Molecular biology: cancer

Question 1

What is the Knudson hypothesis?

Answer 1

‘Two hit’ hypothesis: cancer develops from two separate mutations in DNA
- germline mutation in cancer susceptibility gene
- somatic mutation in the other allele of the same gene

Question 2

Somatic mutations (2)

Answer 2

1 activation of genes that stimulate growth (oncogene e.g. KRAS)
2 deactivation of tumor suppressor genes (TP53)

Question 3

Name a few DNA repair proteins (4)

Answer 3

1 DNA polymerase: proofreading
2 Methyl-directed mismatch repair system
3 Photolyase: activated by UV light to correct thymine dimers (UVB)
4 Nucleotide excision repair

Question 4

p53 protein: role, action (2), somatic or genetic mutation?

Answer 4

Tumour suppressor protein

Detects DNA damage and
1 activate expression of p21 which halts cell cycle, then activates DNA repair
2 triggers apoptosis

Mutations generally somatic

Germline = Li-Farumeni syndrome (1 “hit” required)

Question 5

Checkpoints in tumour cells

Answer 5

= deregulated

• genetic mutations may affect abundance of cyclins/CDK complexes

Question 6

3 main types of skin cancer

Answer 6

1 SCC
2 BCC
3 Melanoma

Question 7

Melanoma: what is it? sun attributation? what melanocytes?

Answer 7

Mutation in melanocytes

86% UV attibuted

Melanocytes produce melanin which protect skin from UV

Question 8

UVA vs UVB

Answer 8

UVA
- penetrates dermis
- indirect damage: ROS

UVB
- penetrates epidermis
- direct damage: thymine base pair dimers + ROS
- repaired by photolyase (activated by IV light) or nucleotide excision repair
- create UVB signature mutations found in skin cancers

Question 9

Melanoma: what pathways are affected? (2) what gene is commonly involved?

Answer 9

1 MAPK pathway
2 AKT/P13K pathway

BRAF gene
- encodes B-RAF protein which directs cell growth
- 90% mutation from amino acid change, greatly increases activation
- progression to melanoma required p53 inactivation
- key therapeutic target in treatment