factor receptor 2 (HER-2).
Amplified and over-expressed in 20-30% of breast cancers
Linked to poor prognosis
What can gene amplification be detected by?
FISH
Immunohistochemistry
What can breast cancer with HER-2 amplification be treated with?
Herceptin - a monoclonal antibody which binds to the receptor and prevents growth by preventing downstream signalling.
Also flags HER2+ cells for destruction by the immune system
What is seen when HER-2 positive cells are stained?
Dark membranes because HER-2 is found on the membrane
Normal function of tumour suppressor genes?
Maintain genetic stability by
- DNA repair
- carcinogen detoxification
- cell cycle control
- apoptosis
- senescence
What causes senescence?
Telomeres shortening
What are the different types of retinoblastoma?
Familial - seen bilaterally - 40%
Sporadic - unilateral - 60%
What is the two hit hypothesis for retinoblastoma?
Tumour triggered by two mutation events
- first recessive mutation inherited and seen in all cells
- only need one more mutational event to affect the other allele to initiate a tumour
Why is sporadic retinoblastoma normally only seen unilaterally?
Need two hits and the chances of two hits happening in the same cell is very small
What makes a cell population more heterozygous?
The more alleles for a gene there are
What is loss of heterozygosity?
When there is a mutation leading to deletion of an allele, can cause LOH.
Where does LOH normally involve on the DNA?
The flanking chromosomal region near the 5’ end
This area of DNA is not normally transcribed into RNA
Why can LOH lead to cancer?
Only have one remaining copy of a tumour suppressor gene which can be inactivated by a point mutation, leaving no tumour suppressor gene.
What is the most commonly mutated gene in cancer?
p53 (seen in 50% of cancers)
What is the function of p53?
Cell cycle G1 arrest in response to DNA damage
Can trigger both cell differentiation and apoptosis.
What is DNA CpG methylation?
Addition of methyl groups to cytosine (where cytosine is found next to a guanine base)
What can promoter methylation cause?
Tumour suppressor gene inactivation - silences the gene
When does promoter methylation normally arise?
Ageing of cells
What possible mutations can you get to genes?
Deletion of base pairs, genes, chromosomes Insertion of base pairs or viruses Substitution of base pairs Amplification of genes/chromosomes Translocation of a chromosome
