2: Oncogenes & Tumour Suppressor genes

Question 1

Define proto-oncogene

Answer 1

Genes that code for proteins involved in maintenance of cell growth, division and differentiation

Question 2

Define oncogene

Answer 2

A result of a single mutation of a proto-oncogene.

Its protein product no longer responds to control influences

Question 3

State 4 ways in which mutation of oncogene occurs

Answer 3

1. Point mutation of deletion
2. Gene amplification (multiple gene copies, overproduction)
3. Chromosomal translocation (overproduction of protien due to chimaeric genes)
4. Insertional Mutagenesis (fusion of viral gene, overproduction of protein or produces hyperactive protein)

Question 4

Give examples of oncogenic mutations

Answer 4

Burkitt's Lymphoma (chromosomal translocation)
Philadelphia Chromosome (Insertional mutagenesis)

Question 5

What is Philadelphia chromosome?

Answer 5

ABL gene translocation - chromosome 9 to 22

Question 6

Give 3 pathways by which cell proliferation can be activated

Answer 6

1. Nuclear/cytosolic receptor: binding of growth factor (GF) translocates it to DNA -> upregulation of transcription/translation -> proliferation
2. Tyrosine-Kinase receptor: binding of GF to receptor causes phosphorylation cascade -> proliferation
3. G-protein Coupled Receptor: binding of GF -> kinase cascade -> phosphorylation -> proliferation

Question 7

Where in the cell do proto-oncogenes regulate cell division?

Answer 7

1. Receptors on plasma membrane that bind GF (e.g. MET codes for tyrosine kinase receptors)
2. Proteins involved in signalling pathways that promote cell proliferation (e.g. RAS/RAF)
3. In the nucleus - proliferative transcription factors (e.g. MYC/fos/jun activate expression of many pro-proliferative genes)

Question 8

How does mutant RAS cause cancer?

Answer 8

• Normally RAS binds to GTP and is activated
• Active RAS then activates RAF, which activates signalling cascade leading to proliferation
• RAS is deactivated by dephosphorylation of GTP to GDP
• Mutant RAS can’t dephosphorylate and remains active

Question 9

Examples of oncogenes

Answer 9

SRC
MYC
JUN
H-RAS
K-RAS

Question 10

Define Tumour Suppressor Gene

Answer 10

Code for proteins that regulate cellular proliferation and maintain cellular integrity

Question 11

How many copies of TSGs and proto-oncogenes in each cell in our body?

Answer 11

2

Question 12

What happens if you damage one copy of TSG?

Answer 12

The remaining TSG is able to compensate for the loss, tumour suppressor function is NOT lost. Does not promote cancer.

Question 13

What happens if you damage one copy of proto-oncogene?

Answer 13

Becomes an oncogene - this is a DOMINANT effect.

Promotes cancer

Question 14

What are the features of inherited cancers?

Answer 14

• Family history of related cancers
• EARLY age of onset unlike other cancers
• BI-LATERAL tumours in paired organs
• SUCCESSIVE tumours
• Tumours in MULTIPLE organs of same person

Question 15

Define retinoblastoma

Answer 15

Malignant cancer of developing retinal cells.

Question 16

How does retinoblastoma present

Answer 16

It is a sporadic disease involving ONE eye (i.e.

Hereditary cases can be unilateral, bi-lateral or multifocal as additional tumours can develop.

Question 17

Cause of retinoblastoma

Answer 17

Mutation in RB1 tumour suppressor gene

Chromosome 13q14

Question 18

What is the role of RB1 tumour suppressor gene in cell cycle

Answer 18

Encodes nuclear protein involved in cell cycle - prevents excessive cell growth by inhibiting cell cycle progression

Question 19

What is the overall function of tumour suppressor genes

Answer 19

To suppress the neoplastic phenotype (i.e. inappropriate cell growth)

Question 20

How is p53 different to other TSGs?

Answer 20

Requires mutation on only ONE copy to become oncogenic, unlike other TSGs which require damage to both copies

Question 21

What is p53 normally bound to when inactive?

Answer 21

MDM2 protein

Question 22

Give examples of stimuli that can activate p53

Answer 22

• DNA damage
• Oncogene activation
• Hypoxia
• Oxidative stress

Question 23

How does p53 have its effects?

Answer 23

1. Acts like a transcription factor - binds to p53 target genes
2. Protein-protein interactions (apoptosis)

Question 24

What are the effects of p53 in mild and severe stress?

Answer 24

In mild stress:
- Metabolic homeostasis
- Antioxidant defence
- DNA repair
- Growth arrest
In severe stress: senescence and APOPTOSIS

Question 25

What disease is APC gene associated with?

Answer 25

Familial adenomatous polyposis coli (benign)

• Deletion in 5q21 resulting in loss of APC tumour suppressor gene
• Multiple benign adenomatous polyps of COLON
• 90% risk of developing colorectal carcinoma

Question 26

What is the role of APC gene

Answer 26

Cell adhesion and signalling

Question 27

How does APC function

Answer 27

Involved in WNT signalling pathway

Controls activity of beta-catenin thereby preventing uncontrolled growth

Question 28

How do successive gene mutations lead to colorectal cancer?

Answer 28

1. APC mutation -> Hyperproliferative epithelium (benign)
2. K-ras mutation -> ADENOMA (still benign)
3. p53 mutation -> CARCINOMA (malignant) -> METASTASIS (death)

Question 29

How are oncogenes different to TSGs?

Answer 29

Oncogenes:

• Usually activated by translocation/point mutations (TSG: deletion/mutations)
• Rarely hereditary unlike TSGs
• DOMINANT
• Broad tissue specificity
• Usually leads to Leukaemia/lymphoma (TSG: solid tumours)

Question 30

Hallmarks of cancer

Answer 30

Disregard of signals to stop proliferating
Disregard of signals to differentiate
Capacity for sustained proliferation
Evasion of apoptosis
Ability to invade
Ability to promote angiogenesis

Question 31

List 5 TSGs

Answer 31

p53
APC
p16-INK4A
BRCA1
PTEN
MLH1

Question 32

Functional classes of TSGs?

Answer 32

• Regulates cell growth/proliferation
• Regulates cell cycle
• Maintains cellular integrity
• Nuclear transcription factors (p53)
• DNA repair proteins
• Cell adhesion molecules
• Apoptosis regulators