Molecular pathology of Tumours Flashcards
What are the properties of malignant cells?
- Disordered proliferation
- Disordered apoptosis
- Disordered differentiation
- Disordered relationship between proliferating cells and the surrounding environment (invasion, metastasis, angiogenesis)
What are the stages of the invasion of malignant cells?
- Normal: normally stratified epithelium
- Dysplasia: Some loss of stratification
- Carcinoma in situ: Total loss of stratification; immature cells throughout the basement membrane intact
- Invasion
- Metastasis: secondary tumour in lymph nodes
Describe the process of clonality
1) A mutation gives a cell an advantage and so it survives and proliferates
2) A second mutation increases the advantage and the cells survive and proliferate
3) A third mutation increases the advantage further and makes the cell invasive
4) Dangerous cell survival, proliferation and invasion
Even when it gets to this stage, the cells in the tumour continue to mutate so they aren’t all genetically identical
What is neoplastic behaviour?
The ability to grow without reference to normal control mechanisms: sustained proliferation even after the stimulus has been removed
What are oncogenes?
- Initial drivers of neoplastic behaviour
* It is a gene which has the potential to cause cancer
What is the name of a cell which has the potential to become an oncogene?
Proto-oncogene
What are the ways a photo-oncogene can become an oncogene?
1) Mutation in the coding sequence produces a hyperactive protein made in normal amounts
2) Gene amplification: the region of a chromosome can be duplicated producing a protein which is overproduced
3) Chromosome rearragement: either:
• Nearby regulatory DNA sequence caused normal protein to be overproduced
• Fusion to the transcribed gene produces hyperactive fusion protein
Give an example of a oncogene being produced from a mutation in the coding sequence
Ras: Change of amino acid 12 from Glycine to Valine, locks the gene onto the ‘on’ position
• Once mutated, it can’t lose the GTP so remains bound and in the on position
• Interference with intracellular signalling
Give an example of an oncogene being produced from a gene amplification
HER 2- growth factor in breast cancer
• Increased/activation of growth factor receptor
What drug is used to target HER 2?
Herceptin
Give an example of an oncogene being produced from a chromosome rearrangement
Philadelphia chromosome in chronic myeloid leukaemia
• From the fusion to transcribed gene
Give an example of the oncogenes involved with transcription factors
myc: direct stimulation of cell cycle dependent on transcription
- -> Burkitts lymphoma
Which oncogene increases the amount of growth factor?
sis in fibrosarcoma
Describe how a mutation in a tumour suppressor gene can result in caner
- Normal cell mutates and inactivates a tumour suppressor gene
- this has no effect as we have 2 tumour suppressor genes
- A second mutation event inactivates this second copy
- The tumour suppressor gene has been eliminated, stimulating cell survival and proliferation
What is retinoblastoma?
- Rare childhood eye tumour which can affect one or both eyes
- 2/3 cases only affects one eye
- 1/3 cases affects both eyes
Explain how research in retinoblastoma has helped to understand tumour suppressor genes
• Knudson’s two hit hypothesis
If one is affected:
• Normally 2 copies of retinoblastoma gene (RB1)
• Mutation in one copy of the RB1 gene
• in a small proportion there is a mutation in the second copy of the same cell resulting in no working RB1 protein
If both are affected
• Inherited the loss of one of the RB1 genes
• Therefore only one mutation is needed in any of the retinal cells is needed in order to get the tumour
Why does mutating RB drive carcinogenesis?
- Active Rb binds to transcription factors and prevents the DNA synthesis
- Phosphorylation of Rb allows transcription (inactive Rb)
What type of tumour suppressor is RB and how does it work to suppress the tumour?
- Gatekeeping tumour suppressor
- Promotes death of cells, especially those with DNA damage
- Inhibits proliferation
- Sends negative signals to the cell
APC gene
Underlies Familial Adenomatous Polyposis Coli (colon cancer)
• Controls the transcription of genes required for proliferation which result in the formation of polyps
What are caretaker tumour suppressor genes?
- Maintains the integrity of the genome by promoting DNA repair
- Nucleotide excision repair (recognises abnormal bases)
- Mismatch repair (e.g. if G was paired with T)
- DNA double strand break repairs
Which cancer would result from faulty nucleotide excision repair damage?
Xeroderma Pigmentosa
Which cancer would result from faulty DNA mismatch repair?
Hereditary non-polyposis colon cancer
Which cancer would result from faulty DNA double strand break repairs?
Hereditary ovarian and breast cancer
How does p53 act?
- Caretaker gene and gatekeeper gene
- Responds when a cell experiences DNA damage
- If there is a small amount of damage, it promotes cell repair
- If there is severe damage, it promote apoptosis
