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Molecular Basis of Disease > Brain cancer > Flashcards

Brain cancer Flashcards

1
Q

What percentage of all cancers do brain tumors make up?

A

3%

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2
Q

What is the average age for peak rate of brain tumour cases?

A

85-89

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3
Q

Why might the average brain tumour age be skewed?

A

Glioblastomas are more common in the elderly

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4
Q

TRUE or FALSE?

The brain tumor incidence has been rising (by about 34%) since the 1990s

A

TRUE

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5
Q

Where are most benign brain tumors found?

A

Meninges

Meningiomas

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6
Q

What is the most common type of brain tumour?

A

Glioblastoma

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7
Q

What is the 5-year survival rate for glioblastomas?

A

Very bad (10% or less)

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8
Q

If you had chemo, surgery and radiation therapy for a glioblastoma what would your average survival be?

A

15 months

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9
Q

What are the obstacles to effective treatment of GBM?

A

Heterogeneity: different people have different mutations and different cells in the tumours

Glioma stem-like cells are treatment-resistant

Invasion

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10
Q

What are the sources of heterogeneity in GBM?

A

Inter- and Intratumoral

Molecular (genetic, transcriptional, epigenetic, cell signaling)

Cellular (GSC and lineage progression)

Therapy-induced (heterogeneity in recurrent GBM)

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11
Q

Describe the concept of intertumoural heterogeneity

A

Each tumour has:

  • Different mutations (e.g. abberations in DNA copy number, gene expression, and DNA methylation)
  • Epigenetic changes
  • Transcriptional changes
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12
Q

What are the three critical signalling pathways where genetic abberations are found?

A
  1. RTK/RAS/PI3K
  2. P53. Normally stop cells from dividing by becoming activated in response to stress signals (e.g. oncogenes). In most tumours this is downregulated
  3. CDKN2A
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13
Q

What is the most common mutation in brain cancers?

A

Amplification in EGF Rs

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14
Q

What are transcriptional sources of intertumoural heterogeneity?

A

Abberation in gene expression of EGFR, NF1, and PDGFRA/IDH1

Each define a different subtype of tumour

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15
Q

Expression of which molecule is associated with the proneural subtype?

A

PDGFRA/IDH1

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16
Q

Expression of which molecule is associated with the classical subtype?

A

EGFR

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17
Q

Expression of which molecule is associated with the mesenchymal subtype?

A

Loss of NF1

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18
Q

The theory of neural subtype of glioblastomas is a scientifically supported theory

TRUE or FALSE

A

FALSE

It was actually an artifact

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19
Q

What are sources of epigenetic intertumoural heterogeneity?

A

Methylation
Histone modification
Higher order structures
Close or open chromatin

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20
Q

How many subgroups of GBMs could be found if looking at DNA methylation patterns?

A

6

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21
Q

What is the most common mutation in brain cancers?

A

IDH1 gene, which codes for an enzyme, and whose mutation causes too much methylation

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22
Q

What is the survival like for patients witch IDH1 mutation?

A

Increased suvival

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23
Q

What are FISH studies and what have they revealed about intratumoural heterogeneity?

A

Fluorescence in situ hybridization (FISH)

Test that “maps” the genetic material in human cells, including specific genes or portions of genes.

PDGFRA and EGF receptor amplifications were found in the same tumour but not in the same cells

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24
Q

What problem does intratumoural heterogenity pose for treatment?

A

Different diagnoses will be given depending on where you sample the tumor

If you use a specific targeted therapy you may only inhibit some cells and not others

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25
Q

What have copy number analysis and RNA-seq revealed about molecular intratumoural heterogeneity?

A

Different regions of a brain tumor harbors different aberrations and alterations in gene copy numbers

Different regions harbour distinct transcriptional profiles

Within the tumour you have samples which classify into different subtypes

26
Q

What is 5 ALA?

A

A substance that, if given to brain cancer patients, causes the tumour to fluoresce

27
Q

What have single cell RNA-seq of molecular intratumoural heterogeneity shown?

A

Single cells from the same tumor present distinct transcriptional profiles and can be categorized into different subgroups

28
Q

What have functional alalyses of GBM clones shown about cellular intratumoural heterogeneity?

A

Clones display different markers, proliferation, and differentiation

Even though they come from the same tumour

29
Q

What are the theories as to how heterogeneity occurs?

A
  1. Survival of the fittest
  2. Glioblastoma stem-like cells (GSCs)
  3. Plasticity driven by the microenvironment (e.g. hypoxic microenverionment select specific mutations)
  4. Branched tree model
30
Q

Explain the survival of the fittest theory for heterogeneity

A

Clonal evolution

Tumor cells divide and acquire mutations

Upon a selective pressure the most fit clone(s) will survive and cause tumor relapse

31
Q

Explain the GSC theory for heterogeneity

A

SCs divide asymmetrically and generate

  • SCs
  • More differentiated tumor cells that can acquire mutations.

Upon treatment, resistant SCs will survive and cause tumor relapse

32
Q

Explain the Plasticity driven by the microenvironment model for heterogeneity

A

microenvironment –> epigenetic mechanisms –> cells with different tumorigenic properties

33
Q

Explain the branched tree model for heterogeneity

A

Mutations shared by all tumor cells proceed from the founder clone which is depicted as the trunk of the tree.

The branches are composed by tumor cells that acquire mutations present only in a subset of the tumor cells.

34
Q

What is the evidence for therapy induced heterogenity?

A

Low grade gliomas and their recurrences are highly divergent with 43% of tumours carrying mutations not detected at recurrence

Emergence of treatment-resistant subclones displaying TMZ-induced hypermutator phenotype, i.e. TMZ imposes distinct evolutionary trajectories

35
Q

TRUE or FALSE?

