Oncogenes and Tumour Suppressors

Question 1

What are the hallmarks of cancer

Answer 1

Sustaining proliferative signalling
Evading growth suppressors and apoptosis
Resisting Cell Death 
Inducing angiogenesis Enabling replicative immortality 
Activating invasion and metastasis

Question 2

Where are the checkpoints in the cell cycle and what is their purpose

Answer 2

At the end of G1, S, and the end of G2

Ensures genetic fidelity

Question 3

What is the role of cyclins in cell cycle checkpoints

Answer 3

Proteins accumulate or are destroyed during the cycle, including cyclins, cyclin-dependent kinases, and cyclin-dependent kinase inhibitors.
Activation of a cyclin can drive a cell through a checkpoint.

Question 4

What are proto-oncogenes

Answer 4

Proto-oncogenes code for essential proteins involved in maintenance of cell growth, division and differentiation

Question 5

What does a mutation in proto-oncogenes result in

Answer 5

Conversion to oncogenes, whose protein product does not respond to control influences

Question 6

Give examples of oncogenes

Answer 6

MYC
RAS
ERB
SIS

Question 7

What are the ways in which proto-oncogenes can be converted to oncogenes

Answer 7

Deletion 
Point mutation 
Gene amplification
Insertional mutagenesis (from viral infection)
Chromosomal translocation

Question 8

What does a deletion or point mutation in the coding sequence for a proto-oncogene lead to

Answer 8

aberrantly active protein

Question 9

What does gene amplification in the coding sequence for a proto-oncogene lead to

Answer 9

overproduction of the protein

Question 10

What does insertional mutagenesis or chromosomal translocation in the coding sequence for a proto-oncogene lead to

Answer 10

Formation of:
Chimaeric genes, which may just lead to a rise in protein level (e.g. Burkitt’s lymphoma)
or
A new fusion protein (e.g. by the Philadelphia chromosome)

Question 11

Describe the Philadelphia chromosome and how an mutation may lead to cancer

Answer 11

Chromosome 9 and 12
2 Key areas: ABL and BCR region
Occasionally, there is chromosomal translocation, and ABL swaps over to chromosome 22.
The result of the combination of BCR and ABL leads to cancer

Question 12

What is the effect of proto-oncogenes on signal transduction pathways

Answer 12

Activation of proto-oncogenes to oncogenes disrupts normal activity. These oncogenes may interfere with any of the signal transduction pathways

Question 13

Describe the RAS pathway and why a mutation may lead to tumour formation

Answer 13

Ras is a protein produced by a proto-oncogene.
It’s a membrane-bound GTP-ase linked to cell proliferation.
When Ras dephosphorylates GTP to GDP (during activation of RAF), it is switched off
Mutant Ras is unable to dephosphorylate and therefore remains active when it shouldn’t be

Question 14

Give some examples of proto-oncogenes

Answer 14

SRC
MYC
JUN
Ha-RAS
Ki-RAS

Question 15

What are tumour suppressor genes

Answer 15

Tend to be inhibitory, where the coded proteins whose function is to regulate cellular proliferation, maintain cell integrity E.g. RB

Question 16

How many copies of the tumour suppressor gene are there in a cell and how does it affect the result of a mutation

Answer 16

Each cell has two copies of each tumour suppressor gene.
Mutation or deletion of one gene copy is usually insufficient to promote cancer.
Mutation or loss of both copies means loss of control.

Question 17

What do cancers due to tumour suppressor gene damage often present with

Answer 17

Family history of related cancers
Tumours earlier in life than usual
Tumours in multiple organ systems
Bilateral tumours occurring in paired organs

Question 18

Give an example of Knudsons two hit hypothesis

Answer 18

retinoblastoma
hereditary/sporadic - involves one eye
Hereditary - unilateral or bilateral and multifocal

Question 19

What is retinoblastoma and what is it due to

Answer 19

Malignant cancer of developing retinal cells, which is due to either sporadic or hereditary disease
Due to the mutation of the RB1 tumour suppressor gene on chromosome 13914
RB1 encodes a nuclear protein that is involved in the regulation of the cell cycle

Question 20

What does retinoblastoma present as and what is the treatment

Answer 20

Presents as a chalky eye, and treatment requires removal of the eye.

Question 21

Why are proto-oncogenes rarely hereditary but tumour suppressor genes sometimes hereditary

Answer 21

Proto-oncogene mutation is rarely hereditary, as you’d be born as a ball of cancer.
TS gene mutations can be passed on because of the need for both copies to be damaged before disease develops.

Question 22

What must TS genes be able to do in order to suppress the neoplastic phenotype (functional classification)

Answer 22

Regulate cell proliferation, growth, and the cell cycle
Maintain cellular integrity
Regulate cell death (apoptosis)
Act as nuclear transcription factors, DNA repair proteins, or cell adhesion molecules

Question 23

Describe the p53 gene

Answer 23

Known as the guardian of the genome
Works in conjunction with MDM2
Involved in regulating p53 target genes and protein-protein interactions
Mutated in most cancers

Question 24

Explain why mutants of p53 are shown in phenotype easily

Answer 24

Mutants of p53 act in a dominant manner and mutation of a single copy is sufficient to get dysregulation of activity (this is because it forms a dimer)

Question 25

What is a common mutation in the APC gene and what doe sit result in

Answer 25

Due to a deletion in 5q21 resulting in loss of APC gene (tumour suppressor gene).
Involved in cell adhesion and signalling

Sufferers develop multiple benign adenomatous polyps of the colon and there is a 90% risk of developing colorectal carcinoma.

Question 26

By which pathway do APC proteins act in and what does it do

Answer 26

WNT signalling pathway to alter transcription and growth

APC protein is a negative regulator of b-catenin, thereby preventing uncontrolled cell division.

Question 27

Compare oncogenes to TS genes

Answer 27

Genes active in tumour vs inactive
Specific translocations/point mutations vs deletions
Mutations rarely hereditary vs inherited possible
Dominant at all cell levels vs recessive
Broad tissue specificity vs considerable
Leukaemia and lymphoma vs solid

Question 28

Give some examples of TS genes

Answer 28

p53
BRCA1
PTEN
APC
P16-INK4A
MLH1