CSIM 1.8 Neoplasia 4 Flashcards
What are the normal functions of oncogene products?
- Growth factors
- Growth factor receptors
- Transcription factors
- Proteins involved in signal transduction
- Cell cycle regulators (e.g. cyclins)
How do proto-oncogenes become oncogenes?
- Changes in structure of the gene result in a product with aberrant function
- Change in regulation resulting in inappropriate production
How can activation occur?
- Chromosomal translocation resulting in a proto-concogene becoming attached and transcribing alongside a heavily-expressed gene resulting in a ‘chimeric protein’
- Point mutation
- Amplification, where the proto-oncogene becomes repeated (IMG 29) so more of the protein is expressed
- Insertional mutagenesis - where a virus inserts DNA upstream from a proto-oncogene, resulting in the viral promotor beginning transcription of the oncogene
- Retroviral transformation gene insertion
Give an example of a cancer which results from chromosomal translocation
Burkitt’s lymphoma
Chronic myeloid lymphoma (BCR-ABL)
Why is retinoblastoma protein called this?
What is its function normally?
How many mutations are needed for this to manifest?
It was first recognised as being the gene mutated in retinoblastoma tumours
Tumour suppressor gene - negative regulator of the cell cycle
Two - one on each allele
What can make people more prone to tumours arising from retinoblastoma protein mutations? How common is this?
Having a family history - as they can inherit one mutated allele, so loss or inactivation of only one (of the remaining one) allele is required for neoplasia. This happens in 40% of cases
(NB: this increases chance of retinoblastoma tumour by 10000X)
What specific mutation affects retinoblastoma protein?
Mutations at 13q14
Which tumour suppressor gene commonly involved in the pathogenesis of neoplasia is a transcription factor?
Which chromosome is it on?
What is the normal function of this transcription factor?
p53 “the guardian of the genome”
Chromosome 17
Causes cell cycle arrest in times of stress, to allow the cell time to repair or to apoptose (to prevent the perpetuation of this damage)
What disease involves the inheritance of mutant p53?
Li-Fraumeni syndrome (this syndrome increases risk of all kinds of tumours)
What are the processes by which a tumour suppressor gene may be inactivated?
The same as the processes which may activate an oncogene (IMG 30):
• Point mutation
• Chromosomal translocation (whereby they are INactivated)
• Viral mechanisms
• Methylation by epigenetics ‘inactivating’ the gene
Which types of genes can be inherited which increase the risk of cancer?
Those which may produce cancer recessively, needing two copies:
• Defective tumour suppressor gene
• Defective DNA repair gene
(NB: dominant oncogenes tend not to be passed on due to the fact they always manifest, so there’s no ‘covert’ way for them to exist long enough to be passed on)
Why does damage to DNA repair genes increase likelihood of cancer?
It reduces the cell’s ability to repair non-lethal damage to:
• Oncogenes
• Tumour suppressor genes
• Apoptosis-regulating genes
Do apoptosis-regulating gene mutations:
1) Act like oncogenes or lost tumour suppressor genes?
2) Have dominant or recessive behaviour?
Explain your answers.
1) Both
2) Both
This is because apoptosis-regulating genes can both increase apoptosis (tumour suppressive, recessive) or decrease apoptosis (oncogene, dominant)
Which apoptosis-regulating genes:
• Inhibit apoptosis (may act as oncogenes)
• Promote apoptosis (may act as tumour suppressor genes)
Inhibit apoptosis:
• bcl-2
• bcl-xl
Promote apoptosis
• bim
• bax
• fas
Why is carcinogenesis a multistep process?
No single oncogene will fully transform cells. Cancer-related gene abnormalities must combine and work together to cause a tumour
• Several oncogenes needed
• Loss of two or more tumour suppressor genes needed
IMG31
How is cancer treatment personalised?
Tumours are assessed for specific mutations and treated accordingly
Why are carcinogens difficult to identify?
Interval between application of carcinogens and detection of tumour are large
Usually no single agent induces all of the changes needed to cause a tumour (some act as ‘initiators’ of the process while others continue it, etc)
What are the types of carcinogens
INITIATION AND PROMOTION:
Initiators - begin cellular damage on a road towards neoplasia
Promotors - INEFFECTIVE without initiators having first had their effect on a particular cell. Enhances action of initiators and continues the process of transformation
DIRECT AND PRO-CARCINOGENS:
Direct - active in form which is administered
Procarcinogens - require metabolic conversion to ‘ultimate carcinogens’
How are carcinogens identified?
Epidemiological evidence, occupational risks, experimental observations, direct exposure (e.g. therapeutic irradiation)
What is the major family of carcinogens in cigarette smoke? Which type of carcinogen are they?
Why can these cause all kinds of cancers?
Polycyclic aromatic hydrocarbons
Pro-carcinogens, which are activated by mixed-function oxidases expressed ubiquitously
The carcinogens, once converted into ultimate carcinogens in the lungs, can be absorbed and transported around the body, potentially affecting any cell.
Which aromatic amine carcinogens exist, and which cancers do they cause
- 2-naphthylamine = bladder carcinogen (no local carcinogenic effect, hydroxylated and glucuronidated, and deconjugated in the urinary tract, where it acts as a carcinogen)
- Dimethylaminoazobenzene (azo dye) = liver carcinogen
Which kind of cancer can nitrosamines cause? What type of carcinogen is this and what metabolises it?
GI cancers - procarcinogen, metabolised by gut bacteria (why bacon causes cancer)
How does ionising and UV radiation cause cancer?
UV light causes cross-linking of pyrimidines in DNA - when DNA repair mechanisms try to repair these cross links they may induce errors
Ionising radiation causes double-standed DNA breaks, leading to chromosomal translocations
