Genes that predispose to cancer Flashcards
What are the six established hallmarks of cancer?
Autonomous growth signalling Evading growth inhibitory signals Activating invasion and metastasis Immortality: unlimited replicative potential (telomeres, telomerase) Angiogenesis Evasion of apoptosis
Describe a deletion mutation that can cause CLL
Deletion of miRNA genes regulating Bcl-2
What three ways in which viruses/bacteria can cause mutations that result in neoplasm?
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)
From which cells to Myeloid neoplasms arise?
Haemopoietic progenitor cells
What do the symptoms of myeloid neoplasms usually result from?
Aberrant/unbalanced haemoppoiesis.
What are the three categories of myeloid neoplasms?
Acute myeloid leukaemias
Myelodysplastic syndromes
Myeloproliferative disorders (e.g. CML)
What are two examples of translocations that cause white cell neoplasias
Bcr-Abl tyrosine kinase in Philadelphia chromosome
Myc translocation to Ig promoter: overexpression of the Myc transcription factor
What is an example of a mutation that can cause white cell neoplasias?
Myc mutation - prevents rapid degradation
Mutation of BCL6 in germinal centre B cells, but must be turned off for B cells to mature.
In most lymphoid neoplasms, does rearrangement of the antigen receptor gene occur before or after transformation?
What does this mean for the daughter cells?
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)
What is the origin of the majority of lymphoid neoplasms?
B-cell
What can you see in a peripheral blood smear of chronic myeloid leukaemia?
Many mature neutrophils and less less mature myelocytes and metamyelocytes.
Where is CML thought to originate from? Why?
Pluripotent stem cell. Because blast crisis cells can be of myeloid or pre-B origin.
What is Abl and what is its role?
It is a cytoplasmic and nuclear tyrosine kinase.
ubiquitous, normal role in cell proliferation, part of a controlled pathway.
What is the Philadelphia chromosome?
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)
What disease is the philadelphia chromosome associated with?
Chronic myelogenous leukaemia
What is Gleevec?
Imatinib mesylate
Targets Bcr-Abl
Why is Gleevec so good?
Very specific for Bcr-Abl. Only binds to 3 other kinases (of 90 known Tyr kinases)
A mutation in which amino acid is usually responsible for rendering Gleevec ineffective against Bcr-Abl?
Threonine.
Why isn’t it possible to cure CML with Gleevec?
Because the early progenitor cells, which contain the causative translocation, do not cycle often and are protected from Gleevec. Gleevec must be taken continuously.
How does Gleevec work?
Freezes the Abl kinase in the inactive configuration.
What would you see on a peripheral blood smear of someone with Chronic Lymphocytic leukaemia?
Flooded with small lymphocytes with condensed chromatin and scant cytoplasm
Smudge cells
Spherocytes: hyperchromatic, round erythrocytes.
Nucleated erythroid cell
Why do you see spherocytes in the blood of CLL patient?
Because of coexistent autoimmune haemolytic anaemia.
Why do you see nucleated erythroid cells in CLL blood smears?
because progenitors are released prematurely from bone marrow, after tumour cells infiltrate the bone marrow.
What are three markers for typical B-cells?
CD19, 20,23 (21)
What is a marker typical for T cells and mantle zone B cells?
CD5
What is the chromosomal abnormality most common on presentation with CLL?
Deletion of chr. 13q.
What is the result of the deletion of chr. 13q?
loss of miRNA and overexpression of Bcl-2 due to loss of its downregulatory miRNAs
What is the presence of high activity ZAP-70 in CLL associated with?
poor prognosis. It is thought to increase the pro-survival effect of bcl-2
What is a deletion in Chr.17p associated with?
Loss of p53 function - Rapidly progressive disease, poor prognosis.
How does reduced expression of miRNA result in overexpression of Bcl-2?
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.
What does RISC do?
It is guided to a target mRNA (e.g. bcl-2) by miRNA, and then leaves the target.
What does the loss of a p53 protein always present?
A poor prognosis.
