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DG & EC > KB L4&12 > Flashcards

KB L4&12 Flashcards

1
Q

What can increase/decreased incidence of ALL in children?

A

Increased affluence - increased ALL
Increased family size - more infections and more resistance to leukaemia (due to BM and immune system development)
Daycare - half risk of leukaemia (infections)
Big changes in environment ie new towns - ALL
EBV - glandular fever as a child may affect ALL as an adult

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2
Q

Why are there fewer steps to childhood cancers?

A

Embryonal cancer cells are rapidly dividing, are motile and have properties of cancers already. They don’t need to change much to become cancer. Only about 5% genetic predisposition because of this.

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3
Q

Three mutations that can cause ALL

A

E2A-PBX1 activation of the transcription factor PBX
MLL-AF4 HMT interacts with AF4 gene function altering epigenetic control 85% of infant ALL
BCR-ABL - activated kinase t(9;22)
SIL-SCL - fusion causes small deletion which up regulates SCL expression. SIL is a strong promoter

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4
Q

What causes AML?

A

MLL-AF6 modification of the transcription factor in 50% of all infant AML

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5
Q

What’s more common? ALL or AML?

A

ALL

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6
Q

What is PNET?

A

Primative neuroectodermal tumour

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7
Q

What is Ewing’s sarcoma?

A

An adolescent bone tumour

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8
Q

Relationship between Ewing’s and PNET?

A

Common translocations around C22

Often balanced translocations producing a fusion protein leading to a Homeric transcription factor which is oncogenic

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9
Q

EWS protein factoids

A

Chr 22
RNA binding domain and 9 transactivation domains
Express in 3T3 cells - transformed so EWS/FLI1 is dominant

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10
Q

What family of proteins from fusion proteins with EWS name 4.

A

Members of the ETS family. Have similar DNA binding domains

FLI1, ERG, ETV1, FEV1

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11
Q

What does EWS:WT1 fusion protein cause and what type of fusion is there?

A

Desmoplastic small round cell tumour. A stromal tumour of unknown origin. t(11;22)
N term of EWS to C term of WT1 - ¾ Zn fingers fuse with EWS to give a novel fusion dominant oncogene

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12
Q

What is rhabdomyosarcoma and what are the forms?

A

It is a childhood muscle tumour
Embryonal RMS - common
Alveolar RMS - rare and aggressive

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13
Q

Where is embryonal RMS mutations?

A

Oncogenes, especially the ras pathways

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14
Q

Alveolar RMS translocations?

A

t(2;13), t(1;13)
Pax 3 (chr2): foxo1a
Pax 7: foxo1a

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15
Q

What is the diagnostic use of chromosome translocations?

A

Use RT-PCR for specific fusion proteins ie. Primers in each gene of the fusion protein so will only get one product of the fusion protein is present

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16
Q

What could be the first hit in Rb?

A

Deletions in C13q14 and allele loss at 13q occurs in 75% of cases

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17
Q

What type of protein is RB1?

A

A 110kDa phosphoprotein involved in cell cycle control

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18
Q

How does RB1 affect E2F?

A

Active pRb binds E2F1/2 and its binding parter DP at the promoter of target genes and prevents its activation by recruiting HDACs leading to compressed/compact chromatin and no progression from G1-S phase.
When pRb is phosphorylated by CDK4 and cyclin D it is not longer able to bind to E2F allowing cell cycle progression.

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19
Q

What other functions (aside from e2f binding) does pRb have?

A

Inhibition of transcription by RNA pol I and III
Activates transcription of some genes
Coordinates assembly of proteins essential for cell cycle control

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20
Q

What happens with Rb is inactivated?

A

Uncoupling of cell cycle control and mitotic control leading to aneuploidy

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21
Q

KO of Rb in mice?

A

Development until 12-13 days gestation then death

Rb+/- mice - pituitary and thyroid tumours but no retinoblastoma in mouse heterozygous

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22
Q

What does NF1 germline mutation lead to?

A

Neurofibromatosis 16x risk of childhood cancer

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23
Q

Are most childhood cancers inhibited?

A

No. Rb is atypical

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24
Q

What mutation is poor prognosis AML?

A

FLT3
Internal tandem duplications of the juxta-membrane domain
Point mutations at position D853 in the activation loop. Leads to constitutive activation of FLT3 with proliferative and anti-apoptotic advantages

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25
Q

In paediatric AML what allelic ratio (mutation to wildtype) in FLt3-internal tandem duplication (itd) leads to what prognosis?

