Adult-type Diffuse Gliomas
2023-07-26 Scott Ryall, PhD Affiliation1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)
Classification
Definition
The 2021 WHO guidelines for CNS tumor classification recognizes the clinical and molecular distinctions between diffuse gliomas that primarily occur in adults (termed “adult-type”) and those that occur primarily in children (termed “pediatric-type”). The goal of this distinction is to enable improved care for both children and adults with CNS tumors by avoiding adult-centric practices being applied in the pediatric setting, and vice versa. 1
In the previous (2016) WHO guidelines for CNS tumor classification diffuse gliomas of adults were divided into 15 entities with varying grades and histologic features. 2 However, the current edition simplifies the classification into three major entities based on both their histology and molecular underpinnings: i) astrocytoma, IDH-mutant, ii) oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and iii) glioblastoma, IDH-wildtype.
| Adult-type Diffuse Gliomas | Genetic Event(s) | |
|---|---|---|
| Astrocytoma, IDH-mutant | Astrocytoma, IDH-mutant tumors are define by the presence of IDH1 or IDH2 mutations. The most common variant is IDH1 p.R132H found in 83–91% of tumors but rare mutations including p.R132C/G/S/L are also seen. 3-5 Analogous IDH2 mutations, located at residue p.R172 are rare, with p.R172K being the most frequent. 4,6 Astrocytoma, IDH-mutant tumors also harbour loss-of-function mutations in TP53 and ATRX. 7-9 ATRX deficiency is associated with genomic instability 10, and the expected resultant cell death is likely circumvented by the co-ocurring TP53 mutations. Characteristic DNA copy-number abnormalities in astrocytoma, IDH-mutant tumors include mutually exclusive amplifications of MYC and CCND2 9 and homozygous deletions of CDKN2A or CDKN2B, which are associated with shorter overall survival. 11 Other copy number abnormlities include amplifications of CDK4, PDGFRA, and MYCN as well as RB1 homozygous deletions. 11 PIK3R1 and PIK3CA mutations have also been reported and associated with shorter survival. 11 | |
| Oligodendroglioma, IDH-mutant and 1p/19q-codeleted | Oligodendroglioma, IDH-mutant and 1p/19q-codeleted are defined by missense mutations in IDH1 or IDH2 combined with whole-arm deletions of chromosomes 1p and 19q. IDH1 p.R132H is present in >90% of oligodendrogliomas while the remaining carry other non-canonical mutations. 9,12-14 Compared to astrocytoma, a higher proportion of IDH2 mutations are observed in oligodendrogliomas. The 1p/19q codeletion is caused by an unbalanced translocation between chromosomes 1 and 19. 15,16 Importantly, incomplete or partial deletions on either chromosome 1p or 19q are insufficient to ascribe a diagnosis of oligodendroglioma. The majority of oligodendroglioma harbor TERT promoter mutations that function to upregulate TERT expression and drive telomere stabilization. 17-20 Mutations in CIC and FUBP1 are present in 70% and 30% of oligodendroglioma, respectively. 9,13,21-23 Other less frequent molecular aberrations include mutations in NOTCH1, SETD2, and PIK3CA. 9,24 As with astrocytoma, homozygous deletions of CDKN2A or CDKN2B are indicative of a worse prognosis in oligodendroglioma. 25-27 | |
| Glioblastoma, IDH-wildtype | IDH-wildtype glioblastomas lack mutations in IDH1 or IDH2, differentiating them from both astrocytoma and oligodendroglioma. IDH-wildtype glioblastomas commonly harbor aberrations in the PI3K–AKT–mTOR pathway, most commonly as amplifications of EGFR and less frequently in PDGFRA, MET, and FGFR3 28-30. Mutations in NF1, PIK3CA, and PIK3R1 have also been reported 30. Other common molecular events in glioblastomas include TP53 mutations 30,31, TERT promoter mutations 32, and, rarely, BRAF p.V600E 33 (primarily in glioblastomas with epithelioid histology 34). Whole chromosome 7 gain (trisomy 7) and whole chromosome 10 loss (monosomy 10) are the most frequent cytogenetic alterations in glioblastoma and commonly occur in combination (+7/−10). 32 This manifests most commonly as amplification of EGFR (7p11.2) and deletion of PTEN (10q23.31). 30,32,35 Other copy number alterations in IDH-wildtype glioblastomas are losses on 9p (which include homozygous deletion of CDKN2A or CDKN2B), 13q (including RB1 which may also be mutated), 22q, and gains of chromosomes 19 and 20 30,36. Focal amplifications of CDK4, CDK6, and MDM2 are also common. 30,35,37,38 Rarely, deletions of CDK2 or amplifications of CCND2 are observed. 30,35 Gene fusions observed in glioblastoma primarily involve EGFR 30,39,40, but also FGFR3 41, MET 42-44 , NTRK1/NTRK2/NTRK3 39,40,43,45, or PDGFRA 30,43,46,46,47 . Other reported fusions include PTPRZ1::ETV1, KLHL7::BRAF, CEP85L::ROS1, and CCDC127::TERT, but their clinical impact is, as of yet, undefined. 40,48 |
Article Bibliography
| Reference Number | Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|---|
| 1 | 34898238 | 2022 | Therapy for Diffuse Astrocytic and Oligodendroglial Tumors in Adults: ASCO-SNO Guideline. | Mohile NA et al |
| 2 | 27157931 | 2016 | The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. | Louis DN et al |
| 3 | 18985363 | 2008 | Analysis of the IDH1 codon 132 mutation in brain tumors. | Balss J et al |
| 4 | 19228619 | 2009 | IDH1 and IDH2 mutations in gliomas. | Yan H et al |
