Oncogenes and Tumour Suppressor Genes

Question 1

What are the six hallmarks of cancer?

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 is gene amplification?

Answer 2

Production of multiple gene copies

Question 3

What are chimeric genes?

Answer 3

Genes that are formed by combinations of portions of one or more coding sequence to produce new genes (e.g. the swapping of tips of chromosomes)

Question 4

When can the formation of chimeric genes be a problem?

Answer 4

If one of the pieces of translocated DNA is a promoter, it could lead to upregulation of the other gene portion (this occurs in Burkitt’s lymphoma)

If the fusion gene codes for an abnormal protein that promotes cancer

Question 5

What is the Philadelphia Chromosome?

Answer 5

Chromosome produced by the translocation of the ABL gene on chromosome 9 to the BCR gene on chromosome 22

The BCR-ABL fusion gene encodes a tyrosine kinase receptor that does not switch off and thus drives uncontrolled proliferation–CML

Question 6

State some important oncogenes in human cancers.

Answer 6

SRC – tyrosine kinase  
Myc – transcription factor  
JUN – transcription factor 
Ha-Ras – membrane bound GTPase 
Ki-Ras – membrane bound GTPase  

these are signal transduction proteins

Question 7

What is an example of an inherited cancer?

Answer 7

Retinoblastoma – malignant cancer of the developing retinal cells

Question 8

What mutation causes retinoblastoma?

Answer 8

RB1 TSG gene on Chr 13q14

Question 9

What are the functional classes of tumour suppressor genes?

Answer 9

Regulate cell proliferation

Maintain cellular integrity

Regulate cell growth

Regulate the cell cycle

Nuclear transcription factors

DNA repair proteins

Cell adhesion molecules

Cell death regulators

Question 10

State some important tumour suppressor genes in human cancers

Answer 10

P53 – cell cycle regulator

BRCA1 – cell cycle regulator

PTEN – tyrosine and lipid phosphatase

APC – cell signalling

p16-INK4- cell cycle regulator (CDK-I)

MLH1- mismatch repair

Question 11

In what form is p53 inactive?

Answer 11

When it is bound to MDM2, dissociates when cell is under stress

Question 12

What is p53 important for?

Answer 12

It is important for regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) and protein-protein interactions (e.g. apoptosis)

mutation of a single gene is enough to make it cause cancer despite being a TSG

Question 13

What is odd about p53 considering it is a tumour suppressor gene?

Answer 13

It acts in a DOMINANT manner –mutation of a single copy is sufficient to achieve dysregulation of activity

Question 14

What deletion causes loss of the APC gene?

Answer 14

5q21

Question 15

What is APC involved in?

Answer 15

Cell adhesion

Cell signalling

Question 16

What is the risk of people with this mutation (APC) developing colon cancer?

Answer 16

90%

Question 17

What signalling pathway is APC involved in?

Answer 17

WNT signalling- helps control beta-catenin

Question 18

What is the main role of APC that prevents uncontrolled growth?

Answer 18

It breaks down beta-catenin so that it doesn’t bind to LEF1 and promote uncontrolled proliferation

Question 19

Describe the step-by-step development of colorectal cancer.

Answer 19

• APC mutations –> hyperproliferative epithelium–> Polyps
• K-ras mutation (+DNA hypomethylation )will make the polyps –> adenomas
• P53 mutation will result in adenoma–> carcinoma
• carcinoma–> metastasis

Question 20

what are the 4 ways oncogenes can be activated

Answer 20

1. mutation in coding sequence
2. gene amplification
3. chromosomal translocations
4. insertional mutagenesis (eg viral infections)

Question 21

how does a defect/ mutation in Ras cause cancer

Answer 21

when bound to GTP, Ras becomes active–> binds Raf–>activates ERK–>proliferation

therefore dephosphorylation of GTP–>GDP deactivates Ras –> unbinds from Raf and prevents ERK cascade activation

mutated Ras fails to dephosphorylate GTP and hence stays bound to Raf and keeps activating ERK and driving phosphorylation

Question 22

what do TSG’s usually encode

Answer 22

TSGs encode proteins whose function is to regulate cellular proliferation and maintain cell integrity

Question 23

what do (proto)oncogenes usually encode

Answer 23

Proto-oncogenes code for essential prot

eins involved in maintenance of cell growth, division and differentiation