oncogenic signlling and tumour suppressor genes

Question 1

% of mutations that cause cancer

Answer 1

only 5-10% of mutations cause cancer

Question 2

What are mutations that don’t cause cancer?

Answer 2

silent mutations

they don’t change the AA sequence

they’re in non-coding regions of DNA that doesn’t affect gene function

Question 3

difference between germline and somatic mutations

Answer 3

germline - hereditary, found in egg and sperm, can be passed down from generation and influence a person’s risk for develoing a disease

somatic - occur in non-reproductive cells, cannot be passed on, cancer cells accumulate somatic mutations, damage we do to body

Question 4

Which more commonly cause cancer - germline or somatic mutations?

Answer 4

somatic

somatic mutations in cell signalling genes

Question 5

gain of function mutation

Answer 5

gain of function mutation only needs one gene copy to be mutated

mutation in ONE gene causes gene to be permanently switched on

overexpression

-> most common

Question 6

loss of function mutation

Answer 6

loss of function mutations need both gene copies to be mutated

with ONE mutation, the second gene compensates

requires both genes to be mutated for loss

-> more rare

Question 7

What is a proto oncogene?

Answer 7

code for proteins that drive normal cell growth, healthy gene

deregulation/if it’s mutated it becomes an oncogenes

Question 8

What is an oncogene?

Answer 8

codes for protein that causes cancer

Question 9

functions that oncogenes can have

Answer 9

1. point mutation: 1 AA change
   - within a control element: growth stimulating protein in excess
   - within the gene: hyperactive or degradation resistant protein (only 1 protein produced but hyperactive)
2. gene amplification - normal protein but in excess
3. translocation or transposition - new promoter, permanently on, normal growth stimulating protein in excess

-> gain of function mutations, accelerate growth/signalling/cell cycle in cancer

Question 10

What are mitogens?

Answer 10

stimulatory signals that stimulate proliferation

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

Question 11

What is PDGF an example of?

Answer 11

mitogen

Question 12

examples of mitogens

Answer 12

TGF-beta

PDGF

EGF

EPO

Question 13

What does TGF-beta do?

Answer 13

inhibits proliferation

direct opposite inhibitors signal

Question 14

What happens cells in absence of mitogen stimulation?

Answer 14

they can enter G0 phase

Question 15

What activates tyrosine kinase receptors?

Answer 15

kinase

Question 16

How does the MAPK signalling pathway work?

Answer 16

• TK R dimerises
• phosphorylation
• RAS - Raf - MEK - ERK
• ERK enters the nucleus
• increased proliferation

Question 17

What does MAPK stand for?

Answer 17

mitogen activated protein kinase

Question 18

What does EGFR stand for?

Answer 18

epidermal growth factor receptor

Question 19

What does EGFR do?

Answer 19

stimulates growth in epidermal and epithelial cells

Question 20

What type of R is EGFR?

Answer 20

TK R
(activates MAPK, stimulates growth via MAPK)

and HER 1

Question 21

What signalling does EGFR activate?

Answer 21

MAPK signalling

Question 22

3 ways EGFR can function as an oncogene

Answer 22

1. over expression of EGFR (inc signalling)
2. mutation in kinase domain (always active)
3. deletion of ligand binding domain EGFR variant III (always active)

Question 23

cancers associated with EGFR overexpression/upregulation/amplification

Answer 23

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

Question 24

examples of EGFR receptor inhibitors

Answer 24

cetuximab

matuzumab
nimotuzumab
panitumumab

Question 25

examples of EGFR dimerisation inhibitors (HER2 inhibitors)

Answer 25

trastuzumab pertuzumab

Question 26

examples of TKIs

Answer 26

gefitinib erlotinib lapatinib

Question 27

How many parts of the EGFR can be targeted/blocked and where?

Answer 27

3 EGFR R inhibitors (outside) EGFR dimerisation inhibitors (outside) TKIs (inside)

Question 28

What are tumour suppressor genes?

Answer 28

genes that protect cells following damage suppress cellular proliferation initiate apoptosis in response to checkpoints or growth suppression signals

Question 29

homozygous, heterozygous and loss of heterozygosity in tumour suppressor genes

Answer 29

homozygous - both genes are WT, protein is active, normal heterozygous - one mutated gene but the other is WT, protein is active, increased risk loss of heterozygosity (LOH) - 2nd gene is now mutated, protein lost/inactive, cancer likely -> loss of function

Question 30

2 hit hypotnesis loss of function theory

Answer 30

Rb1 gene is a tumour suppressor gene loss of function leads to childhood retinal cancer - retinoblastoma sporatic mutation (somatic) of 2 chromosomes at the same site is very unlikely Tx/removal of eye leads to no further cancer in sporadic mutations inherited Rb mutation leads to x500 increased risk of retinoblastoma occurrence

Question 31

guardian of the genome

Answer 31

p53

Question 32

% of cancers that p53 is mutated in

Answer 32

50%

Question 33

What mutation is most common in p53 in cancers?

Answer 33

missense mutation in one allele results in high levels of non-functional protein

Question 34

most commonly mutated tumour suppressor gene in cancer

Answer 34

p53

Question 35

p53 and the 2 hit hypothesis

Answer 35

it doesn't follow the 2 hit rule mutant p53 outcompetes the normal variant loss of one p53 gene is tolerated one gene mutated, pp53 function NOT normal loss of function with one mutation

Question 36

Is p53 an oncogene?

Answer 36

NO

Question 37

How does p53 work?

Answer 37

TSG DNA damage activates p53 p53 activates p21 p21 inhibits cell cycle, reduces proliferation p53 controlled by MDM2 inhibiting MDM2 enables p53 to function in cancer

Question 38

What controls p53?

Answer 38

MDM2

Question 39

example of gene alteration that is inherited in colon cancer

Answer 39

APC gene - familial adenomatous polposis

Question 40

apoptosis

Answer 40

programmed cell death cells shrink, condense and fragment no inflammatory response and undergo phagocytosis

Question 41

difference between apoptosis and necrosis

Answer 41

necrosis - sudden death, swell and burst which causes inflammatory response apoptosis - programmed, not sudden, shrink and condense, no inflammatory response, phagocytosis

Question 42

enzymes that control apoptosis

Answer 42

proteases (end in -ase) CASPASES

Question 43

What do caspase contain?

Answer 43

contain cysteine active sites

Question 44

Where do caspases cleave targets at?

Answer 44

aspartic acid cASPases

Question 45

2 types of caspases

Answer 45

1. initiator caspases 2. executioner caspases

Question 46

examples of initiator caspases

Answer 46

caspases 8 and 9

Question 47

examples of executioner caspases

Answer 47

caspases 3, 6 and 7

Question 48

How do caspases work?

Answer 48

signals trigger initiarot caspases initiators dimerise and activate executioner caspases degrate nuclear proteins caspase activated DNAse (CAD) is activated which cute up DNA in the cell degrades cell adhesion molecules

Question 49

CAD

Answer 49

caspase activated DNAse cuts up DNA in the cell

Question 50

Can apoptosis be stopped?

Answer 50

NO once apoptosis starts, it can't be reversed