Part 1: Introduction + Background Information
Formation
- Brain tumours form through combo of
o Cell of origin (implicates location)
o Mutation
o Window of opportunity the time when the mutation is active AKA the age of the patient
when the tumour manifests
- Knowledge of location and age of patient is essential to formulate hypothesis for work up of a
tumour
- Systematic and logical approach needs holistic consideration of histology, location, and age
- Characteristic morphology facilitates mutation prediction but its impossible when non-specific
Hierarchical model of cancer
1. Stem cells/progenitor cells
2. Monoclonal 1 mutation
3. Monoclonal 2 mutation
4. Monoclonal 3 mutation
5. Polyclonal 4 mutations
The combination of mutations determines tumor type
- If mutation occurs in one of our cells, the tumor is more susceptible to PDGF and starts proliferating
- These cells either undergo apoptosis or acquire a different mutation tumor cells have a growth
advantage
Part 2: Mutations and Diagnosis
- Two major types if IDH-mutant tumours differentiated by distinct molecular features
o Astrocytomas
Additional mutation in ATRX and p53 + deletion of CDKN2A/B delineates high-grade
from lowergrade IDH-mutant astrocytomas
o Oligodendrogliomas
IDH mutation + 1p/19q codeletion + TERT promoter mutation
o IDH wt glioblastomas
Chromosome 7 gain + 10 loss + EGFR amplification + TERT promoter mutation
Diagnosis summary
Targeted use of validated diagnostic biomarkers is essential to define and diagnose glioma entities
sufficient to resolve a majority of diseases
, Tumour
initiating cells
(Cell of origin)
p53 mut MAPK pathway IDH1/2 mut
p53 mut, ATRX 1p/19q
BRAF V600E BRAF Fusion
loss TERT mut
7p +, 10q -
EGFR amp,
TERT mut
PXA,
Astrocytoma Oligodendrogliom
Ganglioglioma, Pilocytic Astro
grades II and III a
pilocytic A.
Early GBM
Additional
CDKN2A/B Del CDKN2A/B CDKN2A/B Del
mutations?
GBM midline GBM Anaplastic
GBM K27M mutant G34R mutant Anaplastic oligodendrogliom
IDH mutant
PXA/Epitheloid Anaplastic PA a
ATRX loss ATRX loss GBM
GBM
IDH1 and IDH2 metabolic pathways
Normal vs mutated IDH
- IDH is an enzyme that converts isocitrate to a-KG succinate myelinate, etc
- Mutation in IDH gene usually happens at codon 132 in IDH1 and codon 172 in IDH2
- Mutation causes different metabolic activity of IDH
o No more isocitrate as substrate
o Causes a completely new metabolite (2-hydroxy-glutarate)
o This metabolite has a profound effect on histone methylation causes a global DNA
hypermethylation increase stemness and less differentiation
Disribution of different mutations
- Frequency of IDH1 and IDH2 mutation in oligodendrogliomas and astrocytomas
o IHC for EDH1 R132H detects 90% of all IDH mutations
o Sequencing of the remaining IDH1 and all IDH2 mutations is advised in patients under 55e
Jaunmuktane et al., 2019
Two IDH mutant tumor types
Formation
- Brain tumours form through combo of
o Cell of origin (implicates location)
o Mutation
o Window of opportunity the time when the mutation is active AKA the age of the patient
when the tumour manifests
- Knowledge of location and age of patient is essential to formulate hypothesis for work up of a
tumour
- Systematic and logical approach needs holistic consideration of histology, location, and age
- Characteristic morphology facilitates mutation prediction but its impossible when non-specific
Hierarchical model of cancer
1. Stem cells/progenitor cells
2. Monoclonal 1 mutation
3. Monoclonal 2 mutation
4. Monoclonal 3 mutation
5. Polyclonal 4 mutations
The combination of mutations determines tumor type
- If mutation occurs in one of our cells, the tumor is more susceptible to PDGF and starts proliferating
- These cells either undergo apoptosis or acquire a different mutation tumor cells have a growth
advantage
Part 2: Mutations and Diagnosis
- Two major types if IDH-mutant tumours differentiated by distinct molecular features
o Astrocytomas
Additional mutation in ATRX and p53 + deletion of CDKN2A/B delineates high-grade
from lowergrade IDH-mutant astrocytomas
o Oligodendrogliomas
IDH mutation + 1p/19q codeletion + TERT promoter mutation
o IDH wt glioblastomas
Chromosome 7 gain + 10 loss + EGFR amplification + TERT promoter mutation
Diagnosis summary
Targeted use of validated diagnostic biomarkers is essential to define and diagnose glioma entities
sufficient to resolve a majority of diseases
, Tumour
initiating cells
(Cell of origin)
p53 mut MAPK pathway IDH1/2 mut
p53 mut, ATRX 1p/19q
BRAF V600E BRAF Fusion
loss TERT mut
7p +, 10q -
EGFR amp,
TERT mut
PXA,
Astrocytoma Oligodendrogliom
Ganglioglioma, Pilocytic Astro
grades II and III a
pilocytic A.
Early GBM
Additional
CDKN2A/B Del CDKN2A/B CDKN2A/B Del
mutations?
GBM midline GBM Anaplastic
GBM K27M mutant G34R mutant Anaplastic oligodendrogliom
IDH mutant
PXA/Epitheloid Anaplastic PA a
ATRX loss ATRX loss GBM
GBM
IDH1 and IDH2 metabolic pathways
Normal vs mutated IDH
- IDH is an enzyme that converts isocitrate to a-KG succinate myelinate, etc
- Mutation in IDH gene usually happens at codon 132 in IDH1 and codon 172 in IDH2
- Mutation causes different metabolic activity of IDH
o No more isocitrate as substrate
o Causes a completely new metabolite (2-hydroxy-glutarate)
o This metabolite has a profound effect on histone methylation causes a global DNA
hypermethylation increase stemness and less differentiation
Disribution of different mutations
- Frequency of IDH1 and IDH2 mutation in oligodendrogliomas and astrocytomas
o IHC for EDH1 R132H detects 90% of all IDH mutations
o Sequencing of the remaining IDH1 and all IDH2 mutations is advised in patients under 55e
Jaunmuktane et al., 2019
Two IDH mutant tumor types
