5. • In the laboratory,
• the key way to distinguish a somatic mutation from a hereditary mutation
• is to sequence the suspected gene mutation in both the tumor and normal tissue.
• In most cases, lymphocyte DNA from a blood sample is used as the normal control.
• If the mutation appears only in the tumor, and not in the normal tissue,
• it is evidence for a somatic mutation acquired during tumor development.
6. Genes related to the cancer
1. Oncogenes
2. Tumour suppressor genes
3. Mutator genes
7. TUMOUR SUPPRESSOR VERSUS ONCOGENES
• Gain of function Mutation of protooncogene Oncogenes activation
Tumour progression
• Loss of function Mutation of Tumour suppressor gene Inactivation
of gene Malignancy
8. Mutator genes
• when mutated
• increases the mutation rate in the cell's DNA.
• This elevated mutation rate leads to critical mutations in oncogenes and tumor suppressors,
• Examples of Mutator genes
• Mostly DNA repair enzymes;
• Pathology
• responsible for MMR syndrome.
• In GBMs, about 5% of tumors have MMR instability, indicating a mutation in one of the DNA MMR
enzymes.
9. GBM
• GBMs have two major classes based on clinical presentation:
• the primary (or de novo) and
• the secondary (or progressive) class.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. SECONDARY GBM
• first present as a grade II or III astrocytoma.
• About 5% of GBMs arise from grade II or III tumors.
• Have different spectrum of mutations.
• arise from grades II and III gliomas and
• As a class are defined by the presence of IDH1 or IDH2 mutations
in nearly all progressive gliomas.
20.
21.
22. p53 Mutation
• of all the astrocytomas,
• gemistocytic astrocytomas (grade II) exhibit the
• highest rate of p53 mutation, with 88% having a mutation, followed next by
• fibrillary astrocytomas,
• with 53% p53 mutation
23. IDH Mutations
• Mutations in one of the IDH genes are tightly linked with
• the Proneural phenotype and secondary glioblastomas.
• Virtually all tumors with IDH mutation are of the Proneural gene expression subtype.
• In addition, IDH mutation was observed to be associated with
• increased DNA methylation, called G-CIMP for Glioma CpG Island Methylation Phenotype.
• IDH 1-Cytosol
• IDH -2- Mitochondria
• IDH-3 –Kreb cycle metabolism
• People with gliomas with mutated IDH are, on average, several years younger than people with gliomas with wild-type IDH.
• The prognostic importance of IDH mutation is independent of other known prognostic factors, including age, grade, and MGMT methylation status.
• The development of a monoclonal antibody against IDH1 R132H allows the detection of the most common mutation seen in gliomas by
immunohistochemistry from paraffin embedded sections, and this method is being used with increasing frequency for clinical classification of tumors.
• It is now clear that mutations in IDH1 and IDH2 are driver mutations in low grade gliomas, likely through 2-HG (Hydroxy Glutarate) production.
24.
25.
26. Chromosomal Changes
• oligodendrogliomas have chromosomal changes also
• So,Oligodendrogliomas are best defined
• cytogenetically by LOH on chromosomal arms 1p and 19q.
• The loss of 1p/19q in oligodendrogliomas predicts very accurately the sensitivity to
chemotherapy
27. •astrocytomas are:
• either IDH mutants
with ATRX loss and
TP53 mutations or
•IDH wild-type,
•whereas
oligodendrogliomas are
IDH mutants with 1p/19q
codeletion.
28. ATRX Importance
• Platelet-derived growth factor receptor alpha gene (PDGFRA) amplification
• has also been shown to be significantly associated with ATRX loss and the ALT phenotype.