Extra reading Flashcards
What is the proper notation for the Philadelphia chromosome?
t(9;22)(q34;q11.2)
What gene fusion is seen in follicular lymphoma?
- t(14;18)(q32;q21)
- IGH promoter and BLC2 fusion
What gene fusion is seen in APL?
- Acute promyelocytic leukaemia
- t(15;17)(q24;q21)
- PML-RARA
What is the MLL gene? (4)
- MLL = mixed lineage leukaemia
- MLL has over 40 gene fusion partners
- E.g. MLL-AF4 and MLL-AF9 most common
- 11q23 disturbance = poor prognosis
What is the location of MLL gene?
11q23
What fusion gene is seen in prostate cancer?
TMPRSS2-ERG results in generation of a neoplastic phenotype
What is the total number of gene fusions identified?
Nearly 10 000
What are TIGFs?
- Transcription-induced gene fusions
- Chimeric transcripts beginning at the promoter region of upstream gene and ending at the termination region of the downstream gene
- E.g. Hodgkin’s lymphoma CD205-DCL1 fusion protein
What happens to MYC in Burkitt lymphoma?
Multiple fusions have been identified involving chromosome 8q24 fusion with immunoglobulin promoter regions (MYC location) = MYC overexpression = proliferation
What are the 3 oncogenic impacts of chromosomal rearrangement?
- Fusion protein formation
- Gene fusion to highly expressed promoter
- Gene truncations resulting in activation of tumour suppressors
What is the targeted therapy for APL?
- ATRA plus arsenic trioxide
- Causes terminal differentiation of APL cells
- 90% achieve long term remission
What are the risks associated with APL?
- High pre-treatment mortality rate usually caused by cerebral haemorrhage
- DIC = disseminated intravascular coagulation, causes abnormal clotting
What are the features of PML and RARA? (2)
- RARA is a transcription factor which is activated by retinoids and acts as a ligand-dependent differentiating factor of normal myeloid haematopoietic cells
- PML is a tumour suppressor protein organised into nuclear bodies (PML-NBs)
What is caused by PML-RARA fusion?
- Alters the structure of the PML-NBs, resulting in nuclear microspeckles
- Fusion protein has a dominant negative and gain of function effect
- PML-RARA represses genes involved in myeloid differentiation
What further abnormalities are seen in APL?
- 1-2% APL patients have novel translocations other than t(15;17) involving RARA
- Almost half of APL patients have further alterations such as del7q and trisomy 8 (most prevalent)
What is CPM?
Confined placental mosaicism
What is the most common viable aneuploidy?
Trisomy 21
What is the most common human aneuploidy?
- Trisomy 16 (observed in pregnancies)
- Estimated to occur in 1-1.5% of all pregnancies
- Trisomic rescue in up to 10% of T16 pregnancies
What abnormality causes Emanuel syndrome?
- t(11;22) - one of the most common non-Robertsonian translocations in humans
- 3:1 meiotic malsegregation of derivative 22 results in partial trisomy for Ch22
What characterises the breakpoints for t(11;22) translocation?
- AT-rich palindromic repeats (PATRRs), susceptible to DSBs which are then
What disease is caused by maternal UPD 14?
Temple syndrome
What are complex abnormalities?
AML patients with 3 or more acquired chromosomal abnormalities other than 15;17, 8;21, inv16 (favourable) can be referred to as AML with complex karyotype
What is an example of epigenetic modifications in cancer?
- EN1 (regulates growth and proliferation) methylation observed to be elevated by up to 60% in human salivary gland adenoid cystic carcinoma
- EN1 and SCTR methylation increased in colorectal and prostate cancers
What is FLT3-ITD?
- Example of a poor prognostic marker in AML
- FLT3 is a tyrosine kinase, mutation leaves it constitutively active = proliferation
- ITD = internal tandem duplication
How prevalent is FLT3 mutation in AML?
Most commonly mutated gene in AML occurring in approx 30-40% AML patients
What is the implication of abnormalities involving chromosome 7 (e.g. del7q, monosomy 7) in AML and MDS?
- Poor prognostic marker
- Loss of tumour suppressor genes e.g. Cux1
*** del5q there’s something about how its good prognosis if the only abnormality with MDS??? not sure find out
What is the prognosis for abnormalities involving loss of TP53 e.g. iso17q?
Poor prognostic marker in AML
What gene fusion occurs as a result of t(8;21)?
- RUNX1-RUNX1T1
- Encodes an aberrant transcription factor which dysregulates gene expression at multiple levels
- Favourable outcome, high rates of remission
Which secondary abnormalities are associated with a worse outcome in AML?
- FLT3 mutations and +8
- Worsens outcome with inv(16) which is favourable
In what proportion of APL cases are secondary abnormalities observed?
- Around 40% of cases
- +8 most common, also FLT3-ITD both poor prognostic markers
What is the prognosis associated with acute leukaemia relapse?
Poor e.g. adult ALL relapses
What role does isodicentric 17q play in cancer formation?
Identified as a primary and secondary abnormality meaning it can be involved in development AND progression
What is the function of BRCA1 and BRCA2? (3)
- Tumour suppressor genes involved in checkpoint activation and DNA repair (homologous recombination)
- It is thought that rapid hormone-driven proliferation of breast cells puts a strain on the DNA repair pathways, leading to accumulation of DNA damage and genomic instability = tumorigenesis
- BRCA1/BRCA2 inactivation often seen alongside TP53 loss = evade checkpoint controls and evade apoptosis so can continue to proliferate unchecked and accumulate further mutations
