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
eg if DNA polymerase is copying the gene and then something is blocking it, it will then go back to the starting point and try again and this will repeat until the barrier has been overcome

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 ie basically fusion 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 fusion 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

Question 6

State some important proto-oncogenes involved in human cancers and what they normally code for

Answer 6

SRC - tyrosine kinase receptor
MYC - tyrosine kinase receptor
JUN- transcription factor
Ha-RAS- G protein of the GPCR
Ki-RAS - G protein of the GPCR
look at slide 13 for more details on what cancers they are associated with

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
Rb1 codes for a protein that regulates the cell cycle

Question 9

What are the functional classes of tumour suppressor genes? (ie what functions do tumour suppressor genes have)

Answer 9

Regulate cell proliferation  
Maintain cellular integrity  
Regulate cell growth  
Regulate the cell cycle  
Nuclear transcription factors  
DNA repair proteins  
Cell adhesion molecules  (important for invasion and metastasis of cancer)
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

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.). P53 is normally bound to MDM2 which makes it inactive. Various stimuli (eg detect oncogene activated) will signal MDM2 to release p53. when it is released, it dimerises with other 53 and it then upregulates transcription in some genes involved in eg growth arrest, DNA repair etc.

P53 regulates genes involved in:
DNA repair
Growth arrest
apoptosis
metabolic homeostasis
antioxidant defence

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
(most TSG follow two hit hypothesis)

Question 14

What type of mutation normally causes loss of the APC gene?

What condition is this mutation associated with?

Answer 14

deletion in 5q21

FAP - familial adenomatous polyposis

Question 15

What is APC involved in?

Answer 15

Cell adhesion   (important in metastasis and invasion of cancer)
Cell signalling

Question 16

What is the risk of people with this 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 tcf-4 and promote uncontrolled proliferation

Question 19

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

Answer 19

APC mutations –> hyperproliferative epithelium (benign at this stage)
DNA hypomethylation + K-ras mutation will make the polyps –> adenomas (still benign)
P53 mutation will result in the progression from adenoma to a MALIGNANT carcinoma

Question 20

Outline the ways for a proto oncogene to be activated

Answer 20

1. Mutations in coding sequence (point mutation/deletion/insertion etc)
2. Gene amplification
3. Chromosomal translocation leading to chimeric genes (fusion genes)
4. Insertional mutagenesis from eg viral infection

Question 21

Outline the RAS and RAF pathway and how it changes in cancer

Answer 21

RAS-GTP complex= active, will activate RAF and cause cell proliferation
RAS-GDP complex= inactive

Dephosphorylation of the GTP to GDP switches RAS off.
Mutant RAS fails to dephosphorylate GTP and remains active.

Question 22

features of inherited cancers?

Answer 22

1. family history
2. unusually early onset
3. bilateral tumours in paired organs eg both kidneys with cancer
4. Synchronous or successive tumours. Ie continuous relapse of tumour in the same organ, this is because the same genes of the organ have lost their tumour suppressing abilities
5. Tumours in different organ systems in same individual.