Oncogenes and Tumour Suppressor Genes

Question 1

ONCOGENES:
What are Proto-oncogenes?

What are Oncogenes?
→ What are the 3 ways in which this activation can occur? Give an example for each

What’s the phenotype of a Proto-oncogene mutation? Can it be inherited easily?

Answer 1

• NORMAL cellular genes that regulate cell growth, division and differentiation
• Proto-oncogene that’s been ACTIVATED by MUTATION OR OVEREXPRESSION
  → • Point mutation - In proto-oncogene (KRAS in Lung/Pancreatic cancer)
  • Gene amplification - Multiple copies of gene (HER2 in Breast cancer)
  • Chromosomal Translocation - Creation of fusion protein (C-myc in Burkitt’s Lymphoma)
• Dominant phenotype - Rarely inherited due to it being a somatic mutation
  o 1 copy of an Oncogene is enough to promote Tumour formation

Question 2

KRAS:
What does this gene encode for? What function do these have?
→ When are these proteins active and inactive?

HER2:
What does this gene encode for?
→ What is required for this product to be active? What causes this?

What occurs to this gene in Breast cancer?

C-myc:
What does this gene encode for?

What occurs to this gene in Burkitt’s Lymphoma?

Answer 2

• Ras proteins, which are signal transducers in cells for growth and differentiation
  → Active when bound to GTP and Inactive when bound to GDP
• Point mutations, leading to a reduction in GTPase activity, so the KRAS protein is constantly active = Constant cell proliferation
• Part of Epidermal Growth Factor Receptor 2 (EGFR2)
  → Receptor Dimerisation, caused by Growth factors
• Amplification
• Trastuzumab and Pertuzumab (Monoclonal Antibodies)
• Transcription factors
• Translocation of Chromosome 8 (C-myc proto-oncogene) and Chromosome 14 (Ig heavy chain gene)

Question 3

TUMOUR SUPPRESSOR GENES (TSG):
What is the function of these genes?
→ What are the 2 ways in which it inhibits the proliferation of damaged/cancerous cells?

What is Knudson’s Two-Hit Hypothesis for how TSGs are inactivated?
→ What can loss of the normal allele lead to?

Answer 3

• Maintains Checkpoints and controls Genome stability
  → Repair of DNA damage (BRCA1/2) or Apoptosis (TP53)
• Most of the loss-of-function mutations that occur in TSGs are Recessive - One normal allele is enough for cellular control
  o A “Second Hit” affecting the normal allele is needed to disrupt control
  → Hereditary cancer

Question 4

BRCA1/2:
What can defects in the DNA repair function of these genes lead to?
→ What processes can all these mutations accelerate?

If a tumour forms due to inherited defects in DNA repair genes, what property does it tend to have?

What product of BRCA 1/2 repairs the breaks in DNA?
→ What can be given to prevent this? Give drug examples
——————-

TP53:
What does this gene encode for? What function do these have?

What occurs to these genes?
→ What can be given to restore the gene’s function?
——————-

RB1:
What does this gene encode for? What function do these have?
→ What is it inactivated by?
→ What’s the effect of it being inactivated?

What do Point mutations of this gene lead to?
→ What can be done to treat this?

Answer 4

• Sequential acquisition of more mutations
  → Activation of Oncogenes and Inactivation of TSGs
• High Mutational Load
• PARP
  → PARP Inhibitors - Olaparib, Rucaparib
  ——————-
• p53 protein, which cause Arrest/Apoptosis when there’s DNA damage in the cell cyle
• Missense mutations
  → MIRA-1, PRIMA-1
  ——————-
• Rb (Retinoblastoma) protein, which inhibits cell cycle until cell is ready to divide
  → Phosphorylation
  → No longer stops E2F1 (Transcription factor) from working, therefore allowing cell to complete its cell cycle
• Retinoblastoma
  → Surgery, Radiotherapy