When recurrent tumours are found in a different location they are the same type of tumour as the first one

A

FALSE

36
Q

To summarize, what are the things that influence heterogeneity?

A

Treatment
Location
Microenvironment
Cellular hierarchy

37
Q

Where does adult neurogenesis occur?

A

Dentate gyrus of the hippocampus

Subventricular zone of the lateral ventricle

38
Q

How did people figure out the involvement of GSCs in tumour development?

A

The tumour cells had stem cell markers and could become different neurons

If you implant CD133- cells they won’t make a tumour but CD133+ caused tumours

39
Q

What is the marker for stem cells?

A

CD133

40
Q

What are properties of glioma stem-like cells?

A

Required functional characteristics:

  • Sustained self-renewal
  • Persistant proliferation
  • Tumour initiation

Common (but not defining characteristics):

  • Frequency in tumour
  • Stem cell marker expression
  • Ability to differentiate along multiple lineages
41
Q

What is the evidence of GSC as the origin of tumour heterogeneity?

A 
Barcoded tumour cells  -->
Passaged them (also doing DNA seq) --> supported the idea of a neural evolution of the tumour (similar to neural stem cell division not survival of the fittest)
42
Q

What is the possible reason for therapeutic resistance in tumours?

A

Chemotherapy: glioma stem cells can quiesce, these approaches only target dividing cells

Radiotherapy: Stem cells have the ability to initiate check point inhibition and repair their DNA

43
Q

In order to cure a cancer what cells do you have to target?

A

The stem cells

44
Q

What are the 3 methods of cancer invasion?

A

Via brain parenchyma
Via blood vessels
Via white matter tracts

45
Q

Which molecules are involved in tumour vascular homing?

A

SDF-1/CXCR4

Bradykinin

46
Q

What are SDF-1 and CXCR4 and how have they been shown to be involved in vascular homing?

A

SDF-1 is a chemokine and CXCR4 is its receptor expressed by tumour cells

If you put SDF-1 in media (to ruin the gradient) or knock down the CXCR4 receptor, the neural stem cells/tumour cells don’t migrate much

47
Q

How is bradykinin part of vascular homing?

A

Brain tumors have bradykinin receptor 2

It is important for tumor migration

Give bradykinin –> increase the Ca2+ signal in the cells –> migrate towards higher bradykinin gradient

48
Q

Which molecule is important for perivascular invasion?

A

Ephrin-B2

49
Q

What are the 3 mechanisms which help tumour cells use blood vessels to invade new regions?

A

Vascular homing

Perivascular invasion

Overcoming barriers to perivascular invasion

50
Q

What is the role of Ephrin-B2 in perivascular invasion?

A

Ephrin-B2 repels migrating cells

Tumour cells are proven to no longer be sensitive to Ephrin B2

If you knock out Ephrin B2 tumour cells stop migrating and forming tumours

Overexpressing ephrin B2–> transform neural stem cell to tumour cell

51
Q

How do tumours overcome barriers to perivasuclar invasion?

A

Astrocyte end feet control how blood vessels constrict.

Tumour cells displace astrocyte end feet –> astrocytes lose control on the vasculature–> Glioma cells then take control of the vasculature (cause diameter of blood vessels to increase)

52
Q

What happens exactly when tumour cells cause astrocytes to lose control of vasculature?

A

Leakage of serum into parenchyma

Loss of tight junctions

Degradation of basement membrane

53
Q

What is glioblastoma survival like compared to other cancers?

A

Much worse

54
Q

What are current treatments for glioblastoma?

A

Surgery (when possible), radiation, chemo (temozolomide)

No major breakthrough apart from TMZ and no success with targeted therapy in trials

55
Q

Define grade

A

How abnormal the tumour cells are to normal cells

56
Q

Define stage

A

How far the tumour has spread

57
Q

How do tumour cells form

A
  1. Cell of origin can be a neural progenitor or even a differentiated astrocyte or neurone which can dedifferentiate
  2. Pre-neoplastic cell (not studies yet)
  3. Neoplastic cells
58
Q

How does methylation affect transcription?

A

It represses the expression of neighbouring genes

59
Q

How does methylation work?

A

DNA methyltransferases methylate cytosine –> recognised by editor enzymes –> mediate the transformation of 5 methyl cytosine to 5 hydroxyl methyl cytosine (on the way to demethylation)

Readers (chromatin remodelling factors) recognise 5 methyl cytosine and lead to further changes in chromatin structure

60
Q

What are the pros and cons of the different models used for identifying good glioblastoma treatment targets?

A

Genetically modified GBM:
Pros: allows for careful modelling
Cons: TIME (though tech is improving fast), how faithful (mouse v. human), availability of drugs, BBB

Patient-derived primary GBM cells:
Pros: TIME, may be used to make decision regarding therapy regimen
Cons: depends on availability of targeting agents; in vitro clonal selection (intra-tumour heterogeneity), cells cannot be derived from every tumour, engraftment issues , BBB

61
Q

What are the types of targets for GBM therapy?

A
  1. Tumour subtype/stage-specific targets (e.g. IDH1 mut)
    a. Target mut IDH1 in the initial tumour
    b. When tumour comes back you could, in principle, perform further (epi)genomic analysis and identify stage specific targets
  2. Targets common to multiple GBM subtypes/subclones
    Example: a number of oncogenic signals could be shared by different tumour subtypes (e.g. Myc transcription factors)
62
Q

What are the problems with the two types of tumour targets?

A

Subtype specific:
Time from molecular analysis to therapy
Availability of experimental models/drugs
Little interest from pharma given small nr. Of patient + issue of costs for health services

Common mutations:
Limited number, might be difficult to target
Toxicity to normal cells

Molecular Basis of Disease (28 decks)

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