Oncogenes and Tumour Suppressor Genes

Question 1

what are the biggest drivers of cancers?

Answer 1

mutations

Question 2

what is the difference between germline mutations and somatic mutations?

Answer 2

germline are hereditary mutations -they are found in the germ cell, also known as the egg and sperm

somatic mutations occur in nonreproductive cells in the body and cannot be passed down from parent to child

Question 3

what is the most common mutation in cancer?

Answer 3

somatic

Question 4

what is gain/ loss of function?

Answer 4

GAIN of function mutations (dominant), needs only
ONE gene copy to be mutated
*LOSS of function mutations (recessive), needs BOTH
gene copies to be mutated

Question 5

what happen when there is a mutation in one gene?- gain of function

Answer 5

causes gene to be permanently switched on
causes overexpression

Question 6

what happens with one mutation in loss of function?

Answer 6

*With ONE mutation
the second gene
compensates.
*Requires BOTH
genes to be
mutated for loss
*More rare
*(LOSS)

Question 7

what are proto-oncogenes?

Answer 7

code for proteins that drive normal cell growth

Question 8

what are oncogenes and how are they formed?

Answer 8

deregulation of proto-oncogenes gives rise to oncogenes
oncogenes code for proteins that cause cancer

Question 9

what do oncogenes code for?

Answer 9

code for proteins involved in cell signalling pathways

Question 10

what do gain of function mutations accelerate?

Answer 10

growth, signalling and cell cycle in cancer

Question 11

give an example of a well known oncogene

Answer 11

MY
EGFR

Question 12

what are miogens?

Answer 12

MITOsis+GENesis - Stimulatory signals that stimulate proliferation

Question 13

give an example of a mitogen

Answer 13

TGF-B

Question 14

what do mitogens do?

Answer 14

Mitogens provide the stimulatory signal to initiate transcription / translation of
proteins and other molecules required for cell division

Question 15

what happens in the absence of mitogen?

Answer 15

simulation cells can enter G0 phase

Question 16

how do receptor tyrosine kinases work?

Answer 16

1- inactive receptor tyrosine kinase
2-kinase activity stimulated through dimerized RTK
3-RTK is activated via autophosphyorylation
4- signal relayed by activated signalling proteins into the cells interior

Question 17

what is the MAPK signalling pathway?

Answer 17

Mitogen Activated Protein Kinases
*One of THE most important & studied pathways of all

Question 18

how does the MAPK signalling pathway work?

Answer 18

*RTK receptor dimerises
*Relays Phosphorylation
*RAS -> Raf -> MEK -> ERK
*ERK enters the nucleus
*Increased Proliferation

Question 19

what happens in the MAPK signalling pathway once the cell receives the signal at receptor level?

Answer 19

*Each event triggers the next
*Transfers signal from the outside
–Starting with receptor signal
*Through the cell
–Signalling in the cytoplasm
*To the nucleus
–Activates gene transcription
*Biological response Occurs
increase in cyclin D

Question 20

what is EGF?

Answer 20

epidermal growth factor
*Stimulates growth in epidermal and epithelial cells

Question 21

how many major receptors are there for EGF?

Answer 21

4 major receptors

Question 22

what does EGFR activate?

Answer 22

MAPK signalling

Question 23

mutations that lead to EGFR overexpression have been associated with:

Answer 23

adenocarcinoma of lung
rectal cancers
gioblastoma
epithelian tumours of the neck and head

Question 24

why is knowledge of these molecular mechanisms so important in oncology?

Answer 24

as we can inhibit them
1- EGRF receptor inhibitors eg cetuximab
2- EGFR dimerisation inhibitors- eg trastumab
3-tyrosine kinase inhibitors- eg gefitinib

Question 25

what is the problem with signalling molecule mutation?

Answer 25

sometimes downstream molecules also mutate

Question 26

what are tumor suppressor genes?

Answer 26

TSGs – the genes that protect the cells following damage
*Suppress cellular proliferation
*Initiate apoptosis
In response to checkpoints or growth suppression signals

Question 27

what is the most commonly known tumor suppressor gene?

Answer 27

p53

Question 28

how are TSG mutated?

Answer 28

either lost OR become non functional due to change in DNA

Question 29

what is the ‘two hit’ loss of function theory?

Answer 29

it is an observation based of retinoblastoma
Rb1 gene is a tumor suppressor gene
loss of function leads to childhood retinal cancer
mutations of two at same site is incredibly unlikely
this mutation demonstrates a 500 fild increased risk of retinoblastoma occurence

Question 30

what responses does p53 have to possible mutagens?

Answer 30

cell cycle arrest
DNA repair
block of angiogensis
apoptosis

Question 31

how often is p53 mutated in cancers?

Answer 31

mutated in aproxx 50% of cancers
- typically a missense mutation in one allele
results in high levels of a non-functional protein

Question 32

what is p53 mutations linked to?

Answer 32

poor response to therapy

Question 33

does p53 obey the 2 hit rule?

Answer 33

no
Loss of one p53 gene is tolerated
*MUTANT p53 out competes the normal variant
*Loss of function with ONE mutation
*p53 Initially thought to be an oncogene!

Question 34

how does p53 work?

Answer 34

*p53 is a tumour
suppressor gene
*DNA damage activates
p53
*p53 activates p21 (CKI)
*p21 inhibits cell cycle –
reduces proliferation
*p53 is controlled by
MDM2
*Inhibiting MDM2
enables p53 to
function in cancer

Question 35

what is apoptosis controlled by?

Answer 35

Apoptosis is Controlled by a family of protease enzymes (so end -ase)
*Contain Cysteine active site and cleave targets at aspartic acids – so are
called CASPASES

Question 36

what are executioner proteins?

Answer 36

Executioner caspase catalyse over a 1000 proteins
during apoptosis
–Degrades Nuclear proteins
–Caspase Activated DNAse (CAD) is activated which cuts up
DNA in the cell – recall cell cycle checkpoints!
–Degrades Cell-cell adhesion molecules (rounding up of cells
and detach from neighbours)

Question 37

what does p53 activate?

Answer 37

intrinsic apoptosis

Question 38

what are the examples of gain of function oncogenes?

Answer 38

–Mitogens in excess levels (e.g. EGF)
–Receptors auto activates (EGFR)
–Signalling molecules autophosphorylate (Ras, Raf)
–Uncontrolled gene transcription
–Cell cycle driven in excess

Question 39

what are examples of loss of function tumor suppressor genes?

Answer 39

–Deregulated cell cycle (p21)
–Loss of cell cycle checkpoints (p53)
–Deregulated apoptosis (p53 and caspase)
–DNA damage not repaired
–Increased proliferation due to lack of “brakes”