Molecular biology of cell growth and neoplasia

Question 1

What is the mechanism of mutation for cancer development?

Answer 1

1. Mutation inactivates suppressor gene –> cells proliferate
2. Mutations inactivate DNA repair genes
3. Proto-oncogenes mutate to oncogenes
4. More mutations, more genetic instability –> metastatic disease
5. Mutations inactivate genes that regulate apoptosis –> cells do not die normally

Question 2

What are tumour suppressor genes?

Answer 2

• Repress cancer
• A mutation in the tumour suppressor gene may prevent it from doing its normal job –> uncontrolled cell division
• Mutation in tumour suppressor gene - most mutations that inactivate tumour suppressor genes act recessively (need both alleles mutated)

Question 3

Describe the p53 tumour suppressor gene.

Answer 3

o A transcription factor that has an important role in DNA repair, cell cycle progression and cell death
o If DNA cannot be repaired, p53 ensures the cell undergoes apoptosis (programmed cell death)
o Mutation in TP53 gene can prevent p53 functioning normally and lead to cancer

Question 4

What is Li-Fraumeni Syndrome?

Answer 4

• Caused by inherited mutations in the TP53 gene – autosomal dominant
• Children and young adults susceptible to cancer
• Soft-tissue and bone sarcomas, breast cancer, brain tumours, adrenocortical carcinoma and acute leukaemia
• Frequency: 1:5,000 – 1:20,000 general population

Question 5

What is the mismatch repair system?

Answer 5

• Function: maintains the fidelity (accuracy) of DNA replication by correcting nucleotide mispairing and small insertions or deletions
• Mutations in MMR gene (tumour suppressor gene) increase mutation rate

Question 6

What is Lynch syndrome?

Answer 6

• Caused by inherited mutations in DNA mismatch repair genes
• Increased risk of developing several cancers at early age
• Frequency: 1:370-1:2,000
• Autosomal dominant transmission (only need 1 copy of mutated gene to cause disease)

Question 7

What is homologous recombination?

Answer 7

• Maintains the accuracy of DNA replication by homologous recombination
• Mutations in the Breast Cancer susceptibility genes BRCA 1 + BRCA 2 (tumour suppressor genes) increases chance of breast cancer
• Frequency: 1:400/500 (excluding Ashkenazi jews)
• Autosomal dominant transmission

Question 8

Outline key regulators of cell signalling.

Answer 8

a. Cells respond to cues through receptors on the cell membrane.
b. Stimulation of receptors activate signalling pathways inside the cell.
c. Mutation in these genes are commonly found in cancer cells –> affecting cell growth
d. The Kirsten rat sarcoma viral oncogene homolog (KRAS) proto-oncogene is commonly mutated in cancer
i. Normal: GTPase-activating protein (GAP) switch KRAS “off”; Guanine nucleotide exchange factors (GEF) switch KRAS “on”
ii. Some mutations keep KRAS switched “on”
iii. This activates signalling pathways in the absence of growth factors  cancer development

Question 9

Outline genetic alterations in cancer.

Answer 9

a. Mutations (Summary of 1-3)
i. Activation of protooncogenes  oncogenes: cell signalling regulation (KRAS proto-oncogene)
ii. Inactivation of tumour suppressor: cell cycle regulation (p53), DNA repair (MMR, BRCA1, BRCA2)

b. Gross abnormalities
i. Polyploid DNA content: increase in genome DNA content (>2 sets of chromosomes)
ii. Gene amplifications
iii. Deletions, duplications, inversions, insertions, translocation

c. Microsatellite instability
i. Gain or loss of nucleotide repeats which occurs as a result of deficient MMR