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

Chromosomal translocation
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

1. 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)
2. 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 protein that promotes the development of cancer
-Example of Insertional Mutagenesis!

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

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 gene

13q14

Question 9

What are the functional classes of tumour suppressor genes?

Answer 9

1. Regulate cell proliferation
2. Maintain cellular integrity
3. Regulate cell growth
4. Regulate the cell cycle
5. Nuclear transcription factors
6. DNA repair proteins
7. Cell adhesion molecules
8. Cell death regulators

Question 10

State some important tumour suppressor genes in human cancers

Answer 10

1. P53 – cell cycle regulator
2. BRCA1 – cell cycle regulator
3. PTEN – tyrosine and lipid phosphatase
4. APC – cell signalling

Question 11

In what form is p53 inactive?

Answer 11

When it is bound to MDM2

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)

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 the APC mutation developing colon cancer?

Answer 16

90%

Question 17

What signalling pathway is APC involved in?

Answer 17

WNT signalling

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

1. APC mutations –> hyperproliferative epithelium
2. DNA hypomethylation + K-ras mutation will make the polyps –> adenomas
3. P53 mutation will result in the development of carcinoma
4. Metastasis

Question 20

What are the four ways in which a normal photo-oncogene can be activated?

Answer 20

1. Mutation in coding sequence
   - point mutation or deletion
2. Gene amplification
   - protein may block DNA polymerase so it repeatedly backs up over same area a few times creating many identical genes
3. Chromosomal Translocation
   - chimeric genes
4. Insertional Mutagenesis
   - vial infections, viruses may insert genome into our DNA which is fine as most of our DNA doesn’t code, if inserted into coding region could cause cancer

Question 21

Give an example of insertional mutagenesis?

Answer 21

Philadelphia chromosome

Question 22

What class of genes are signal transduction proteins?

Answer 22

Proto-oncogenes

Question 23

Give an example of a cancer caused by a chromosomal translocation

Answer 23

Burkitt’s Lymphoma

Question 24

What gene and class is important in Burkitt’s Lymphoma?

Answer 24

MYC, its a transcription factor and class is ONCOGENE

Question 25

Describe the normal pathway of RAS and explain what happens with mutant RAS

Answer 25

Upon binding GTP, Ras becomes active
This binding allows Ras to bind Raf and deliver signal to Mek and Erk
Dephosphorylation of GTP to GDP unbinds Raf from Ras
Mutant Ras fails to dephosphorakate GTP and remains active and bound to Raf and hence drives proliferation

Question 26

What is the function of TSG’S?

Answer 26

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

Question 27

What is the function of proto-oncogenes?

Answer 27

Encode essential proteins involved in maintenance of cell growth, division and differentiation

Question 28

How do you go from a proto-oncogene to an oncogene and what does this mean?

Answer 28

PO’s can be converted to oncogenes by a SINGLE mutation
Oncogene’s protein product does NOT respond to control influences
Oncogenes can be aberrantly expressed, over expressed or aberrantly active

Question 29

What does RB1 encode?

Answer 29

Nuclear regulation protein

Question 30

Where are mutation’s in APC commonly seen?

Answer 30

Colon cancer

Question 31

What are the differences between Oncogenes and Tumour Suppressor genes?

Answer 31

Oncogene vs TSG

1. Gene active in tumour VS Gene inactive in tumour
2. Specific translocations/point mutations VS Deletions or mutations
3. Mutations rarely hereditary VS Mutations can be inherited
4. Dominant at cell level VS Recessive at cell level
5. Broad tissue specificity VS Considerable tumour specificity
6. Leukaemia and lymphoma VS Solid tumours