Biology 4 - Cancers are Genetic Diseases II (Keith Spriggs)

Question 1

What causes cancer?

Answer 1

Abnormal proliferation and survival of cells as a result of changes in gene expression and gene function.

Question 2

What is the difference between genetic and inherited?

Answer 2

Cancers are genetic; mutations normally arise in somatic cells - for a cancer to be inherited the mutation would have to arise in a gamete.

Question 3

How many mutations are needed in order for them to have an effect?

Answer 3

Atleast two mutations are necessary to initiate cancer e.g. a RAS-like oncogene (cytoplasmic) and an MYC-like oncogene (nuclear).

Question 4

On average, how many mutations are needed in order to cause cancer in adults?

Answer 4

4 or 5

Question 5

How can cancerous mutations be described as a ‘vicious circle’?

Answer 5

> 100 genes in a cell contribute to DNA repair
If one of these was to mutate then it could predispose to a higher mutation rate allowing further tumour progression.
Without genes that are able to repair DNA then the chromosome can become unstable. (Fusion, breaking, instability)

Question 6

What changes to genetic information can have profound effect on the cell behaviour?

Answer 6

Gene amplification, deletion, chromosome rearrangements, small mutations at critical sites.

Question 7

What is p53?

Answer 7

A transcription factor

Question 8

What is the most mutated gene is human cancers?

Answer 8

TP53

Question 9

What is a hotspot residue? Give an example

Answer 9

A residue that, if mutated, is more likely to lead to cancer. In TP53, R175 is a hotspot residue.

Question 10

What happens in a ‘loss of function’ mutation in p53?

Answer 10

Loses its function as a tumour supressor

Question 11

What happens in a ‘gain in function’ mutation of p53?

Answer 11

Gains oncogene activity - it does this by antagonising unmutated p53 function by aberrant binding to DNA or proteins.
STOPS normal functioning p53.

Question 12

What is INK4?

Answer 12

INK4 is a family of cyclin-dependent kinase inhibitors (CKIs).

Question 13

What is the role of INK4?

Answer 13

Inhibit cyclin-dependent kinase

• Prevent cell cycle progression
• Prevent Rb phosphorylation
• Tumour suppressor

Question 14

What happens to INK4 in cancers?

Answer 14

INK4 deletion

Question 15

What is p16?

Answer 15

Part of the INK4 family of cyclin-dependent kinase inhibitors - it is a tumor suppressor protein

Question 16

What gene is amplified in approximately 7% of all cancers?

Answer 16

MDM2 amplification

Question 17

What is the consequence (balance) of more MDM2 when it is amplified in cancer?

Answer 17

Less p53 because MDM2 adds ubiquitin (small regulatory protein) to p53.
Errors in DNA replication and repair lead to the copying of a gene multiple times.

Question 18

What genes, as well as MDM2, are commonly amplified in cancer?

Answer 18

MDM2
MYC
RAS
HER2
EGFR

Question 19

What is the premise of the Philadelphia chromosome?

Answer 19

Reciprocal translocation of chromosomes 9 and 22

This fuses BRC and Abl.

Question 20

What is BRC?

Answer 20

A serine threonine kinase and GTPase

Question 21

What is ABL?

Answer 21

A signalling tyrosine kinase

Question 22

What happens after the reciprocal translocation of chromosome 9 and 22 in the Philadelphia chromosome and fusing of BRC and ABL?

Answer 22

The fusion protein has TK activity, but is no longer regulated

Question 23

What cancer is the Philadelphia chromosome commonly associated with?

Answer 23

Chronic myeloid leukaemia.

Question 24

How can the Philadelphia chromosome treated pharmacogologically?

Answer 24

Tyrosine kinase inhibitors

Imatinib, Nilotinib, Dasatinib

Question 25

What can happen to EGFR that can cause cancer?

Answer 25

Partial deletion of EGFR The extracellular portion of the receptor is deleted, this means that the ligand can no longer bind but the domain is constantly active (continuous phosphorylation).

Question 26

What makes EGFR variant III constitutively active?

Answer 26

Lacks most of extracellular domain Variant III has undergone partial deletion and so the remaining segment is within the intracellular domain and remains constantly turned on.

Question 27

What cancer shows a variant (variant III) in 20-60% of glioblastoma multiformes?

Answer 27

Variant III after partial deletion of EGFR

Question 28

What sequence is constantly activated as a result of truncated EGFR?

Answer 28

RAS --> RAF --> MEK | Switches on approximately 100 genes for cell division

Question 29

What form of mutation can occur in RAS that leads to cancer?

Answer 29

Point mutations in RAS affecting codons 12, 13 or 61 leads to constitutively active RAS protein RAS is a GTPase regulating pathways for proliferation and survival

Question 30

What is RAS?

Answer 30

RAS is a GTPase regulating pathways for proliferation and survival

Question 31

What can lead to variation in patient pharmacogenetics?

Answer 31

``` Drug targets Metabolising enzymes ( so consequently pro-drug actication) ```

Question 32

What can be used to predict variation in pharmacogenetics of patients?

Answer 32

Gene sequencing

Question 33

What is Tamoxifen metabolised to from pro-drug to active metabolite?

Answer 33

CYP2D6 (a cyp450)

Question 34

In patients that do not have the required enzyme to metabolise Tamoxifen into its form, what can be done?

Answer 34

CYP2D6 deficient patients | Patients require an increased dose to compensate for reduced active products ( doubling the dose is recommended)

Question 35

What is genetic exceptionalism?

Answer 35

Genetic information is not just about a patient at present; it tells us about their future and also about their family (1/2 genetic info shared with offspring and 1/4 with siblings).

Question 36

What are the ethical dilemmas associated with genetic testing / sequencing?

Answer 36

Predicts genetic dispositions Impact on family members Significance may not be apparent at the time of collection May have cultural significance Can be obtained from any cell (even if separate from body) Potential for abuse +Scientific research value (-)

Question 37

How do acquired mutations affect treatment type?

Answer 37

Tumour genomes can be sequenced in order to personalise treatment (not yet routine but as cost reduces and use becomes more widespread it may become standard)

Question 38

Give some examples of when genome of tumours allows personalised medicine;

Answer 38

HER2 for Herceptin EGFR for Erlotinib, Cetuximab Uses for monoclonal antibodies

Question 39

What kind of oncogenic mutations can cause cancer?

Answer 39

``` Chromatin modifications Transcription control Splicing control microRNA Translation Post-translational modifications ```

Question 40

Which oncogenes can be activated by changes to genetic code?

Answer 40

RAS, MDM2, EGFR, (TP53 - inactivates functional p53)

Question 41

Which tumour supressors can be inactivated by mutation?

Answer 41

TP53, INK4

Question 42

Give an example of chromosomal rearrangement

Answer 42

9 and 22 The Philadelphia Chromosome | BRC and ABL

Question 43

What are DTC genetic tests?

Answer 43

Direct to consumer