9 TSGs

Question 1

Are TSGs dominant or recessive?

Why is this important?

Answer 1

recessive

both alleles of a TSG need to be eliminated or inactivated to abolish TS properties

Question 2

What is Knudson’s 2 hit hypothesis?

Answer 2

One germline mutation

Second somatic mutation

Question 3

What is the genetic principle of familial Rb?

Answer 3

fertilised egg has one mutant Rb allele, and one normal one
every body cells as 1 wild type and 1 mutant allele

after 1st somatic mutation this leads to 2 mutant Rb alleles

activation of TS properties,

Question 4

What is the genetic principle of sporadic Rb?

Answer 4

1st somatic mutation creates one mutant Rb allele

2nd somatic mutation creates 2nd mutant Rb allele

Question 5

How are familial and sporadic Rb inheritance patterns characterised?

Answer 5

familial - bilateral

sporadic - unilateal

Question 6

What cancer risks are familial Rb sufferers at greater risk of?

Answer 6

soft tissue sarcomas
osteogenic sarcomas
non-retinal tumours

Question 7

What cancer risks are sporadic Rb sufferers at greater risk of?

Answer 7

some sarcomas

Question 8

What proportion of childhood Rb cases are cured?

Answer 8

90%

Question 9

What is the genotype of familial Rb?

Answer 9

20% - large deletions
50% - single base substitutions
30% - small length mutations

Question 10

What is the mutation mechanism for Rb?

Answer 10

hyperthemylation of the 5’ region

Question 11

What happens in the cell cycle of those mutating Rb?

Answer 11

in affected individual at G1, 1 mutant and 1 wildtype allele

after S, 2 of each

G2 and M - homologous recombination

upon segregation daughter cells retain heterozygosity or don’t

Question 12

What would be observed in karyotyping of lost heterozygosity of Rb?

Answer 12

banding is lost at 13q1 near centromere

Question 13

What is the normal function of pRB?

Answer 13

by the restriction point, pRB is very phospharylated.

cell pass through into S phase

Question 14

What drives pRB phosphorylatoin?

Answer 14

Cyclin D/cdk4/6 complexes in early G1 of the R point

Question 15

What function does pRB serve in the cell cycle?

Answer 15

inhibits E2F/DP regulated promoters to inhibit cell cycle

pRB phospharylation changes repression complex (histone de-acetylase removed from pRb, allowing p300 to prime promoters)

Question 16

What does cyclin Ecdk2 do?

Answer 16

phospharylates pRB, dissociating it

this allows E2F TF to drive formation of proteins required for passage through R point

Question 17

What is the significance of losing pRB in cancer?

Answer 17

nothing to stop S phase entry

Question 18

What are cyclin cdk6’s regulated by?

Answer 18

cdk inhibitors, preventing ck-dependent phosphorylation of pRB

Question 19

What is P16?

Answer 19

TSG product inactivated in cancer (melanoma)

Question 20

What proportion of human cancers carry TP53 missense mutations?

Answer 20

30-50%

Question 21

During which stage of cancer development is TP53 typically inactivated?

Answer 21

late stages of cancer progession

Question 22

What are the 4 primary activities of p53?

Answer 22

pro-apoptotic activity
growth arresting activity
induces cellular senescence
inhibits angiogenesis

Question 23

How many p53 isoforms are there?

Answer 23

12

Question 24

What function does the N-terminal of p53 provide?

Answer 24

transciptional activation

Question 25

What function does the proline-rich domain of p53 serve?

Answer 25

apoptosis

Question 26

What function does the sequence-specific DNA binding domain of p53 serve?

Answer 26

transcription

Question 27

What function does the C-terminal of p53 serve?

Answer 27

nuclear localisation signal
oligermisation
regulatory domain

Question 28

What might p53 be activated by?

Answer 28

cellular stresses:
- dsDNA damage
- Loss of adhesion
- Hypoxia
- Oncogenic activation
Ribosomal stress
ROS

Question 29

What does mdm2 do?

Answer 29

switches off p53

an E3 ubiquitin ligase which feeds back to inactivate p53 through targeted ubiquitylation

Question 30

Wht do ATM and CHK2 do?

Answer 30

phospharylate p53 activating it

Question 31

What does p19ARF do?

Answer 31

inhibits mdm2

Question 32

What are the 3 activities of ATM?

Answer 32

phospharylates p53
phospharylates CH2 kinase, which phospharylates p53
phosphorylates mdm2 (inhibiting it)

Question 33

What does p53 increase the expression of?

Answer 33

p21

Question 34

What proportion of women have germline mutations in BRCA1 gene?

Answer 34

1 in 500 women

Question 35

What is the founder mutation of BRCA1?

Answer 35

185delAG found in 1% Ashkenazic Jewish population

Question 36

How does BRCA1 protein respond to DNA damage?

Answer 36

transciption and chromatin remodelling

BRCA1 E3ligase controls G2/M phase checkpoints

Question 37

What does BRCA2 increase risk of?

Answer 37

prostate cacner
Gall bladder + bile duct cacner
stomach cancer
malignant melanoma

Question 38

What is the histological difference between BRCA1 and BRCA2 tumours?

Answer 38

1 - higher mitotic rate and more lymphocyte infiltration

2 - higher tubule formation

Question 39

How many BRC repeats does BRCA2 contain?

What are these required for?

Answer 39

8

bind Rad51 recombinase for homologous recombination

Question 40

What do BRCA2 and Rad52 do?

Answer 40

displace RPA complex from resected ssDNA

helps orm Rad51 nucleoprotein filaments

Question 41

Generally, what is BRCA1 involved in?

Answer 41

checkpoint control

Question 42

Generally, what is BRCA2 involved in?

Answer 42

DNA damage repair, modulating DNA DSB repair through Rad51 interaction

Question 43

How do BRCA1 and 2 inactivation affect radiosensitivty?

Answer 43

increase it

Question 44

Wat are BRCA1 and 2 levels in the cdell reduced by?

What is the effect of this?

Answer 44

reduced by RNA interference

cells lacking either of these undergo cell death at lower doses of radiation