1. Tumour supressor genes

Question 1

How do mutations in TSGs contribute to cancer?

What’s the inheritance pattern?

Answer 1

AR at cellular level - both alleles must be inactivated for tumour development (second hit is somatic)

AD in familial cancer syndromes

Question 2

What are the main ways that TSGs act to control cell growth/division?

Answer 2

1. Control progression through cell cycle, inhibit proliferation (TP53, RB, APC)
2. Maintain genome integrity (MLH1, MSH2, BRCA1/2)
3. Stimulate apoptosis in cells deviating from normal growth (TP53)

Question 3

What’s the clinical background of retinoblastoma?

Answer 3

Aggressive childhood cancer of eye - unilateral (sporadic), bilateral (heritable)

Presenting sign = leukoconia (whitening of pupil)

Increased risk of osteogenic & soft tissue sarcoma, melanoma

Question 4

What is the role of the pRB protein?

Answer 4

Nuclear phophoprotein - role in cell cycle progression

HYPOphosphorylated in G1 & bound to E2F TFs required for transition to S phase - prevents DNA replication

Mitogen stimulation –> cyclin-dependent kinases phosphorylate RB –>RB dissociates from E2F –>cell cycle progresses

Question 5

How to mutations in RB1 cause cancer?

Answer 5

Biallelic inactivation of RB1 in a cone cell precursor in the developing retina

Both sporadic and heritable forms require 2 hits - first hit = inherited or somatic, second hit = somatic

60-70% of tumours show LoH with mutation in remaining copy

Question 6

What type of mutations are seen in RB1?

Answer 6

Hypermethylation of RB1 promoter in 10% of tumours

LoF variants = complete penetrance
Missense = incomplete penetrance

Question 7

What are the two main roles of p53?

Answer 7

Centre of network of signalling pathways essential for cell growth, proliferation and apoptosis, reacts to cell stress (e.g. due to DNA damage)

1. p53 is phosphorylated and acetylated –> increased expression, acts as TF to upregulate p21.

When p21 is complexed with cell division-stimulating protein (cdk2), cell cannot pass from G1 to S phase - p53 activates DNA repair before mitosis

2. Triggers apoptosis if DNA cannot be repaired

Question 8

What types of mutation cause loss of p53 function?

Answer 8

LoF or dominant negative

p53 somatic mutations in 50% of tumours

Question 9

What do germline variants in p53 cause? How is it characterised?

Answer 9

Li Fraumeni syndrome

Cancer predisposition syndrome, risk of adrenocortical carcinomas, breast cancer, CNS tumours, osteosarcomas, and soft-tissue sarcomas.

Question 10

Give two examples of microRNAs acting as TSGs

Answer 10

1. let7 - negatively regulates cell cycle oncogenes e.g. RAS, MYC. Frequently lost in NSCLC
2. miR34 - transcription activated by p53 –> represses cell cycle & survival genes e.g. BCL2, promotes apoptosis

Question 11

What is the importance of identifying microRNAs involved in cancer progression?

Answer 11

Used as markers for diagnosis, prognosis and therapeutic targets

Question 12

What are the two types of LOH? How do they arise?

Answer 12

CNL-LOH - due to deletion of region

CNN-LOH - due to homologous recombination event (gene conversion) or because retained chromosome was duplicated before or after the LOH event