Genes That Predispose to Cancer Flashcards
What is G-CSF used for in chemotherapy?
as an adjuvant to enhance the production of blood cells to enhance the fight against infection
In which type of cancer is there the philadelphia chromosome?
mainly CML as the primary mutation but also in ALL as a secondary or tertiary mutation
Describe the cell cycle
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
What controls the cell cycle?
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
What is the role of p53?
p53 synthesises a growth inhibitor factor to inhibit CDK to stop the cell cycle progresssing, it also stimulates DNA repair and signals for apoptosis
What are the 6 hallmarks of cancer?
evasion of apoptosis, autonomous growth, evading growth inhibitory signals, angiogenesis, immortality and activating invasion and metastasis
What are the 4 emerging hallmarks of cancer?
deregulating cellular energetics, avoiding immune destruction, tumour promoting inflammation, genome instability and mutation
How is the Bcr-Abl gene created?
from a chromosomal translocation which joins the two genes together
Why are B cells prone to chromosomal translocation and point mutations?
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
What does a blood smear of chronic myeloid leukaemia show?
many mature neutrophils and few mature myelocytes and metamyelocytes
What are the phases of chronic myeloid leukaemia?
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
Why is it known that CML originates from a transformation in a pluripotent haemopoietic stem cell?
because it has the capability of having a blast crisis
What is the origin of CML?
a translocation of chromosome 9 and 22 resulting in the the philadelphia chromosome which has the Bcl-Abl gene
What is the mechanism of action of Bcl-Abl?
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
What is the mechanism of action of Gleevec?
Gleevec binds to the active site of Bcl-Abl kinase to inhibit it
Why is Gleevec so well tolerated?
because it only inactivates 3 other kinases apart from Bcl-Abl
Why does Gleevec sometimes stop working?
because the Bcl-Abl develops further mutations - commonly a mutation in the threonine blocking it from accessing the active site
How are the effects of Gleevec tested?
look at the blood smear to look for fewer neutrophils or use PCR to measure the Bcr-Abl mRNA
Why does Gleevec treatment have to be continuing?
because it blocks the kinase activity but doesnt extinguish the CML stem cells
What is the treatment if new mutations make Gleevec ineffective?
make personalised modifications to the drug
What is the most common leukemia of adults?
chronic lymphocytic leukemia
What is the median age of diagnosis of chronc lymphocytic leukemia?
60
What genetic changes occur in CLL?
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)
What differentiates CLL and SLL?
the degree of peripheral blood involvement
