Oncogenes and tumour suppressors

Question 1

What are the basic hallmarks of the cancer cell phenotype?

Answer 1

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 2

What are proto-oncogenes?

Answer 2

Code for essential proteins involved in maintenance of cell growth, division and differentiation.
Critical gene target.
Mutation converts proto-oncogene to an oncogene.

Question 3

What are oncogenes?

Answer 3

Protein product no longer responds to control influences. Proto-oncogenes can be converted to an oncogene by a single mutation.
Can be aberrantly expressed, over-expressed or aberrantly active.

Question 4

How are oncogenes activated?

Answer 4

Mutation in the coding sequence (point mutation of deletion).
Gene amplification (multiple gene copies).
Chromosomal translocation (chimeric genes).
Insertional mutagenesis (e.g. viral infection).

Question 5

What are the functional classes of proto-oncogenes?

Answer 5

Growth factors
Growth factor receptors
Intracellular transducers (signalling proteins)
Intracellular receptors
Transcription factors
Cell cycle regulatory proteins
Cell death regulators

Question 6

How does RAS become active?

Answer 6

Binding GTP

Question 7

What switches RAS off?

Answer 7

Dephosphorylation/hydrolysis of GTP to GDP

Question 8

What can make RAS oncogenic?

Answer 8

Mutant RAS fails to dephosphorylate/hydrolyse GTP and remains inappropriately active- increased proliferation stimulus.
Mutant RAS has aberrant activity.

Question 9

What are tumour suppressor genes?

Answer 9

Typically proteins whose function is to regulate cellular proliferation, maintain cell integrity, e.g. RB.

Question 10

What is the 2-hit hypothesis?

Answer 10

Each cell has 2 copies of each tumour suppressor gene.
Mutation or deletion of one gene copy is usually insufficient to promote cancer, unless the mutant gene acts dominant (e.g. p53).
Mutation or loss of both copies means loss of control.

Question 11

What are the functional classes of tumour suppressor genes?

Answer 11

Regulate cell proliferation.
Maintain cellular integrity.
Regulate cell growth.
Regulate cell cycle.
Nuclear transcription factors.
DNA repair proteins.
Cell adhesion molecules.
Cell death regulators.
Suppress the neoplastic phenotype.

Question 12

What is the most commonly mutated tumour suppressor gene in human cancer?

Answer 12

p53

>50% of all tumours

Question 13

What does loss of APC tumour suppressor gene result in?

Answer 13

Familial adenomatous polyposis (FAP).
Sufferers develop benign adenomatous colon polyps.
Become highly susceptible to colon cancer later in life- 90% risk of colorectal carcinoma.

Question 14

Why is the APC tumour suppressor gene important?

Answer 14

Participates in WNT signalling pathway.
Helps control activity of beta-catenin, preventing uncontrolled growth.
Involved in cell adhesion and signalling.