Lecture 27

Question 1

Are all genetic changes which occur in cancer random?

Answer 1

No there are some non-random changes reflecting specific gene alterations

Question 2

What can cause gene amplification in cancer?

Answer 2

Extra chromosomes in which the gene is found
Multiple small (double minute) chromosomes which contain the relevant gene
Multiple copies of the gene arranged in a head to tail fashion in a chromosome

Question 3

How does gene amplification affect cancer with regards to EGFR?

Answer 3

This gene is often amplified in cancer, this protein binds EGF and TGFalpha resulting in tyrosine kinase activity which induces cell growth

Question 4

How does gene activation by deletion affect EGFR in cancer?

Answer 4

The ligand binding domain of the protein is lost, this results in loss of ligand regulation for the tyrosine kinase activity driving uncontrollable growth

Question 5

What is the role of chromosome translocation in cancer?

Answer 5

Many characteristic transloactions are seen in cancer which results in the misregulation of genes as they are placed in new environments

Question 6

How does chromosome transloaction play a role in Mantle cell lymphomas?

Answer 6

A t(11;14) mutation occurs where a section of c11 which contains BCL-1 is combined with a section on c14 resulting in BCL-1 being regulated by the IgH gene

Question 7

How does point mutation lead to cancer?

Answer 7

Some genes such as RAS reqire only a single mutation to cause disease

Question 8

Where can the oncogenic mutations occur in RAS?

Answer 8

1 of 3 locations:

codon 12.13 or 61

Question 9

What is the difference between a partially transformed cell and a fully transformed cell?

Answer 9

A partially transformed cell has been immortalized while a fully transformed cell has undergone further oncogenic mutations which reduce dependance on growth factors,
reduce density-dependent inhibition of proliferation causing cells to form multiple layers,
Reduced adherence to substrate,
anchorage independant proliferation,
tumour formation in mice

Question 10

What is an example of genetic inactivation inducing a cancer?

Answer 10

Retinoblastoma which is a rare cancer of the eye in children, caused by los of a normal RB1 gene

Question 11

What is the pathogenesis of retinoblastoma?

Answer 11

The RB1 allele is lost on both chromosomes (one of these may be due to an inherited mutation)
inherited retinoblastoma develops in a single hit pattern as only one functional RB1 gene is inherited
Sporadic retinoblastoma requires two hits as both copies of the RB1 gene must undergo a mutation

Question 12

What is an example of genetic inactivation via promoter methylation causing cancer?

Answer 12

Some cancers will have a functional RB1 gene but as the promoter is methylated they will not express its product as cytosines in the promoter are methylated resulting in the binding of repressors

Question 13

What is the normal function of proto-oncogenes?

Answer 13

Activate proliferation

Suppress differentiation

Question 14

What is the normal function of tumour suppressor genes?

Answer 14

Inhibit proliferation

Promote differentiation

Question 15

What is the mechanism for oncogenic change in proto-oncogenes?

Answer 15

Amplification
Or deregulated activity (EGFR domain deletion)
Translocation (cyclin D)
Point mutation (Ras)

Question 16

What are the changes to protein functions in proto-oncogenes that typically induce cancer?

Answer 16

Mutation gives increased or altered activity, typically gain of function

Question 17

What changes to cell behaviours are induced by proto-oncogenes in cancer?

Answer 17

Drives abnormal cell growth

Question 18

What is the mechanism for oncogenic change in tumour suppressor genes?

Answer 18

Gene silencing by methylation (RB1)

Question 19

What are the changes to protein functions in tumour suppressor genes that typically induce cancer?

Answer 19

Mutation gives less activity or loss of function

Question 20

What changes to cell behaviours are induced by tumour suppressor genes in cancer?

Answer 20

Releases cells to an abnormal phenotype

Question 21

What are the 4 stages of the cell cycle?

Answer 21

Mitosis, Gap1 (G1), S (DNA Synthetic Phase), G2

Question 22

What occurs in mitosis?

Answer 22

Culmination in cytokiensis where two daughter cells are produced

Question 23

What occurs in G1 phase?

Answer 23

Cells sense the environment for growth factors, space and substrate attachment to determine if they should enter cell division or not
If non-proliferating state is enetered then the cell remains in a G0 phase

Question 24

What is the restriction point?

Answer 24

The point in the G1 phase where the cell decides if it will enter another round of cell division or not control of this point is lost in cancer

Question 25

What occurs in the S phase?

Answer 25

DNA is replicated in preparation for cell division | These cells can be recognised by providing marked DNA precursors

Question 26

What occurs in the G2 phase?

Answer 26

Quality control pathways check the competion of replication, and cells prepare for mitosis

Question 27

How is control over the cell cycle regulated?

Answer 27

Cyclin dependant kinases which contain both catalytic and regulatory units These proteins oscillate in concentration reaching peaks at G1/S tansition, S phase, G2/Mitosis transition

Question 28

What are the different cyclin-dependant kinases and when do they reach there peaks?

Answer 28

G1/S- Cyclin E-Cdk2 During S phase- cyclin A-Cdk2 G2/M- cyclin B-Cdk1

Question 29

What is the role of growth factors with regards to the cell cycle?

Answer 29

Promotion of cell division (mitogenic compounds), this action is down via receptor dimerisation, TK activation, receptor phosphorylation and phosphorylation of signalling molecules

Question 30

What may cause the EGFR to show excessive tyrosine kinase activity in cancer?

Answer 30

High concenctrations of growth factors High concentrations of receptors Mutant receptors lacking the ligand-binding domain mutant receptor with signal base changes in the TK domain

Question 31

What is the relationship between RAS proteins and Growth Factor Receptors?

Answer 31

These integrate signals from GF receptors, receptor activation causes RAS to bind GTP inducing a conformational change so that other signalling molecules can cause progression through the cell cycle This stops when RAS hydrolyses GTP, in cancer this function is impaired

Question 32

What is the function of the BCL-1 gene?

Answer 32

Activated via RAS signalling, encoding cyclin D1 which results in the activation of Cyclin-dependent kinase Cdk4 stimualting entry int othe cell cycle I cancer regulation of this process and therefore entry into the cell cycle is lost

Question 33

What is the function of the RB gene product?

Answer 33

``` pRb protein (from RB1 gene) exists in two forms which change within the cell cycle In early G1 it is weakly phosphorylated preventing entry into the cycle In late G1 it is heavily phosphorylated (ppRb) allowing entry into the cycle ```

Question 34

What is the kinase that phosphorylates pRb and thus stimulates entry into the cell cycle?

Answer 34

Cyclin D (Cdk4) this phosphorylation eventually allows for the transcription of genes needed for the S phase of the cell cycle including cyclin E