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L3 Clinical Genomics > Extra reading > Flashcards

Extra reading Flashcards

1
Q

What is the proper notation for the Philadelphia chromosome?

A

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

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2
Q

What gene fusion is seen in follicular lymphoma?

A
  • t(14;18)(q32;q21)
  • IGH promoter and BLC2 fusion
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3
Q

What gene fusion is seen in APL?

A
  • Acute promyelocytic leukaemia
  • t(15;17)(q24;q21)
  • PML-RARA
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4
Q

What is the MLL gene? (4)

A
  • MLL = mixed lineage leukaemia
  • MLL has over 40 gene fusion partners
  • E.g. MLL-AF4 and MLL-AF9 most common
  • 11q23 disturbance = poor prognosis
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5
Q

What is the location of MLL gene?

A

11q23

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6
Q

What fusion gene is seen in prostate cancer?

A

TMPRSS2-ERG results in generation of a neoplastic phenotype

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7
Q

What is the total number of gene fusions identified?

A

Nearly 10 000

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8
Q

What are TIGFs?

A
  • 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
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9
Q

What happens to MYC in Burkitt lymphoma?

A

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

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10
Q

What are the 3 oncogenic impacts of chromosomal rearrangement?

A
  • Fusion protein formation
  • Gene fusion to highly expressed promoter
  • Gene truncations resulting in activation of tumour suppressors
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11
Q

What is the targeted therapy for APL?

A
  • ATRA plus arsenic trioxide
  • Causes terminal differentiation of APL cells
  • 90% achieve long term remission
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12
Q

What are the risks associated with APL?

A
  • High pre-treatment mortality rate usually caused by cerebral haemorrhage
  • DIC = disseminated intravascular coagulation, causes abnormal clotting
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13
Q

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

A
  • 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)
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14
Q

What is caused by PML-RARA fusion?

A
  • 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
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15
Q

What further abnormalities are seen in APL?

A
  • 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)
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16
Q

What is CPM?

A

Confined placental mosaicism

17
Q

What is the most common viable aneuploidy?

A

Trisomy 21

18
Q

What is the most common human aneuploidy?

A
  • Trisomy 16 (observed in pregnancies)
  • Estimated to occur in 1-1.5% of all pregnancies
  • Trisomic rescue in up to 10% of T16 pregnancies
19
Q

What abnormality causes Emanuel syndrome?

A
  • 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
20
Q

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

A
  • AT-rich palindromic repeats (PATRRs), susceptible to DSBs which are then
21
Q

What disease is caused by maternal UPD 14?

A

Temple syndrome

22
Q

What are complex abnormalities?

A

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

23
Q

What is an example of epigenetic modifications in cancer?

A
  • 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
24
Q

What is FLT3-ITD?

A
  • Example of a poor prognostic marker in AML
  • FLT3 is a tyrosine kinase, mutation leaves it constitutively active = proliferation
  • ITD = internal tandem duplication
25
Q

How prevalent is FLT3 mutation in AML?

A

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

26
Q

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

A
  • Poor prognostic marker
  • Loss of tumour suppressor genes e.g. Cux1
27
Q

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

A
28
Q

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

A

Poor prognostic marker in AML

29
Q

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

A
  • RUNX1-RUNX1T1
  • Encodes an aberrant transcription factor which dysregulates gene expression at multiple levels
  • Favourable outcome, high rates of remission
30
Q

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

A
  • FLT3 mutations and +8
  • Worsens outcome with inv(16) which is favourable
31
Q

In what proportion of APL cases are secondary abnormalities observed?

A
  • Around 40% of cases
  • +8 most common, also FLT3-ITD both poor prognostic markers
32
Q

What is the prognosis associated with acute leukaemia relapse?

A

Poor e.g. adult ALL relapses

33
Q

What role does isodicentric 17q play in cancer formation?

A

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

34
Q

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

A
  • 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
35
Q
A

L3 Clinical Genomics (14 decks)

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