Genes that predispose to cancer

Question 1

What are the six established hallmarks of cancer?

Answer 1

Autonomous growth signalling
Evading growth inhibitory signals
Activating invasion and metastasis
Immortality: unlimited replicative potential (telomeres, telomerase)
Angiogenesis
Evasion of apoptosis

Question 2

Describe a deletion mutation that can cause CLL

Answer 2

Deletion of miRNA genes regulating Bcl-2

Question 3

What three ways in which viruses/bacteria can cause mutations that result in neoplasm?

Answer 3

Viral proteins blocking or activating cellular proteins (HPV E6/7 block p53, Rb, p16)
Viral promoters activating normal genes/viral oncogenes affecting cell cycle
Chronic inflammation promoting mutations and translocations by promoting hypermutation and class switching in B cells (EBV, Helicobacter pylori)

Question 4

From which cells to Myeloid neoplasms arise?

Answer 4

Haemopoietic progenitor cells

Question 5

What do the symptoms of myeloid neoplasms usually result from?

Answer 5

Aberrant/unbalanced haemoppoiesis.

Question 6

What are the three categories of myeloid neoplasms?

Answer 6

Acute myeloid leukaemias
Myelodysplastic syndromes
Myeloproliferative disorders (e.g. CML)

Question 7

What are two examples of translocations that cause white cell neoplasias

Answer 7

Bcr-Abl tyrosine kinase in Philadelphia chromosome

Myc translocation to Ig promoter: overexpression of the Myc transcription factor

Question 8

What is an example of a mutation that can cause white cell neoplasias?

Answer 8

Myc mutation - prevents rapid degradation

Mutation of BCL6 in germinal centre B cells, but must be turned off for B cells to mature.

Question 9

In most lymphoid neoplasms, does rearrangement of the antigen receptor gene occur before or after transformation?
What does this mean for the daughter cells?

Answer 9

Rearrangement is before transformation.
Daughter cells:
- share the same antigen receptor gene configuration and sequence
- synthesise identical antigen receptor proteins ) either Ig or T-cell receptors)

Question 10

What is the origin of the majority of lymphoid neoplasms?

Answer 10

B-cell

Question 11

What can you see in a peripheral blood smear of chronic myeloid leukaemia?

Answer 11

Many mature neutrophils and less less mature myelocytes and metamyelocytes.

Question 12

Where is CML thought to originate from? Why?

Answer 12

Pluripotent stem cell. Because blast crisis cells can be of myeloid or pre-B origin.

Question 13

What is Abl and what is its role?

Answer 13

It is a cytoplasmic and nuclear tyrosine kinase.

ubiquitous, normal role in cell proliferation, part of a controlled pathway.

Question 14

What is the Philadelphia chromosome?

Answer 14

abl gene is translocated from chromosome 9 to the Breakpoint Cluster Region (BCR) or Chromosome 22.
BCR constitutively activates the Abl kinase and contributes many new interaction domains into other signaling pathways (many of which promote neoplasia)

Question 15

What disease is the philadelphia chromosome associated with?

Answer 15

Chronic myelogenous leukaemia

Question 16

What is Gleevec?

Answer 16

Imatinib mesylate

Targets Bcr-Abl

Question 17

Why is Gleevec so good?

Answer 17

Very specific for Bcr-Abl. Only binds to 3 other kinases (of 90 known Tyr kinases)

Question 18

A mutation in which amino acid is usually responsible for rendering Gleevec ineffective against Bcr-Abl?

Answer 18

Threonine.

Question 19

Why isn’t it possible to cure CML with Gleevec?

Answer 19

Because the early progenitor cells, which contain the causative translocation, do not cycle often and are protected from Gleevec. Gleevec must be taken continuously.

Question 20

How does Gleevec work?

Answer 20

Freezes the Abl kinase in the inactive configuration.

Question 21

What would you see on a peripheral blood smear of someone with Chronic Lymphocytic leukaemia?

Answer 21

Flooded with small lymphocytes with condensed chromatin and scant cytoplasm
Smudge cells
Spherocytes: hyperchromatic, round erythrocytes.
Nucleated erythroid cell

Question 22

Why do you see spherocytes in the blood of CLL patient?

Answer 22

Because of coexistent autoimmune haemolytic anaemia.

Question 23

Why do you see nucleated erythroid cells in CLL blood smears?

Answer 23

because progenitors are released prematurely from bone marrow, after tumour cells infiltrate the bone marrow.

Question 24

What are three markers for typical B-cells?

Answer 24

CD19, 20,23 (21)

Question 25

What is a marker typical for T cells and mantle zone B cells?

Answer 25

CD5

Question 26

What is the chromosomal abnormality most common on presentation with CLL?

Answer 26

Deletion of chr. 13q.

Question 27

What is the result of the deletion of chr. 13q?

Answer 27

loss of miRNA and overexpression of Bcl-2 due to loss of its downregulatory miRNAs

Question 28

What is the presence of high activity ZAP-70 in CLL associated with?

Answer 28

poor prognosis. It is thought to increase the pro-survival effect of bcl-2

Question 29

What is a deletion in Chr.17p associated with?

Answer 29

Loss of p53 function - Rapidly progressive disease, poor prognosis.

Question 30

How does reduced expression of miRNA result in overexpression of Bcl-2?

Answer 30

miRNA genes are expressed into RNA, which is processed into short miRNA fragments that bind to and cause degradation of their target mRNA (e.g. Bcl-2). Therefore, bcl-2 is overexpressed.

Question 31

What does RISC do?

Answer 31

It is guided to a target mRNA (e.g. bcl-2) by miRNA, and then leaves the target.

Question 32

What does the loss of a p53 protein always present?

Answer 32

A poor prognosis.