A

allelic ratio >0.4 is poor outcome

Allelic ration

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26
Q

Acquired isodisomy is?

A

Gain of chromosome/duplication of segment and loss of homologue
Can arise from trisomy and LOH or monosomy (already mutated) from 2nd hit and then mitotic recombination to replace lost chromosome and correct imbalance

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27
Q

What is imatinib mesylate?

A

The targeted therapy for CML with the Ph chromosome. Imatinib occupies the ATP binding pocket of the ABL kinase domain. Preventing substrate phosphorylation and signalling - lack of proliferation and survival

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28
Q

Where do DNA breaks that result in chromosomal translocations occur in the gene?

A

In introns

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29
Q

In twins with ALL where do the chromosome breaks occur and what does this show?

A

In exactly the same place. Suggesting the fusion protien formed in utero in one twin and then all the progeny of this cell contained the fusion protein and spread to the other twin in utero via shared mono chorionic placentas . This shows that childhood leukaemia can originate from before birth as twin leukaemia may arise from 2 months to 14 years after birth

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30
Q

How else can evidence of childhood leukaemia originating before birth be shown?

A

Scrutiny of neonatal blood spots or Guthrie card studies. Using pcr tests for specific fusion genes. In a blood spot can detect 1-20 leukaemia cells
Guthrie cards show that leukaemia is of fetal origin in all causes of MLL fusion infant leukaemia and most cases in ALL TEL-AML1

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31
Q

How much risk of developing ALL of a twin who has it?

A

100 fold risk

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32
Q

What does epidemiological evidence suggest may be part of development of leukaemia subtypes?

A

Ionising radiation, chemicals (benzene), viruses and bacteria (H. Pylori)

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33
Q

Infant leukaemia risk gene?

A

Polymorphic variants of NQ01 - detoxifies benzene metabolites and quinone containing flavoids

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34
Q

Childhood ALL risk genes?

A

HLA II alleles

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35
Q

ALL risk in infants and older children and adults has been linked to what?

A

Inheritance of alleles of MTHFR - folate metabolism. Which may affect the fidelity of DNA replication and possibly vulnerability to chromosomal breaks

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36
Q

p53 mutations are rare at leukaemia presentation but?

A

They are more common at relapse helping to explain therapeutic resistance in more advanced disease

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37
Q

PML-RARA fusions occur in what cancer and what is the treatment?

A

Promyeloblastic leukaemia. Use of a derivative of retinoic acid to induce remission in acute PMBL

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38
Q

What drug inhibits ABL and has been shown to have a major impact on CML?

A

STI-571, and is non-toxic

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39
Q

How can paediatric ALL be assessed?

A

Using qt PCR to look for fusion genes

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40
Q

Where are neuron lasting tumours derived from?

A

Embryonic cells that form the neural crest and eventually give rise to the peripheral nervous system among other organ systems

41
Q

PHOX2B mutations cause what type of NB?

A

A small subset of familial NB due to mutations in the germline

42
Q

What is ALK implicated in?

A

It is a tyrosine kinase and has been implicated in amplification and translocation of genomic sequences in non-hodgkins lymphoma and various solid tumours and also it is a major non-syndromic neural asthma predisposition gene

43
Q

ALK has mutational hotspots which mean it

A

Has characteristic gain of function mutations in ‘cancer predisposing oncogenes’ that lead to increased activity of the oncoprotein

44
Q

Somatic single-nucleotide mutations in ALK are associated with?

A

More aggressive tumours and lethality of the cancer

45
Q

How does point mutations in ALK disrupt signalling pathways and could this be targeted?

A

L-R at 1174 ALK - phone of STAT3 and Akt proteins
R-Q at 1275 assoc with phos of Akt and Erk1/2
Inhibit ALK via these mutations to treat NB using multi signalling pathway inhibitors and protein specific inhibition

46
Q

Incidence if neuroblastoma

A

Commonest solid childhood cancers 1/7000 live births 7% of childhood cancers
100 cases per year in the uk

47
Q

Cellular origins of NB?

A

Embryonal tumour begins before birth. Originates in the neural crest stem cells. Tumours may arise anywhere along the sympathetic ganglia but the most common site is the adrenal medulla

48
Q

NB metastasis?

A

CNS, lungs, LN, liver, BM and bone. Most likely is BM and this is probably what kills most children in refractory NB

49
Q

Histology of NB?

