Prognostic relevance of genetic alterations in diffuse lower-grade gliomas

Abstract

Background: Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown.

Methods: Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA).

Results: In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA.

Conclusions: Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.

Keywords: diffuse lower-grade glioma; genetic alteration; prognostic factor.

Fig. 1

Association of genetic alterations with clinicopathological features. (A) Kaplan–Meier curves of OS of LGG patients in the JPN cohort, classified based on the number of broad CNVs. (B) Mean numbers of broad CNVs in each molecular subtype in the JPN cohort plotted with 25% and 75% quartiles according to WHO grade. (C) Kaplan–Meier curves of LGG patients in the cohort from TCGA, classified based on the number of broad CNVs. (D) Mean numbers of broad CNVs of each molecular subtype in the cohort from TCGA, plotted with 25% and 75% quartiles according to WHO grade. (E) Kaplan–Meier curves of LGG patients in the combined JPN and TCGA cohort, classified based on the number of somatic mutations. (F) Mean numbers of somatic mutations of each molecular subtype in the combined JPN and TCGA cohort, plotted with 25% and 75% quartiles according to WHO grade. Oligo = oligodendroglioma; Astro = astrocytoma.

Fig. 2

Hazard ratios (HRs) for OS in univariate and adjusted Cox regression models, according to the presence or absence of mutations or CNVs on each LGG subtype. (A, B, C) Hazard ratios and their 95% CIs plotted for mutations, focal and broad CNVs, and signaling pathways in each LGG subtype, from univariate (blue) and age- and WHO grade–adjusted (red) Cox regression models. Results of HRs and 95% CIs are shown on a log₁₀ scale. (D) Among genetic alterations significantly associated with poor prognosis in univariate Cox analysis of IDH-wildtype LGGs, positive (red) and negative (blue) correlations were detected. Size and color gradients of each circle indicate the level of significance as expressed by Q-values and odds ratios of correlations, respectively. TERT promoter mutation, gain of chromosome 7p, and loss of chromosome 10q were strongly correlated and are indicated by yellow bars. RTK-PI3K-mTOR = receptor tyrosine kinase-phosphoinositide 3-kinase-mammalian target of rapamycin; SWI/SNF = SWItch/sucrose non-fermentable; HMT = histone methyltransferase.

Fig. 3

OS in each LGG subtype, according to prognostic factors. (A, B) OS of patients with Oligodendroglioma IDH-mut/1p19q-codel according to the presence or absence of prognostic factors, including NOTCH1 mutations and extent of resection (partial resection), in the (A) JPN and (B) TCGA cohorts. For comparison, survival curves for patients with Astrocytoma IDH-mut are also presented. (C, D) OS of patients with Astrocytoma IDH-mut according to the presence and absence of prognostic factors, including PIK3R1 mutations and altered RB pathway genes, in the (C) JPN and (D) TCGA cohorts. For comparison, survival curves for patients with GBM, IDH-mutant from the cohort from TCGA are also presented. (E, F) OS of patients with IDH-wildtype LGGs according to the presence and absence of prognostic factors, including WHO grade (grade III) and co-occurrence of gain of chromosome 7p, loss of chromosome 10q, and TERT promoter mutation (pTERT) in the (E) JPN and (F) TCGA cohorts. For comparison, survival curves for patients with GBM, IDH-wildtype from the cohort from TCGA are also presented. P-values were calculated using the log-rank test.