Cellular + Molecular events in carcinogenesis

Question 1

What is the reason for the long interval between exposure to a carcinogen and clinical recognition of the tumour

Answer 1

Tumours result from clonal proliferation of single cells

It takes a large time for one cell to grow into a nodule of cells

Question 2

Describe the initiation stage of tumour formation

Answer 2

1. When carcinogens induce a genetic alteration that gives transformed cell neoplastic potential

Question 3

Describe the promotion stage of tumour formation

Answer 3

1. Stimulation of clonal proliferation of the initiated transformed cell

Question 4

Describe the progression stage of tumour formation

Answer 4

1. Process culminating in malignant behaviour characterised by invasion and its consequences

Question 5

How does successive applications of a carcinogen and promotor cause a malignant tumour on a mouse

Answer 5

1. A single application results in a visible tumour if it is followed by repeated painting of the site with the promotor
2. Carcinogen is the initiator which induces the lesions on the DNA of target cells
3. Promoter is the one that promotes the growth of the initiated cells - further events lead to malignancy

Question 6

How many genetic alterations are needed to transform a normal cell to a neoplastic cell and what are they

Answer 6

Many:

1. Expression of telomerase
2. Loss or inactivation of both copies of a tumour suppressor gene to remove inhibitory control of cellular replication
3. Activation or abnormal expression of oncogenes to self-stimulate cell proliferation

Question 7

How do tumour suppressor gene inactivation and abnormal oncogene expression work together to form neoplastic cells

Answer 7

Drive cells from their normal state of regulated growth to deregulated and uncontrolled growth

Question 8

How is genomic instability effected by age

Answer 8

Increases with age

Question 9

What are the two types of tumour suppressor genes

Answer 9

Caretaker

Gatekeeper

Question 10

What are caretaker genes

Answer 10

Maintain the integrity of genome by repairing DNA damage

Question 11

Role of BRCA 1

Answer 11

Tumour suppressor caretaker gene involved in DNA repair

Question 12

Role of BRCA2

Answer 12

Involved in DNA repair

Question 13

Mutation of BRCA1 and BRCA2 can cause what

Answer 13

Breast, prostate and pancreatic cancer

Question 14

What are gatekeeper genes

Answer 14

Genes inhibiting the proliferation or promote the death of cells with damaged DNA

Question 15

What is p53

Answer 15

Transcription factors that responds to DNA damage

Question 16

Where is p53 found

Answer 16

Chromosome 17

Question 17

What are the normal functions of p53

Answer 17

1. Repair of damaged DNA before S phase in the cell cycle by arresting it in G1 until damage is repaired
2. Apoptotic cells each if there is extensive DNA damage

Question 18

What happens to p53 levels in cells with sustained DNA damage

Answer 18

They rise until damage is repaired or cell goes through apoptosis

Question 19

How can p53 lose its function

Answer 19

Non-sense mutation - Unreadable
Missense mutation - defective protein

Complexes of normal and mutant p53 prevent normal function

Binding of normal p53 to proteins encoded by oncogenic DNA viruses

Question 20

What syndrome does INHERITED mutation of p53 result in

Answer 20

Li-fraumeni syndrome

Question 21

What is RB1

Answer 21

Transcriptional regulatory - controls cell cycle G1/S checkpoint

Question 22

What are RB1 associated with

Answer 22

retinoblastoma

Question 23

What are retinoblastoma

Answer 23

Bilateral Malignant tumours derived from the retina in children

Question 24

When can retinoblastoma become unilateral

Answer 24

Sporadic when there’s no family association

Question 25

What usually results in hereditary retinoblastoma

Answer 25

gremlin deletion on chromosome 13 where RB1 gene is

Only one further mutational loss is needed in any target retinal cell for a tumour to develop

Question 26

What do sporadic retinoblastoma requires in order for a tumour to develop

Answer 26

They have two normal chromosome 13s and require 2 mutations or losses of RB1 in the same cell

Question 27

Where are oncogenes found

Answer 27

In oncogenic RNA retroviruses which have th ability to transfer theirs or parts of their genomes to cells they infect

Question 28

How do oncogenic RNA retroviruses infect host cell genomes

Answer 28

1. Reverse transcriptase that enables viral RNA to be reverse transcribed into complementary DNA which is incorporated into genome

Question 29

What are five types of oncoprotein

Answer 29

1. Growth factors
2. Receptors for growth factors
3. Signalling mediator with tyrosine kinase activity
4. Nuclear-binding transcription factor oncoprotein
5. Signalling mediator with nucleotide binding activity

Question 30

How can oncogenes be activated

Answer 30

1. Mutation resulting in an oncoprotein molecule altered in such a way that it is excessively active
2. Excessive production of a normal oncoprotein because of gene amplification or enhanced transcription

Question 31

How common is oncogene activation

Answer 31

Present in most tumours

Question 32

Describe the translocation mechanism of oncogene activation

Answer 32

1. If an oncogene is translocated from an untranscribed site to a position adjacent to an actively transcribed gene (e.g. in Burkitt’s lymphoma where oncogene is translocated form chromosome 8 to 14 and placed adjacent to one of the immunoglobulin genes

Question 33

What is the point mutation mechanism of oncogene activation

Answer 33

1. E.g. in codon 12 of ras oncogene where substitution of a single base is translated into amino acid substitution causing it to become hyperactive

Question 34

What is the amplification mechanism of oncogene activation

Answer 34

Insertion of multiple copies of the oncogene resulting in cellular proliferation stimulated by excessive quantities of the oncoprotein