L3, Cancer Genetics II (TS Genes) Flashcards
1
Q
Illustrate the original 6 hallmarks of cancer, with appropriate examples..
A
- Sustained proliferative signalling (Myc, bcr-abl)
- Evading growth suppressors (Rb, p53)
- Activating invasion and metastasis (MMPs etc)
- Enabling replicative immortality (TERT)
- Inducing angiogenesis (VEGFA/B)
- Resisting cell deaths (e.g. bcl)
2
Q
Tumour Suppressor Gene Mechanistic Overview:
A
- Absence leads to cancerous phenotype
- Usually recessive; often show dominant inheritance in cancer predisposition syndromes
- Prime examples: RB, p53
3
Q
What does Rb do? How does it work?
A
- Negatively regulates proliferation by acting as a brake until GFR-signalling received
- Binds E2F until GFR-signalling received (Active G1-Cdk); thus phosph., releasing active E2F
- Active E2F -> S-phase gene transcription -> G1/S-cyclin -> Active S-cdk (S-phase entry) and DNA synthesis
- Multiple positive feedback loops in place
4
Q
Effect of oncogenic activity on G1/S checkpoint:
A
Upregulation of TFs (e.g. Myc) allows oncogenes to ‘short-circuit’ normal growth regulatory pathways…
- TFs are involved in controlling expression of proliferation-associated genes
- Increased cyclinD-Cdk4 activity
- Able to overcome G1/S checkpoint
- CCND1/CCND2 and CDK4 also act as proto-oncogenes
5
Q
How does loss of Rb in cancers affect G1/S transition?
A
- No Rb; E2F constitutively active
- No hindrance on S phase entry
6
Q
Retinoblastoma forms:
A
- Unilateral: 1 eye, no family history, can be cured -> usually good prognoses
- Bilateral: 2 eyes, often family history, lifelong risk of disease
7
Q
Knudson’s 2-hit hypothesis:
A
- In bilateral, only one ‘hit’ required to produce cancer
- In unilateral, 2 are required
- Familial Rb is cancer predisposition syndrome
8
Q
What key genes does p53 regulate?
A
- Cell cycle arrest genes (e.g. p21)
- DNA repair genes (e.g XPA)
- Inhibition of angiogenesis (e.g. TSP-1)
- Apoptosis (e.g. Killer/DR5)
- Autophagy (e.g. DRAM1)
- Metabolism (e.g. PANK1)
9
Q
How is p53 activated under stress, and what is the downstream effect?
A
- p53 is stabilised following stress
- Phosphorylation by activated Chk1/Chk2 kinase prevents Mdm2 binding (no longer degraded by Ub targeting to proteasome)
- -> Stable, active p53
- Active p53 binds to regulatory region of p21
10
Q
p21 function:
A
- Binds Cdks inhibiting their function and causing cell cycle arrest (inhibiting cell-cycle progression)
- Several hundred genes are regulated by p53 in a similar manner
11
Q
What is the result of loss of p53?
A
- Leads to evasion of apoptosis an unregulated cell growth
- Oncogenic signalling no longer activates p53 downstream effectors since removal of Mdm2 by Arf has no effect
- Multiple ways for cancers to do this aside from loss of p53
12
Q
How do telomerases impact replicative immortality?
A
- Ends of chromosomes are protected by telomeres
- See structure: D-loop and T-loop produced by telomeric DNA… Demonstrate
- Telomeres get progressively shorter with successive generations until crisis point
- Telomerases resynthesis telomeres by first extending 3’ end
13
Q
How do cancer cells induce replicative immortality?
A
- Telomerase is usually only expressed in germ cells and stem cells
- Most cancer cells become immortal by expressing TERT (telomerase gene)
- Expression of telomerase extends the telomeres -> not senescing
- Expression of telomerase is associated with poor prognosis in these paediatric cases
14
Q
Warburg Effect
A
- Deregulation of cellular energetics
- Normal cells divert most of their pyruvate to the kerbs/citric acid cycle for efficient ATP production
- In contrast, most of cancers rely on aerobic glycolysis for energy
15
Q
Glucose and PET/CT scanning:
A
- Fluorine-18 FDG in small amounts is uptaken as glucose by cells; lack of Oh in pstn occupied by f-18 prevents normal glucose metabolism -> FDG ‘locked’ in cell
- Cancers uptake large amounts of glucose/FDG
- Combined PET and CT scans detect radiation from tracer and reveal precise location of tumour within body
