User Tools

Site Tools


idh_mutant_glioma

IDH mutant glioma

see also Glioblastoma IDH Mutant.


Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct subtype, reflected in WHO 2016 revised diagnostic criteria.

IDH1 and IDH2 mutations stratify individuals into molecular subtypes with distinct clinical outcomes – the mutations are associated with lower-grade astrocytomas, oligodendrogliomas (grade II/III) and secondary gliomas with better overall survival, progression-free survival and chemosensitivity than glioblastomas that are wild type for both genes 1) 2) 3).

IDH mutant gliomas are comprised of the majority of grade II-III gliomas and nearly all secondary glioblastomas. These progressive gliomas arise from mutations in IDH1 or IDH2 that pathologically produces D-2-hydroxyglutarate (2HG). 2-HG interferes with cell reactions using alpha ketoglutarate leading to a hypermethylated genome and epigenetic dysregulation of gene expression initiating tumorigenesis 4).


Tumor location predilection for isocitrate dehydrogenase (IDH) mutant tumors was found in both glioblastoma and lower-grade glioma cohorts, each showing a concordant predominance in the frontal lobe adjacent to the rostral extension of the lateral ventricles (permutation-adjusted p=0.021 for the glioblastoma and 0.013 for the lower-grade glioma cohort). Apart from that, the VLSM analysis did not reveal a significant association of the tumor location with any other key molecular alteration in both cohorts (permutation-adjusted p>0.05, each).

A study highlights the unique properties of IDH-mutations and underpins the hypothesis that the rostral extension of the lateral ventricles is a potential location for the cell of origin in IDH-mutant gliomas 5).


Gliomas are the most frequent intrinsic tumours of the central nervous system and encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern ('non-diffuse gliomas'). In the revised 4th edition of the World Health Organization Classification of Tumors of the Central Nervous System published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p19q codeletion. Following this approach, the diagnosis of anaplastic oligoastrocytoma can be expected to largely disappear 6).


A study published online in Neuro-Oncology in December 2013 demonstrated that IDH-mutant malignant astrocytomas are more amenable to complete surgical resection of enhancing tumour (93% complete resections in the IDH-mutant group versus 67% in the IDH wildtype group). In contrast with IDH wild-type grade III and IV astrocytomas, which didn’t show significant benefit from further resection of non-enhancing tumour, the IDH-mutant grade III and IV astrocytoma group showed a survival benefit with maximal resection of both enhancing and non-enhancing tumour.


IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there may be distinguishable subtypes. We analyzed 170 WHO grade II to IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of the TCGA was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas: AA), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas: AO). Of the 88 IDH-wild type GBMs, 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival (OS) compared to 19q-intact AAs (p=0.001). This tendency was observed in the TCGA Lower Grade Glioma dataset. In contrast, there was no difference in OS between the 19q-loss GBM and 19q-intact GBM (p=0.4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas 7).

Case series

Miller et al., retrospectively analyzed 275 IDH mutant glioma patients treated at the Massachusetts General Hospital. Progression was determined using low grade glioma RANO criteria. They calculated survival statistics with the Kaplan-Meier method and survival proportions were correlated with molecular, histologic and clinical factors.

During a median follow-up of 6.4 years, 44 deaths (7.6%) and 149 first progression (PFS1) events (54.1%) were observed. Median PFS1 was 5.7 years (95% CI 4.7-6.4) and OS was 18.7 years (95% CI 12.2 years - not reached). Consistent with prior studies, we observed an association of grade, molecular diagnosis and treatment with PFS1. Following the first progressive episode, 79 second progression events occurred during a median follow-up period of 4.1 years. Median PFS following an initial progressive event (PFS2) was accelerated at 3.1 years (95% CI 2.1-4.1). PFS2 was a surrogate prognostic marker, identifying patients with poorer overall survival.

They reported outcomes in a large cohort of IDH mutant glioma, providing a well-characterized historical control population for future clinical trial design. Notably, the interval between first to second recurrence (PFS2 - 3.0 years) is shorter than time from diagnosis to first recurrence (PFS1 - 5.7 years), evidence that these tumors clinically degenerate from an indolent course to an accelerated malignant phase. Thus, PFS2 represents a relevant outcome for trials investigating drug efficacy at recurrence 8).

References

1)
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Rig- ginsGJ,FriedmanH,FriedmanA,ReardonD,Hern- don J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl JMed. 2009; 360:765–773
2)
Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikol- skaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velcu- lescu VE, Kinzler KW. An integrated genomic anal- ysis of human glioblastoma multiforme. Science. 2008; 321:1807–1812
3)
Yen KE, Bittinger MA, Su SM, Fantin VR. Cancer- associated IDH mutations: biomarker and thera- peutic opportunities. Oncogene. 2010; 29:6409– 6417
4)
Yamashita AS, da Costa Rosa M, Borodovsky A, Festuccia WT, Chan T, Riggins GJ. Demethylation and epigenetic modification with 5-Azacytidine reduces IDH1 mutant glioma growth in combination with Temozolomide. Neuro Oncol. 2018 Sep 3. doi: 10.1093/neuonc/noy146. [Epub ahead of print] PubMed PMID: 30184215.
5)
Tejada Neyra MA, Neuberger U, Reinhardt A, Brugnara G, Bonekamp D, Sill M, Wick A, Jones DTW, Radbruch A, Unterberg A, Debus J, Heiland S, Schlemmer HP, Herold-Mende C, Pfister S, von Deimling A, Wick W, Capper D, Bendszus M, Kickingereder P. Voxel-wise radiogenomic mapping of tumor location with key molecular alterations in patients with glioma. Neuro Oncol. 2018 Aug 9. doi: 10.1093/neuonc/noy134. [Epub ahead of print] PubMed PMID: 30107597.
6)
Wesseling P, Capper D. WHO 2016 Classification of Gliomas. Neuropathol Appl Neurobiol. 2017 Aug 16. doi: 10.1111/nan.12432. [Epub ahead of print] PubMed PMID: 28815663.
7)
Otani R, Uzuka T, Higuchi F, Matsuda H, Nomura M, Tanaka S, Mukasa A, Ichimura K, Kim P, Ueki K. IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis. Cancer Sci. 2018 May 12. doi: 10.1111/cas.13635. [Epub ahead of print] PubMed PMID: 29752851.
8)
Miller JJ, Loebel F, Juratli TA, Tummala SS, Williams EA, Batchelor TT, Arrillaga-Romany I, Cahill DP. Accelerated progression of IDH mutant glioma after first recurrence. Neuro Oncol. 2019 Jan 22. doi: 10.1093/neuonc/noz016. [Epub ahead of print] PubMed PMID: 30668823.
idh_mutant_glioma.txt · Last modified: 2019/03/17 10:15 by administrador