A

Rosettes - clusters of cells
Small blue round neuroblasts GanlioNB - slightly less aggressive, with neuroblasts and larger differentiated ganglia cells
Ganglioneruoma - ganglia cells in stroma, completely differentiated. Less aggressive no dediff to a less mature phenotype

50
Q

What cell lines can be derived from NB tumours and how aggressive are then?

A

N & I type are more aggressive
S type is less aggressive but can interdifferentiate. Can treat cells with different chemicals to get them to become each other

51
Q

What used to be used as screening markers for NB?

A

VMA of HVA in the urine. But this only picked up good prognosis and thought that VMA secretion was before ‘bad’ tumour arose. This is not the case

52
Q

How can NB be identified?

A

NB cells take up MIBG a noradrenaline analogue. Radioactive iodine labelling of MIBG for diagnosis and therapy

53
Q

Children less than 18 months with S1/S2 NB can be cured by?

A

Surgery and minimal chemo

>80% survival

54
Q

What stage of NB sometimes undergoes spontaneous remission and why?

A

4S - disseminated but spontaneous remission can occur. NB has the highest spontaneous remission rate of any human cancer. May be due to cells experiencing

  1. Neurotrophins deprivation - apoptosis
  2. Immune mediated cell killing
  3. Telomere shortening - apoptosis or normal senescence
  4. Epigenetic chances specific to 4s that predisposes spontaneous regression
55
Q

What are he three NB subtypes?

A

1 - hyperdiploidy or near triploidy with a few segmental abnormalities with high trophomyosin receptor kinase A
2A & 2B - near diploidy and recurrent SCAs many of these have unbalanced gain of C17q and most over express trkB and its ligand BDNF

56
Q

Favourable outcome NB tumours

A

Near triploid, whole chromosome gains rare structural rearrangements

57
Q

Poor outcome NB tumours

A

Near diploid karyotypes. Frequent rearrangements 1p, 11q deletions and 17q gains - prognostic marker

58
Q

On neurotrophin binding to trkA what happens?

A

It phosphorylated itself and triggers the MAPK pathway

59
Q

NB subset 2 is assoc with?

A

Older age advanced tumour stages and worse clinical outcome

60
Q

NB is inherited in what fashion?

A

Autosomal dominant

61
Q

Weak predispositions with SNPs for NB

A

LMO1, BARS1 and 1q21 CNV (1.5-2x predisposition)

62
Q

What chromosome is ALK on?

A

C2 so co-amplified with MYCN sometimes

63
Q

What chromosome is MYCN on?

A

C2

64
Q

ALK forms dimers in the membrane and switches on well defined pathways it consists of?

A

An EC MAM and LDL domain
A transmembrane domain
And an IC kinase domain

65
Q

Genome sequencing have shown what changes in NB?

A

Chromothripsis - local shredding of chromosomes due to improper separation in cell division and localisation to a micronucleus
Defects in nuritogenesis genes
Mutations in chromatin remodelling genes (ATRX which loads H3.3)
Mutations in rac-rho pathway
These changes cluster in high risk tumours

66
Q

In relapse NB tumours

A

There are increased mutations often involving ras-MAPK
Some of these mutations may have presented in a minority of tumour cells at diagnosis or could be spontaneous subclones or therapy induced after chemo

67
Q

Mutations In what genes are more frequent in relapsed NB and what pathway do they feed into?

A

ALK, Nras, BRAF and feed into ras-MAPK pathway. Potential therapy targets. Relapses are often what kills the child

68
Q

DNA methylation in NB?

A

TSG hyper methylation and large regions of epigenetic silencing CpG methylation is associated with poor prognosis

69
Q

Histone modifications in NB?

A

HDAC inhibitor sensitivity in NB suggests histone mods are important. Some TSGs are silenced by repressive histone modifications
NSD1 a HMT gene is inactivated by methylation. These may drive primary tumours but Unknown

70
Q

Future therapy of NB?

A

Anti-GD2 - ganglioside often seen on the surface

Chimeric antigen receptors agains GD2 - initiation of T cell activation signals targeting NB cell

71
Q

Retanoids for treatment of NB do what?

A

Induce differentiation of NB cells in culture to a more mature cell type

72
Q

MYCN is somatic ally mutated in NB what are the factoids?

A

Cytogenetics shows double minutes (small chromosome fragments, duplicated over and over) and homogenous staining regions (expanded regions) both associated with DNA amplification
Poor prognosis tumours

73
Q

How many times is MYCN amplified in NB?

A

10-100

74
Q

Single copy of MYCN and localised tumours in NB?

