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6: Cancer genetics and treatment > 16. Genetics of ALL > Flashcards

16. Genetics of ALL Flashcards

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Biology 101 flashcards
1
Q

What type of cells accumulate in ALL?

A

Immature lymphoid blasts

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2
Q

What are the main types of ALL and how do they differ?

A

B-ALL - most common, early childhood, worse prognosis with increasing age. Normal trilineage haematopoiesis not preserved

T-ALL - much rarer. Normal trilineage haematopoiesis preserved

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3
Q

What are the symptoms of ALL?

A

Fever, fatigue, weight loss, bone pain, swelling, swollen lymph nodes

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4
Q

What is mixed lineage ALL?

A

Caused by rearrangements including KMT2A/MLL

> 100 partner genes for KMT2A

Most common abnormality in infants <1yr

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5
Q

When do KMT2A rearrangements usually occur?

A

In utero

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6
Q

What is the prognosis of mixed lineage ALL?

A

Poor

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7
Q

What sort of FISH probe is used to detect KMT2A rearrangements? Why?

A

Breakapart probe

Due to >100 different fusion partners

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8
Q

What is the most common sub-type of ALL in adults?

A

BCR-ABL associated ALL

25% of adult ALL, 2-4% of childhood ALL

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9
Q

What is the consequence of BCR-ABL in ALL?

A
  • Constitutive ABL1 kinase activity –> deregulated proliferation, apoptosis, differentiation –> growth and survival advantage
  • Treated with TKIs
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10
Q

What is the prognosis of BCR-ABL associated ALL?

A

Poor

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11
Q

How does BCR:ABL differ in ALL and CML?

A

70% of ALL patients with BCR:ABL have IKZF1 deletion as cooperative mutation – not seen in CML

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12
Q

Why is FISH used for KMT2A rearrangements, BCR-ABL and ETV6-RUNX1 instead of karyotyping?

A

Rearrangments can be cryptic so not detectable by karyotype

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13
Q

What abnormality is most commonly seen in childhood B-ALL?

A

ETV6-RUNX1 – t(12;21)

25% of childhood cases, translocation arises in utero

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14
Q

What is the prognosis of ETV6-RUNX1?

A

Good

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15
Q

What is the consequence of ETV6-RUNX1?

A

Fusion protein affects normal function of CBF (formed of RUNX1 and CBFB) - a TF that regulates normal haematopoiesis by promoting differentiation

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16
Q

What is high hyper diploidy?

What is the prognosis?

A

51-65 chromosomes

Usually gain of 4, 6, 8, 10, 14, 17, 18, X

Good

17
Q

What other mutations are often seen in high hyperdiploidy ALL?

A

Cooperating mutations in RAS activating pathway – FLT3, KRAS, NRAS, PTPN11

18
Q

What are the different sub-types of hypodiploidy?

What’s the prognosis?

A

Near haploidy (23-29 chromosomes)
- Very poor prognosis

Low hypodiploidy (30-39 chr)
- Very poor prognosis

High hypodiploidy (40-44 chr)
- Most common, best prognosis

19
Q

What’s the most common type of IGH rearrangement in ALL?

What’s the prognosis?

A

t(5;14) IL3-IGH

Hypereosinophilia

Intermediate

20
Q

Describe 2 rearrangements involving TCF3 and the prognosis

A
  1. t(1;19) TCF3-PBX1 is most common
    Intermediate prognosis
  2. t(17;19) TCF3-HLF
    Poor prognosis
21
Q

What is the consequence of iamp(21)?

What is the prognosis?

A

Intrachromosomal amplification of chr 21

  • Gain of at least 3 copies of large region of chr 21 including RUNX1
  • High risk of relapse on standard chemotherapy, improved outcome on intensive chemo

Poor prognosis

22
Q

Why are paediatric B-ALL patients tested by SNP array?

A

Frequent deletions involving 8 genes involved in B-cell differentiation, cell cycle regulation, proliferation, cell survival etc. ​

Usually secondary to a primary chromosomal abnormality

Helps with prognosis - further risk stratification when combined with cytogenetic risk - use UKALL-CNA classifier

23
Q

What are the 8 frequently deleted regions in paediatric B-ALL?

A

BTG1
IKZF1​
PAX5
CDKN2A/B​
RB1
EBF1​
PAR1
ETV6

24
Q

What types of B-ALL have a good prognosis?

A

High hyperdiploidy
ETV6-RUNX1 t(12;21)

25
Q

What types of B-ALL have an intermediate prognosis?

A

t(1;19) TCF3-PBX1
t(5;14) IL3-IGH

26
Q

What types of B-ALL have a poor prognosis?

A

KMT2A
BCR-ABL
TCF3-HLF
iAMP(21)
Hypodiploidy

27
Q

What genes are associated with an inherited susceptibility to ALL?

A

ETV6
PAX5

28
Q

What is the role of KMT2A?

A

Encodes a lysine histone methyltransferase

Transcriptional co-activator with key role in hematopoiesis

6: Cancer genetics and treatment (22 decks)

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