Extra reading

Question 1

What is the proper notation for the Philadelphia chromosome?

Answer 1

t(9;22)(q34;q11.2)

Question 2

What gene fusion is seen in follicular lymphoma?

Answer 2

• t(14;18)(q32;q21)
• IGH promoter and BLC2 fusion

Question 3

What gene fusion is seen in APL?

Answer 3

• Acute promyelocytic leukaemia
• t(15;17)(q24;q21)
• PML-RARA

Question 4

What is the MLL gene? (4)

Answer 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

Question 5

What is the location of MLL gene?

Answer 5

11q23

Question 6

What fusion gene is seen in prostate cancer?

Answer 6

TMPRSS2-ERG results in generation of a neoplastic phenotype

Question 7

What is the total number of gene fusions identified?

Answer 7

Nearly 10 000

Question 8

What are TIGFs?

Answer 8

• 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

Question 9

What happens to MYC in Burkitt lymphoma?

Answer 9

Multiple fusions have been identified involving chromosome 8q24 fusion with immunoglobulin promoter regions (MYC location) = MYC overexpression = proliferation

Question 10

What are the 3 oncogenic impacts of chromosomal rearrangement?

Answer 10

• Fusion protein formation
• Gene fusion to highly expressed promoter
• Gene truncations resulting in activation of tumour suppressors

Question 11

What is the targeted therapy for APL?

Answer 11

• ATRA plus arsenic trioxide
• Causes terminal differentiation of APL cells
• 90% achieve long term remission

Question 12

What are the risks associated with APL?

Answer 12

• High pre-treatment mortality rate usually caused by cerebral haemorrhage
• DIC = disseminated intravascular coagulation, causes abnormal clotting

Question 13

What are the features of PML and RARA? (2)

Answer 13

• 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)

Question 14

What is caused by PML-RARA fusion?

Answer 14

• 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

Question 15

What further abnormalities are seen in APL?

Answer 15

• 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)

Question 16

What is CPM?

Answer 16

Confined placental mosaicism

Question 17

What is the most common viable aneuploidy?

Answer 17

Trisomy 21

Question 18

What is the most common human aneuploidy?

Answer 18

• Trisomy 16 (observed in pregnancies)
• Estimated to occur in 1-1.5% of all pregnancies
• Trisomic rescue in up to 10% of T16 pregnancies

Question 19

What abnormality causes Emanuel syndrome?

Answer 19

• 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

Question 20

What characterises the breakpoints for t(11;22) translocation?

Answer 20

• AT-rich palindromic repeats (PATRRs), susceptible to DSBs which are then

Question 21

What disease is caused by maternal UPD 14?

Answer 21

Temple syndrome

Question 22

What are complex abnormalities?

Answer 22

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

Question 23

What is an example of epigenetic modifications in cancer?

Answer 23

• 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

Question 24

What is FLT3-ITD?

Answer 24

• Example of a poor prognostic marker in AML
• FLT3 is a tyrosine kinase, mutation leaves it constitutively active = proliferation
• ITD = internal tandem duplication

Question 25

How prevalent is FLT3 mutation in AML?

Answer 25

Most commonly mutated gene in AML occurring in approx 30-40% AML patients

Question 26

What is the implication of abnormalities involving chromosome 7 (e.g. del7q, monosomy 7) in AML and MDS?

Answer 26

- Poor prognostic marker - Loss of tumour suppressor genes e.g. Cux1

Question 27

*** del5q there's something about how its good prognosis if the only abnormality with MDS??? not sure find out

Question 28

What is the prognosis for abnormalities involving loss of TP53 e.g. iso17q?

Answer 28

Poor prognostic marker in AML

Question 29

What gene fusion occurs as a result of t(8;21)?

Answer 29

- RUNX1-RUNX1T1 - Encodes an aberrant transcription factor which dysregulates gene expression at multiple levels - Favourable outcome, high rates of remission

Question 30

Which secondary abnormalities are associated with a worse outcome in AML?

Answer 30

- FLT3 mutations and +8 - Worsens outcome with inv(16) which is favourable

Question 31

In what proportion of APL cases are secondary abnormalities observed?

Answer 31

- Around 40% of cases - +8 most common, also FLT3-ITD both poor prognostic markers

Question 32

What is the prognosis associated with acute leukaemia relapse?

Answer 32

Poor e.g. adult ALL relapses

Question 33

What role does isodicentric 17q play in cancer formation?

Answer 33

Identified as a primary and secondary abnormality meaning it can be involved in development AND progression

Question 34

What is the function of BRCA1 and BRCA2? (3)

Answer 34

- 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