Oncogenes and Tumour Suppressor Genes

Question 1

6 hallmarks of cancer

Answer 1

SPINAP
Self-sufficient (Sustaining proliferative signalling)
Pro-invasive + metastatic
Insensitive to anti-growth signals
Non-senescent (Enabling replicative immortality)
Anti-apoptotic
Pro-angiogenic

Question 2

What is gene amplification?

Answer 2

Production of multiple gene copies

overproduction of normal protein

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= Chromosomal translocation)

Question 4

When can the formation of chimeric genes be a problem?

Answer 4

1. If 1 of the pieces of translocated DNA is a promoter, it could lead to upregulation of another gene portion (e.g. 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 chr 9 (promotor) to the BCR gene on chr 22 (anti-apoptotic)
The BCR-ABL fusion gene encodes a protein that promotes development of cancer

Question 6

State 5 important oncogenes in human cancers and their functions

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 TSG

on Chr 13q14

Question 9

What are the 8 functional classes of tumour suppressor genes?

Answer 9

Regulate cell proliferation   
Regulate cell growth  
Regulate cell cycle  
Maintain cellular integrity 
Nuclear transcription factors  
DNA repair proteins  
Cell adhesion molecules  
Cell death regulators 
All these functions suppress the neoplastic phenotype

Question 10

State 4 important tumour suppressor genes in human cancers

Answer 10

P53: cell cycle regulator
BRCA1: cell cycle regulator
PTEN: tyrosine + 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

Regulation of p53 target genes (involved in DNA repair, growth arrest, senescence etc.) + 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 loss of 5q21 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

Breaks down beta-catenin so that it doesn’t bind to LEF1 + promote uncontrolled proliferation

Question 19

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

Answer 19

APC mutations –> hyperproliferative epithelium
DNA hypomethylation + K-ras mutation cause polyp formation–> adenomas
P53 mutation will result in the development of carcinoma

Question 20

What are the 4 emerging hallmarks of cancer?

Answer 20

DIE U
Dysregulated metabolism  (less dependent on aerobic resp.)
Inflammation 
Evades immune system 
Unstable DNA

Question 21

What do proto-oncogens code for?

Answer 21

Essential proteins involved in maintenance of cell growth, division + differentiation

Question 22

How is a protein product coded for by an oncogene different to that coded for by a proto-oncogene?

Answer 22

Protein no longer responds to control influences

Question 23

In what ways can oncogenes be expressed?

Answer 23

Aberrantly expressed
Over-expressed
Aberrantly active

Question 24

What is required to convert a proto-oncogene to an oncogene?

Answer 24

A single mutation

Question 25

How could a viral infection convert a proto-oncogene to an oncogene?

Answer 25

Insertional mutagenesis

Question 26

How is mutant Ras different to normal Ras?

Answer 26

Normal Ras becomes active on binding GTP
Dephosphorylation to GDP switches Ras off
Mutant Ras fails to dephosphylate GTP + remains aberrantly active

Question 27

What is the function of tumour suppressor genes?

Answer 27

Regulate cellular proliferation + maintain cell integrity

Each cell has 2 copies of each TSG

Question 28

What has to happen to tumour suppressor genes to cause cancer?

Answer 28

Mutation of both copies of a TSG results in loss of control

Question 29

What is haploinsufficiency?

Answer 29

Where 1 mutated copy of a TSG is sufficient to promote cancer

Question 30

What does Knudson’s 2 hit hypothesis show?

Answer 30

Sporadic cancer: Requires two acquired mutations of the same gene
Hereditary cancer: Requires an acquired mutation to a TSG that already has 1 inherited mutant form

Question 31

What are 6 features of inherited cancer susceptibility?

Answer 31

FH of related cancers
Unusually early age of onset
Bilateral tumours in paired organs
Synchronous/ successive tumours
Tumours in different organ systems
Mutation inherited through germline

Question 32

Describe the state, mutations required, specificity and types of cancer associated with oncogenes

Answer 32

Gene active in tumour
Specific translocations/ point mutations
Mutations rarely hereditary
Dominant at cell level
Broad tissue specificity 
Leukaemia + lymphoma

Question 33

Describe the state, mutations required, specificity and types of cancer associated with tumour suppressor genes

Answer 33

Gene inactive in tumour
Deletions or mutations
Mutations can be inherited
Recessive at cell level
Considerable tissue specificity 
Solid tumours