A

good prognosis

75
Q

Transgenic mice with tyrosine hydroxylase (gene expression in sympathetic nervous system) driving MYCN gives?

A

NB in mice

76
Q

1p36 chromosomal abnormalities may have a role in?

A

Malignant transformation it predisposition to NB. But familial neuroblasts a is not linked to 1p36 suggests any predisposition lies elsewhere.

77
Q

Patients that have a genetic predisposition to NB usually have?

A

Multi focal primary tumours that arise at an early age with a predisposition locus in 16p

78
Q

Mass NB screening of infants aged 6-12 months led to?

A

Increased prevalence of NB but no decrease in mortality from NB. Suggesting majority of cases are the favourable phenotype

79
Q

When does ploidy of NB lose its prognostic significance?

A

In patients older than 1-2 years due to increase in structure rearrangements

80
Q

MYCN is amplified in NB and what advantage to cells?

A

Selective

81
Q

What is amplified MYCN associated with in NB?

A

Advanced stages of disease and poor outcome and with rapid tumour progression and a poor prognosis even in infants and patients with lower stages of disease with survival of those with the amplification being around 1.5 years

82
Q

MYCN copy number is what in tumour progression and what does this mean for those who don’t have the amplification?

A

Consistent throughout disease progression. Suggesting MYCN amplification is an intrinsic Biological property of a subset of aggressive NBs and those without having amplification at diagnosis rarely develop it

83
Q

MYCN dimerises with? And targets?

A

With MAX and complex is a transcriptional activator and targets ODC, MCM7 and MRP1 activation of these genes leads to progression through G1 phase of the cell cycle. Thus high levels of MYCN (regardless of short half life) ensures cells stay in cell cycle and do not enter G0

84
Q

NB cell lines without MYCN amplification do?

A

Express high MYCN mRNA or MYCN protein perhaps due to alterations in protein degradation rather than loss of MYCN in auto regulation

85
Q

There is correlation between MYCN in amplification and deletion of?

A

1p LOH. Both strongly correlated with poor outcome and each other

86
Q

In terms of 1p LOH and MYCN what comes first?

A

1p LOH as this can occur in NB without MYCN amplification but MYCN amplification is mostly accompanied by 1p LOH. So, 1p may have a gene that regulates MYCN that is deleted it there is an abnormality that leads to genomic instability that predisposes 1p LOH and MYCN amp.

87
Q

Alleoltyping and CGH studies have shown that trisomy of 17q may occur in…?

A

More than half of all NBs and more aggressive NBs

88
Q

High expression of Hras in NB is associated with?

A

Lower stage of disease and better outcome

89
Q

11q loss was detected in 43% of patients by analysis of DNA polymorphisms and CGH techniques and is associated with?

A

14q deletion and inversely correlated with 1p deletion and MYCN amplification. 111q LOH was assoc wth decreased event free survival (but only when lacking MYCN amplification)

90
Q

What causes malignant transformation of sympathetic neuroblasts to NB cells?

A

Neurotrophin receptor expression

91
Q

Activation of TrkA by NGF leads to?

A

Survival and differentiation of neuroblasts into ganglion cells. Selected neuroblasts induce the invasion and proliferation of Schwann cells and these stromal cell produce neurotrophic factors that lead to neuroblast differentiation

92
Q

Absence of NGF in environment in NB where cells have high TrkA means

A

Apoptosis and regression

93
Q

Some NB cells manage to become resistant to chemotherapy by?

A

Over expressing genes that confer resistance by enhancing drug efflux ie MDR1 and MRP

94
Q

Spontaneous regression of NB may happen because?

A

Bcl2 up regulation and caspases up regulation

95
Q

NB Patients with primary tumours in the adrenal gland seem to do…?

A

Worse than patients with tumours originating at other sites

96
Q

How is neuron-specific endolase associated with NB?

A

It is a cytoplasmic protein associated with neural cells and survival is substantially worse for patients with advanced disease and high NSE

97
Q

Cd44 expression in NB?

A

Has prognostic significance with high expression associated with more differentiated tumours and a better outcome

98
Q

Microscopic neuroblastic nodules occur?

A

Uniformly in fetuses at around 17-20 weeks and are likely to be remnants of fetal adrenal development. In adrenal based NB these cells may be where NB begins to develop.

99
Q

TreAtment of high risk NB patients with what after BM transplant shows significant survival advantage and minimal extra toxicity?

A

13-cis retinoic acid

DG & EC (6 decks)

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