Oncogenes

Question 1

What is a Driver Mutation?

Answer 1

A mutation which directly or indirectly offers a cell a selective growth advantage

Question 2

What is a passenger mutation?

Answer 2

A mutation which does not directly or indirectly offer a cell a selective growth advantage

Question 3

Number of driver and passenger mutations per cell?

Answer 3

Driver: 5-8
Passenger: 100s

Question 4

Examples of positive regulators for cancer susceptibility genes

Answer 4

Classical Oncogenes
Telomerases
Anti-apoptotic genes

Question 5

Examples of negative regulators for cancer susceptibility genes

Answer 5

Classical tumour suppressor genes
Indirectly acting tumour supressor genes
Apoptotic genes

Question 6

Number of casual contributing cancer genes?

Answer 6

729

Question 7

Role of proto-onocgenes in growth signalling pathways

Answer 7

Promote cell proliferation
Inhibit apoptosis

Question 8

What do oncogenes do

Answer 8

Increase the activity of a specific protein due to mutation

Question 9

Are oncogenes genetically dominant or recessive

Answer 9

Dominant, only 1 allele usually needs to undergo the mutation to contribute to cancer development

Question 10

How do oncogenes drive cell proliferation?

Answer 10

Resist apoptosis
Replicative immortality
Self-sufficient growth signalling
Evade growth suppressors

Question 11

6 Classes of cellular oncogenes

Answer 11

Transcription factors
Growth factors/mitogens
Growth factor/mitogen receptors
Cell death inhibitors
Cell cycle regulators/drivers
Signal transduction component

Question 12

How do proto-oncogenes become oncogenes via genetic changes

Answer 12

Amplification of gene - Overexpression of normal, growth-stimulating protein
Translocation/transposition of gene - Overexpression of normal, growth-stimulating protein
Point mutation - Hyperactive or degradation-resistant protein

Question 13

Mitogen and mitogen receptors

Answer 13

Mitogens stimulate cell division by binding to receptor in cell membrane

EGFRs (Epidermal growth factor receptors) mutated in 40-50% brain tumours, 20% breast cancers, 15-30% ovarian cancers

EGFR mutations can involve amplification or deletion of gene, leading to their being too many or too little receptors for mitogens

Question 14

Signal Transduction components

Answer 14

Signalling protein - Activated by growth factor binding to receptor

Ras inactive when bound to ADP

Raf kinase is responsible for production of ATP from mitogen bound ADP in activating signalling

Ras activation usually transient

Ras intrinsic GTPase hydrolyses GTP to GDP

Question 15

Part 2 signal transduction

Answer 15

30% cancers have Ras mutation

Mutation on codons 12, 13 or 61 can lead to inactive GTPase activity, leading to constant cell signalling and proliferation

Leads to tumour formation

Question 16

Transcription factors with oncogenes

Answer 16

Myc is a protein responsible for cell growth and division

Oncogenes overexpress Myc
Amplification - leads to 100s of copies of oncogene, cancer causing
Point mutation - Stabilizes Myc
Translocation increases gene expression leading to cancer e.g. Burkett’s lymphoma increases mutant B-cell proliferation

Question 17

Cyclin D and Cdk4

Answer 17

Cyclin D overexpression is initiated by CCND1
Found in 35% oesophageal cancers, 15% of breast and bladder cancer
50% in breast cancers
Mutation leads to unauthorized entry to S-phase from G1
CDK4 gene forms Cdk4 in G1 which is amplified in 12% gliomas, 11% sarcomas

Question 18

Restriction point mechanism

Answer 18

1. In G0 and G1, E2F is bound to and inhibited by Rb protein
2. To enter cell cycle, cyclin D associates with Cdk4 or Cdk6
3. Cdk then phosphorylates Rb protein releasing it from E2F
4. E2F is free to transcribe genes for G1/S transition

Question 19

What does overexpression of CCND1 or CDK4 lead to?

Answer 19

Unregulated phosphorylation of Rb protein

Question 20

What is apoptosis and what does it cause?

Answer 20

Programmed cell death which results in controlled cell suicide

-Cells shrink and condense
-Cytoskeleton collapses
-Nuclear envelope disassembles
-Nuclear chromatin condenses and breaks into fragments
- ‘Eat me’ signal - Cell engulfed by macropage

Question 21

Intrinsic vs extrinsic pathway

Answer 21

Intrinsic - Depends on release into cytosol of mitochondrial proteins usually found in intermembrane space
Extrinsic - Triggered by extracellular signal proteins binding to cell surface death receptors

Question 22

What is the intrinsic pathwayof apoptosis inhibited by?

Answer 22

Bcl2 proteins
Proto-oncogenes - Anti-apoptotic
Tumour-suppressor genes - Pro-apoptotic

Bax-Bax homodimer -> Apoptosis -> cells die

Bax-Bcl2 heterodimer -> Normal cell

Bcl2 overexpression -> Apoptosis blocked -> Cell immortalized

Question 23

How does MDM2 regulate TSG activity

Answer 23

1. MDM2 ubiquitinates lysines in p53 C-terminal domain
2. Any remaining p53 exported from nucleus
3. MDM2 and p53 phosphorylated
4. p53 accumulates
5. MDM2 found to amplify in 19/28 tumour types
6. MDM2 mutations prevent p53 accumulation

Question 24

What is hayflick limit

Answer 24

Normal cells cease to divide after 50-70 doublings

Question 25

What happens to telomerases after division

Answer 25

Get shorter

Question 26

What occurs with senescent behaviours

Answer 26

1. telomerases change shape
2. Shortening becomes critical and cells withdraw from cycle
3. Cancer cell immortalisation caused by increased gene expression of telomerases by oncogenic mutations

Question 27

What cancer types are there increased telomerase expression?

Answer 27

All major cancer types