Genes That Predispose to Cancer

Question 1

What is G-CSF used for in chemotherapy?

Answer 1

as an adjuvant to enhance the production of blood cells to enhance the fight against infection

Question 2

In which type of cancer is there the philadelphia chromosome?

Answer 2

mainly CML as the primary mutation but also in ALL as a secondary or tertiary mutation

Question 3

Describe the cell cycle

Answer 3

G0 is the resting phase for cells when they are not dividing - then a cell enters G1 where it increases in size - then there is R which is a checkpoint to see whether the cell can procede to replicate - then there is S phase where the DNA is copied, G2 where the cell increases in size again and then M phase where there is mitotic divison

Question 4

What controls the cell cycle?

Answer 4

a cytokine will bind to its cytokine receptor which will initiate a signalling cascade (involving the Ras protein) which will result in the activation of a transcription factor e.g. Myc - which will transcribe cyclin D which activates CDK4 which is the kinase for entering the cell cycle

Question 5

What is the role of p53?

Answer 5

p53 synthesises a growth inhibitor factor to inhibit CDK to stop the cell cycle progresssing, it also stimulates DNA repair and signals for apoptosis

Question 6

What are the 6 hallmarks of cancer?

Answer 6

evasion of apoptosis, autonomous growth, evading growth inhibitory signals, angiogenesis, immortality and activating invasion and metastasis

Question 7

What are the 4 emerging hallmarks of cancer?

Answer 7

deregulating cellular energetics, avoiding immune destruction, tumour promoting inflammation, genome instability and mutation

Question 8

How is the Bcr-Abl gene created?

Answer 8

from a chromosomal translocation which joins the two genes together

Question 9

Why are B cells prone to chromosomal translocation and point mutations?

Answer 9

because they have an enzyme (AID) which creates mutations in DNA - this is useful for somatic hypermutation but increases the risk of mutations in non Ig genes

Question 10

What does a blood smear of chronic myeloid leukaemia show?

Answer 10

many mature neutrophils and few mature myelocytes and metamyelocytes

Question 11

What are the phases of chronic myeloid leukaemia?

Answer 11

the chronic phase which is relatively asymptomatic and slow, the accelerated phase where further mutations are accumulated and the blast crisis where it progresses to act like an acute leukaemia

Question 12

Why is it known that CML originates from a transformation in a pluripotent haemopoietic stem cell?

Answer 12

because it has the capability of having a blast crisis

Question 13

What is the origin of CML?

Answer 13

a translocation of chromosome 9 and 22 resulting in the the philadelphia chromosome which has the Bcl-Abl gene

Question 14

What is the mechanism of action of Bcl-Abl?

Answer 14

The Bcl part of the gene (from chromosome 22) contains a dimerisation domain that self associates leading to the activation of the Abl kinase (from chromosome 9) which can phosphorylate proteins to induce growth, proliferation, metabolism, migration and survival

Question 15

What is the mechanism of action of Gleevec?

Answer 15

Gleevec binds to the active site of Bcl-Abl kinase to inhibit it

Question 16

Why is Gleevec so well tolerated?

Answer 16

because it only inactivates 3 other kinases apart from Bcl-Abl

Question 17

Why does Gleevec sometimes stop working?

Answer 17

because the Bcl-Abl develops further mutations - commonly a mutation in the threonine blocking it from accessing the active site

Question 18

How are the effects of Gleevec tested?

Answer 18

look at the blood smear to look for fewer neutrophils or use PCR to measure the Bcr-Abl mRNA

Question 19

Why does Gleevec treatment have to be continuing?

Answer 19

because it blocks the kinase activity but doesnt extinguish the CML stem cells

Question 20

What is the treatment if new mutations make Gleevec ineffective?

Answer 20

make personalised modifications to the drug

Question 21

What is the most common leukemia of adults?

Answer 21

chronic lymphocytic leukemia

Question 22

What is the median age of diagnosis of chronc lymphocytic leukemia?

Answer 22

60

Question 23

What genetic changes occur in CLL?

Answer 23

deletion of miRNA 15a and 16-1 on chromosome 13q regulating Bcl-2 resulting in over expression of Bcl-2, with subsequent changes in ZAP-60 (activation) and p53 (deletion)

Question 24

What differentiates CLL and SLL?

Answer 24

the degree of peripheral blood involvement

Question 25

What is seen on blood smear of CLL?

Answer 25

small round lymphocytes with small nuclei and condensed chromatin and smudge cells (ruptured tumour cells)

Question 26

What is the cell of origin for CLL?

Answer 26

naive B cell or memory B cell

Question 27

How does over expression of Bcl-2 result in an inability to apoptose?

Answer 27

Bcl-2 is a pro survival protein which blocks the release of cyt-c from the mitochondria so the intrinsic apoptotic pathway can’t be activated

Question 28

What is involved in the intrinsic apoptotic pathway?

Answer 28

cyt-c activates the apoptosome which activates the initiator procaspase which activates the executioner caspase

Question 29

How does p53 stimulate apoptosis?

Answer 29

by stimulating synthesis of BH3 only pro apoptotic proteins to outweigh the ratio of pro apoptotic to survival proteins

Question 30

What is the mechanism of action of ABT-199?

Answer 30

it is a BH3 only mimetic so will stimulate apoptosis

Question 31

What is ZAP-70 and what happens when its upregulated in CLL?

Answer 31

ZAP-70 is a tyrosine kinase that is normally involved in T cell receptor signalling- it phopsphorylates substrates involved in proliferation - in CLL it is thought to increase the survival effect of Bcl-2

Question 32

How does p53 regulate the cell cycle?

Answer 32

by synthesising an inhibitor of CDK (p16)

Question 33

If p53 is mutated why do mutations accumulate rapidly?

Answer 33

because the cell cannot arrest the cell cycle to repair mutations, the cell cannot activate repair processes and the cell cannot be directed to apoptosis

Question 34

What may be the effect of radiation or chemotherapy in cancer treatment?

Answer 34

DNA damage which cannot be repaired resulting in further mutations

Question 35

What is the common mutation leading to Burkitt’s lymphoma?

Answer 35

t(8;14) translocation of the myc gene to the Ig promoter

Question 36

What cancer is linked to an EBV infection?

Answer 36

Burkitt’s lymphoma