Prognostic significance of genetic biomarkers in isocitrate dehydrogenase‐wild‐type lower‐grade glioma: the need to further stratify this tumor entity – a meta‐analysis

Abstract

The clinical outcomes of isocitrate dehydrogenase‐wild‐type (IDH‐wt) lower‐grade glioma (LGG) have been the subject of debate for some time. In this meta‐analysis, we aimed to assess the prognostic values of several known genetic markers (e.g. TERT promoter mutation, H3F3A mutation, CDKN2A loss) in this tumor group. Four electronic databases, including PubMed, Scopus, Web of Science and Virtual Health Library, were searched for relevant articles. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival were calculated using a random‐effect model weighted by an inverse variance method. A total of 11 studies were finally selected from 2274 articles for meta‐analyses. Several genetic alterations were demonstrated to have a negative impact on prognosis of IDH‐wt LGGs, specifically TERT promoter mutation (HR, 1.96; 95% CI, 1.42–2.70), H3F3A mutation (HR, 3.21; 95% CI, 1.86–5.55) and EGFR amplification (HR, 1.67; 95% CI, 1.02–2.74). However, CDKN loss, ATRX mutation and coexisting gain of chromosome 7/loss of chromosome 10 showed no clinical significance in this glioma entity. Our study results demonstrated that IDH‐wt LGGs are heterogeneous in clinical outcome and not all tumors have a poor prognosis. The presence of TERT promoter mutation, H3F3A mutation and EGFR amplification showed negative prognostic impacts in this tumor entity. These genetic events can be used to better stratify patient outcomes.

Molecular Classification of Diffuse Gliomas

“…34 A more recent meta-analysis by Vuong et al also demonstrated a propensity for IDH-wildtype low-grade gliomas to have a poor prognosis when associated with TERT promoter mutations, EGFR amplifications, and H3F3A mutations, whereas ATRX mutation, 7q gain/10q loss, and CDKN loss did not influence prognosis. 54 Thus, there is not enough evidence that IDH status alone should dictate the classification of glioma; instead, IDH status must be taken in conjunction with other prognostic mutations commonly found in gliomas in addition to the clinical and radiological status of the patient. This is reflected in the cIMPACT-NOW consortium guidelines (2018) which designate IDH-wildtype Grade II or III tumors, with one of the following molecular characteristics: EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation, as "diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV."…”

Molecular subtyping reveals immune alterations in IDH wild‐type lower‐grade diffuse glioma

“…The cIMPACT-NOW group addressed the molecular definition of 'molecular GBM', a cohort of IDH wild-type LGG characterized by either EGFR amplification, combined gains of chromosome 7 and loss of chromosome 10, or TERT promoter mutations [10]. A meta-analysis also assessed the prognostic values of several genetic markers and found that TERT promoter, H3F3A mutation, and EGFR amplification have a negative impact on survival of IDH wild-type LGG [11]. However, the transcriptional and biological heterogeneities within IDH wild-type diffuse LGGs need further dissection.…”

<p>Prognostic Significance and Related Mechanisms of Hexokinase 1 in Ovarian Cancer</p>

“…For example, HK2, fructose phosphate kinase, pyruvate kinase 2, and isocitrate dehydration may be prognostic biomarkers of multiple myeloma, prostate cancer, oral squamous cell carcinoma, and glioma. [22][23][24][25][26] This is because glucose metabolism enzymes have the ability to promote cancer migration, invasion, and angiogenesis. 27 Moreover, the characteristics of metabolic…”