Clinical examples lecture Flashcards
How can a proto-oncogene be converted into an oncogene?
There may be a change in the coding sequence resulting in a hyperactive protein made in normal amounts
There can be gene amplification where normal proteins is greatly over produced
Chromosome rearrangement can occur which can lead to the gene being placed near a strong enhancer leading to over expression of normal protein, alternatively it may produce an overactive fusion protein
There may be removal of regulation by miRNA leading to increased protein expression
How are somatic hyper-mutation and class switch recombination initiated in B cells?
A single-strand DNA deaminase (AID) which mutates cytidine residues to uracyl when this occurs at V/D regions it leads to somatic mutations while the same alteration in switch regions ensures class switching During class switch recombination AID lesions are sometimes converted to a DSB, most lymphoid cancers carry chromosomal translocations that involve RAG1/2 or AID target genes
What are the immunophenotypic markers that indicate the maturation of B lymphoid cells?
The earliest cells will produce CD34, HLA-DR and TdT as the cell progresses it will begin to produce CD19 and CD20 then, after antigen stimulation it will express CD10 and if it goes on to from a plasma cell, CD138
What are two of the pirate oncogenes which can cause B cell derived cancer through reciprocal translocations?
MYC which is found on chromosome 8 and can cause Burkitt lymphoma
BCL2 which is found on chromosome 18 and can cause follicular lymphoma
These both recombine with the IGH locus on chromosome 14 of B Cells using its promoter to transform from proto-oncogenes to oncogenes
What is MYC?
This is a powerful proto-oncogene
It is a ubiquitously expressed transcription factor which contains a basic helix-loop-helix
It has many target genes involved in the regulation of cell growth, division, death, metabolism, adhesion and motility
Its effects allow it to control virtually all of the cancer hallmarks except for avoiding apoptosis
What are the biological effects of MYC overexpression?
Increased cell cycle progression and cell proliferation
Decreased cell differentiation
Increased activity of telomerase
Altered cell metabolism- active glutaminolysis
Decreased cell adhesion assisting invasion
Apoptosis is maintained and cells die rapidly
What are the clinical manifestations of sporadic burkitt lymphoma?
These typically occur in young men and form rapidly growing, large abdominal tumours which quickly spread to the blood, bone marrow and brain
These patients will require urgent chemotherapy as days and even hours can make a difference to these patients, they will frequently have tumour lysis syndrome and respond well to chemotherapy and anti CD20 therapy
What is the endemic form of burkitt lymphoma?
This occurs in sub-saharan Africa with 90% of them being driven by EBV
What is the morphology of burkitt cells?
These are blasts that typically have dark blue cytoplasm and vacuoles
Dividing cells and smear cells
Proliferating and dying cells are easier seen in sections from tumour tissue
As burkitt cells die rapidly so the tumours show a lot of apoptotic and necrotic cell debris
There is high expression of Ki-67 which marks proliferating cells and mitotic figures
What is the burkitt lymphoma phenotype in terms of the CD molecules?
There is expression of CD34 TdT HLA-DR Surface IgM alond with a kappa or lambda restriction CD20 CD10 and Ki-67 100%
What is the immunophenotype of lymphoblastic leukaemia?
CD19
CD20
No BCR
aberrant CD10, CD13 and CD33
Why does Burkitt lymphoma respond well to treatment?
The cells have an intact apoptotic pathway therefore they remain sensitive to steroids and chemotherapy
What did Denis Burkitt do with regards to burkitt lymphoma?
He established cell lines from tumours and brought them to England which assisted genetic characterisation and identification of the EBV in tumours
What are the features of follicular lymphoma in comparison to Burkitt lymphoma?
Follicular lymphoma cells proliferate slowly however unlike burkitts lymphoma they are resistant to apoptosis and accumulate
Tumours grow slowly, patients often present with isolated lymphoadenopathy which may be an accidental finding
There is progressive spread to other lymph nodes, spleen and bone marrow
What is the morphology of follicular lymphoma cells?
These are mature and small lymphocytic cells with frequent nuclear cleaving (where prominent nuclear clefts can be seen)
Lymph nodes will also enlarge slowly as cell accumulate
