L3, Cancer Genetics II (TS Genes) Flashcards

1
Q

Illustrate the original 6 hallmarks of cancer, with appropriate examples..

A
  1. Sustained proliferative signalling (Myc, bcr-abl)
  2. Evading growth suppressors (Rb, p53)
  3. Activating invasion and metastasis (MMPs etc)
  4. Enabling replicative immortality (TERT)
  5. Inducing angiogenesis (VEGFA/B)
  6. Resisting cell deaths (e.g. bcl)
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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16
Q

What is ‘neoplastic progression’?

Nature of the progression:

A
  • Process of evolving a normal cell into a life threatening metastatic cancer cell
  • Benign state must come before metastasis if the cancer is to be successful; the process generally follows a discrete sequence of events