Thank you Longfellow. Sorry Sentiment. So IDH1 type and methylation are distinct characteristics. I worried a little that they might be. I was oversimplifying. Much to learn and an absolute pain deciphering this stuff. As you say Longfellow they don't relate this to the four subgroups that we are familiar with. The article does not show a date, so it might pre-date those subgroup identifications. One can guess some of how that panned out, but the info is probably out there so better to just research it. I guess I have an obligation to do so now.
Very good article. Thank you.
One side piece of info was that (at least at the time of the article, and probably still the case) it did in fact take a tumor biopsy to determine methylation.
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Discussion
GBMs are extremely heterogeneous tumors with multiple complex genetic abnormalities. Among various prognostic biomarkers, IDH1mutations appeared most important and defined a distinct subgroup of GBMs with favorable outcome [18], [19]. Similarly, the present study also highlighted the prognostic significance of IDH1. However, other molecular genetic alterations, namely, TP53 mutation, NF1 mutation, EGFR amplification, and PDGFRA amplification, did not demonstrate any significant association with survival in the IDH1 wild-type group. MGMT promoter methylation status has been one of the well-known positive prognostic as well as an independent predictive marker for therapeutic response to TMZ in high-grade astrocytic tumors [6], [20]. Its relevance for prognostication of GBMs was also confirmed in the present series. TERT is another frequently mutated gene in GBMs with prognostic implication. In the present study, the frequency of TERT promoter mutation was slightly lower as compared to the reported Western literature. However, similar to previous studies, this genetic alteration was found to be significantly more frequent in older adults as compared to young adults [8]. Hence, the lower frequency of TERT promoter mutation in the present series may be attributable to the lower mean age of our cohort. Our data also showed that TERT mutation was associated with poorer outcome in GBMs, consistent with previous data on gliomas [12].
Few studies in recent years have prognostically stratified GBMs based on combination of various biomarkers. Interestingly, all these studies included IDH1 mutation in the marker panel for prognostication. Based on the IDH1 and MGMT status, Molenaar et al. [11] stratified GBMs (n-98) into three prognostically different subgroups. Patients with IDH1 mutation and MGMT methylation had the longest survival, followed by patients with IDH1 mutation or MGMT methylation alone, whereas patients without both these alterations had the shortest survival. Similar prognostic stratification using MGMT and IDH1 was also described by Hartmann et al. [21] in cases of high-grade astrocytoma (grade III and IV; n = 338). Interestingly, the authors did not observe any significant difference in prognosis between IDH1 wild-type GBMs and anaplastic astrocytomas. Killela et al. [12] analyzed IDH1/2 and TERT status in 415 cases of gliomas of different grades and showed that, based on these genetic alterations, grade III and IV tumors can be effectively classified into four prognostic subgroups irrespective of tumor histomorphology and WHO grade. The cases with both TERT and IDH mutation (morphologically oligodendroglioma) had the best prognosis, whereas cases with only TERT mutation had the worst prognosis. Interestingly, within the GBM group, concomitant IDH and TERT mutation was extremely rare. Hence, GBM cases were subdivided into three prognostic subgroups. Cases with only IDH mutation had the best prognosis (OS = 42.3 months), followed by cases with IDH/TERT wild-type (16.6 months) and only TERT mutation (11.3 months). Recently, Eckel-Passow et al. [13] subdivided 1087 cases of gliomas (615 grade II or III and 472 grade IV) based on IDH, TERT, and 1p/19q co-deletion. Among the GBMs, majority (74%) showed only TERT mutation, 17% were triple negative, 7% had only IDH mutation, and only 2% showed combined TERT and IDH mutation. Similar to the previous studies, cases with only IDH1 mutation had the best and cases with only TERT mutation had the worst survival.
All the above-mentioned studies including ours highlight the importance of IDH in prognostic stratification of GBMs. Unfortunately, IDH1 mutation is rare in primary GBMs and seen mainly in secondary GBMs which constitute only 10% to 15% of all GBMs [22].On the other hand, there is considerable heterogeneity among the IDH1 wild-type cases in terms of clinical outcome, indicating the necessity of further stratification. For the first time, the present study demonstrated that IDH1 wild-type cases which constitute majority of GBMs (approximately 83% in present series) can effectively be subclassified into three prognostic subgroups based on MGMT and TERT status. Interestingly, IDH1 wild-type cases with only MGMT methylation (group 1) had survival similar to the IDH1 mutated cases, whereas IDH1 wild-type cases with TERT mutation demonstrated worst survival. IDH1 mutated cases need not be further stratified based on MGMT and TERT because majority of these cases are MGMT methylated and rarely have TERT mutation.
Therefore, based on the results of the present study, we recommend routine assessment of a panel of only three markers, namely, IDH1 mutation, MGMT promoter methylation, and TERT mutation status for GBM prognostication. All cases of GBMs should be analyzed for IDH1mutation first by Sanger sequencing or immunohistochemistry with mutant-specific antibody followed by assessment of TERT and MGMT status especially in IDH wild-type cases. All these assessments require a small quantity of tumoral DNA and can be done on DNA extracted from FFPE tissue. The International Society of Neuropathology-Haarlem Consensus Guidelines state that “It is also entirely possible that genetic tests not discussed at this meeting (eg, TERT mutation) will be incorporated into diagnostic definitions at the time of the eventual WHO classification revisions” [23]. Our study thus supports the incorporation of these tests into the final revised WHO classification. prognosis
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