IDH-1/2 mutation
[isocitrate dehydrogenase 1 (R132H/C/L/S/G)] [isocitrate dehydrogenase 2 (R172K/M/G/W)]
|
- IHC - Sanger sequencing - Pyrosequencing - NGS |
- Both |
- Recommended in all gliomas -Sequencing recommended if IDH1 R132H negative by IHC |
- Low grade gliomas - WHO grade II and III astrocytomas - Oligodendrogliomas - Secondary GBM |
- Molecular parameters for glioma classification - Presence of both variant and 1p/19q codeletion defines oligodendroglioma - Defines grade II and III astrocytomas, grade II and III oligodendrogliomas and secondary grade IV GBMs - Benefit from radiation or alkylating chemotherapy - Relatively favorable prognosis compared to IDH-wild-type astrocytic tumor with the histologically same WHO grade - Important in stratification for clinical trials - Associated with MGMT promoter methylation - Increased survival with alkylating chemotherapy or radiation -IDH1 R132H mutation may represent a promising target for mutation specific vaccination |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
1p/19q codeletion
[short arm of chromosome 1 (1p)]
[long arm of chromosome 19 (19q)]
|
- FISH - PCR - Array- or NGS-based methods |
-Diagnostic |
- Recommended in oligodendrogliomas |
- Oligodendroglimoa - Anaplastic oligodendroglioma - Oligoastrocytoma - Anaplastic oligoastrocytoma |
- Presence of both codeletion and IDH variant defines oligodendroglioma diagnosis - Diagnostic value enhanced by combined use of IDH-1/2, ATRX, CIC and FUBP1 - Predictive of response to alkylating chemotherapy and combination of radiation and alkylating chemotherapy - Relatively favorable prognosis |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
MGMT promoter hypermethylation
(O-6-methylguanine–DNA methyltransferase)
|
- Pyrosequencing - MSP - Array-based methods |
- Prognostic |
- Recommended for all grade III and IV gliomas |
- Anaplastic astrocytoma - Anaplastic oligodendroglia - Anaplastic oligoastrocytoma - GBM - Anaplastic gliomas |
- Associated with IDH-1/2 and G-CIMP phenotype - Benefit from TMZ treatment for high-grade gliomas - Prolongs PFS and OS in patients with high-grade diffuse gliomas - Extent of MGMT promotor methylation in glioma WHO grade II depends on IDH mutation and on 1p/19q co-deletion - Important in stratification for clinical trials - Independent favorable prognostic factor in GBM - Sensitivity to alkylating chemotherapy |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
ATRX loss of function mutations
(Alpha-thalassemia/mental retardation syndrome X)
|
- IHC - Sanger sequencing - NGS |
- Diagnostic |
- Strongly recommended for gliomas |
- Grade II/III astrocytoma - Secondary GBM |
- Frequently present in IDH-mutant astrocytic tumors - Mutations are observed in grade II/III astrocytomas, where they commonly co-occur with IDH mutation and are associated with extremely long telomeres - Whether this is independent of the effects of IDH mutation remains unclear - Relatively favorable prognosis in IDH-wildtype GBM - ATRX variants rarely found with 1p/19q codeletion |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349.; Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278.; Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
TERT promoter
mutations
[Telomerase reverse transcriptase (C228T/C250T)]
|
- Sanger sequencing - Pyrosequencing - NGS |
- Both |
- Recommended for gliomas |
- Grade II/III astrocytomas - Oligodendrogliomas - GBMs |
- Diagnostic parameters for diffuse astrocytic glioma, IDH-wildtype, with molecular features of GBM, WHO grade IV - Present in almost all IDH-mutant, 1p/19q-codeleted oligodendrogliomas - Frequent in IDH-wildtype GBM - Relatively worse prognosis in wild-type IDH or GBMs with unmethylated MGMT - Relatively favorable prognosis in IDH-mutant gliomas |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
H3 G34 mutation
[H3 Histone Family Member 3A (H3F3A)]
H3 K27M mutation [H3 Histone Family Member 3A (H3F3A) or Histone
Cluster 1 H3 Family Member B/C (HIST1H3B/C)]
|
- IHC - Sanger sequencing - NGS |
- Diagnositic |
- Recommended if clinically appropriate |
- Pediatric high-grade gliomas - GBMs in adults |
- Occurs most often in high-grade, IDH-wildtype tumors in young patients with glial or embryonal histology - Diagnostic parameter diffuse midline glioma (DMG) H3 K27M-mutant and diffuse glioma H3.3 G34-mutant - Poor prognosis in DMG - Prognostic meaning in other tumors remains unclear - Relatively worse prognosis than that of wildtype diffuse midline gliomas slightly longer survival time than IDH-wildtype GBM, but shorter than IDH-mutant astrocytoma, WHO grade IV - Mutations in the promoter of TERT and ALT secondary to mutations in ATRX are complementary mechanisms for telomere lengthening and are an essential step in gliomagenesis -Potentially predictive of effect of EZH2 inhibitors |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
EGFR amplification
EGFRvIII
(Epidermal growth factor receptor)
|
- FISH -Digital PCR - Array- or NGS-based methods - RT-PCR - Digital PCR - IHC - MLPA - NGS |
- Diagnostic |
- Recommended if clinically appropriate |
- GBM |
- Diagnostic parameters for IDH-wildtype astrocytoma, with molecular features of GBM - High copy number amplification frequent in IDH-wildtype GBM - EGFRvIII present in about half of EGFR-amplified GBMs - Possible therapeutic target |
Staedtke et al. 2016STAEDTKE V, DZAYE O & HOLDHOFF M. 2016. Actionable molecular biomarkers in primary brain tumors. Trends Cancer 2(7): 338-349., Kristensen et al. 2019KRISTENSEN BW, PRIESTERBACH-ACKLEY LP, PETERSEN JK & WESSELING P. 2019. Molecular pathology of tumors of the central nervous system. Ann Oncol 30: 1265-1278., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
BRAF mutation
(BRAF V600E) or fusion (KIAA1549:BRAF)
|
- IHC - Sanger sequencing - NGS - Pyrosequencing |
- Diagnostic |
- Recommended if clinically appropriate |
- Pleomorphic xanthoastrocytomas - Gangliogliomas - Pediatric low-grade gliomas - Epithelioid GBMs |
V600E mutation associated with: - Diagnostic value for a variety of gliomas, including epithelioid GBMs - Increased response to BRAF inhibitors - Must be interpreted in conjunction with histology and other prognostic factors Fusions associated with: - Indolent tumors - Pilocytic astrocytomas - Possible therapeutic target |
Monga et al. 2017MONGA V, JONES K & CHANG S. 2017. Clinical Relevance of Molecular Markers in Gliomas. Rev Méd Clín 28: 343-351., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |
Ki67
|
- IHC - Sanger sequencing - NGS - Pyrosequencing |
|
- Not included in the NCCN recommendations. |
- Gliomas |
- Conflicting results about glioma prognosis. |
Monga et al. 2017MONGA V, JONES K & CHANG S. 2017. Clinical Relevance of Molecular Markers in Gliomas. Rev Méd Clín 28: 343-351., Jiang et al. 2021JIANG T ET AL. 2021. Clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett 499: 60-72., NCCN 2020NCCN - NATIONAL COMPREHENSIVE CANCER NETWORK. 2020. Clinical Practice Guidelines in Oncology, Central Nervous System Cancers, Version 4.2020.. |