| 5 | 19246647 | 2009 | IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. | Watanabe T et al |
| 6 | 15173171 | 2004 | Structures of human cytosolic NADP-dependent isocitrate dehydrogenase reveal a novel self-regulatory mechanism of activity. | Xu X et al |
| 7 | 22869205 | 2012 | Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. | Jiao Y et al |
| 8 | 23104868 | 2012 | Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. | Kannan K et al |
| 9 | 26061751 | 2015 | Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. | Brat DJ et al |
| 10 | 23284920 | 2012 | Loss of Atrx sensitizes cells to DNA damaging agents through p53-mediated death pathways. | Conte D et al |
| 11 | 31996992 | 2020 | cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. | Brat DJ et al |
| 12 | 19554337 | 2009 | Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. | Hartmann C et al |
| 13 | 26061753 | 2015 | Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. | Eckel-Passow JE et al |
| 14 | 29522183 | 2018 | IDH2 mutations are commonly associated with 1p/19q codeletion in diffuse adult gliomas. | Appay R et al |
| 15 | 17021403 | 2006 | Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. | Griffin CA et al |
| 16 | 17047046 | 2006 | A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. | Jenkins RB et al |
| 17 | 23530248 | 2013 | TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. | Killela PJ et al |
| 18 | 23764841 | 2013 | Upregulating mutations in the TERT promoter commonly occur in adult malignant gliomas and are strongly associated with total 1p19q loss. | Arita H et al |
| 19 | 24154961 | 2013 | Distribution of TERT promoter mutations in pediatric and adult tumors of the nervous system. | Koelsche C et al |
| 20 | 32204305 | 2020 | The Solo Play of TERT Promoter Mutations. | Hafezi F et al |
| 21 | 21817013 | 2011 | Mutations in CIC and FUBP1 contribute to human oligodendroglioma. | Bettegowda C et al |
| 22 | 22588899 | 2012 | CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. | Sahm F et al |
| 23 | 24030748 | 2014 | Loss of CIC and FUBP1 expressions are potential markers of shorter time to recurrence in oligodendroglial tumors. | Chan AK et al |
| 24 | 25848751 | 2015 | Mutational landscape and clonal architecture in grade II and III gliomas. | Suzuki H et al |
| 25 | 7977648 | 1994 | Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. | Reifenberger J et al |
| 26 | 28030632 | 2016 | Contribution of 1p, 19q, 9p and 10q Automated Analysis by FISH to the Diagnosis and Prognosis of Oligodendroglial Tumors According to WHO 2016 Guidelines. | Michaud K et al |
| 27 | 31832685 | 2019 | CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. | Appay R et al |
| 28 | 20129251 | 2010 | Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. | Verhaak RG et al |
| 29 | 22837387 | 2012 | Transforming fusions of FGFR and TACC genes in human glioblastoma. | Singh D et al |
| 30 | 24120142 | 2013 | The somatic genomic landscape of glioblastoma. | Brennan CW et al |
| 31 | 26919320 | 2017 | Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel. | Zacher A et al |
| 32 | 30187121 | 2018 | Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma. | Stichel D et al |
| 33 | 21274720 | 2011 | Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. | Schindler G et al |
| 34 | 23552385 | 2013 | Epithelioid GBMs show a high percentage of BRAF V600E mutation. | Kleinschmidt-DeMasters BK et al |
| 35 | 18772890 | 2008 | Comprehensive genomic characterization defines human glioblastoma genes and core pathways. | |
| 36 | 30542515 | 2018 | Whole genome duplication is an early event leading to aneuploidy in IDH-wild type glioblastoma. | Boisselier B et al |
| 37 | 7728764 | 1995 | Loss of P16INK4 expression is frequent in high grade gliomas. | Nishikawa R et al |
| 38 | 8044775 | 1994 | Amplification of multiple genes from chromosomal region 12q13-14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. | Reifenberger G et al |
| 39 | 23917401 | 2013 | The integrated landscape of driver genomic alterations in glioblastoma. | Frattini V et al |
| 40 | 32466770 | 2020 | CICERO: a versatile method for detecting complex and diverse driver fusions using cancer RNA sequencing data. | Tian L et al |
| 41 | 23298836 | 2013 | The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma. | Parker BC et al |
| 42 | 25135958 | 2014 | RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas. | Bao ZS et al |
| 43 | 29718398 | 2018 | Targetable Gene Fusions Associate With the IDH Wild-Type Astrocytic Lineage in Adult Gliomas. | Ferguson SD et al |
| 44 | 30343896 | 2018 | Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor. | Hu H et al |
| 45 | 25384085 | 2014 | Anchored multiplex PCR for targeted next-generation sequencing. | Zheng Z et al |
| 46 | 20889717 | 2010 | PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. | Ozawa T et al |
| 47 | 23074200 | 2012 | Prevalence, clinico-pathological value, and co-occurrence of PDGFRA abnormalities in diffuse gliomas. | Alentorn A et al |
| 48 | 31381204 | 2020 | A novel PTPRZ1-ETV1 fusion in gliomas. | Matjašič A et al |
Citation
Scott Ryall, PhD
Adult-type Diffuse Gliomas
Atlas Genet Cytogenet Oncol Haematol. 2023-07-26
Online version: http://atlasgeneticsoncology.org/solid-tumor/209196/adult-type-diffuse-gliomas
