We recruited 314 patients who, according to the 4th edition WHO [9] were classified as follows: 277 GBM (267 IDH-wt and 10 IDH-mut), 17 AA (5 IDH-wt and 12 IDH-mut), and 20 DA (8 IDH-wt and 12 IDH-mut),. As expected in adult patients, the fraction of patients with lower grade (DA) IDH-mut tumors was rather low (∼4%) while the large majority of cases had IDH-wt tumours.
We first grouped all cases according to the IDH status, into IDH-wt (n = 280) and IDH-mut (n = 34). Then, we assessed how the cIMPACT 3 signature was distributed between these two subgroups. As expected, the large majority of IDH-wt cases (276; 98.5%) harbored, at bio-molecular markers that define the high risk cIMPACT 3 (c-IMPACT 3+) signature. In particular, 243/276 cases were positive for at least two markers, and TERTp mutations were detected in 244 cases. The histological classification of c-IMPACT 3 + cases was: GBM in 263 (95%) and DA/AA in 13 (35%) cases (Fig. 1A). Instead, as far as regard the IDH-wt/cIMPACT 3- cases, there were 4 GBM with none of the cIMPACT 3 risk markers. Interestingly, 3 of them had a long follow-up, i.e. 48, 63, and 96 months from diagnosis; the latter two were still alive.
Unexpectedly, a consistent number of IDH-mut cases (20/34; 58.8%), including 11 DA/AA and all GBM cases (= 9), was cIMPACT 3+ (Fig. 1A). Overall, monosomy 10 was present in 11 case, TERTp mutations in 6, and EGFR amplification in 3. In 13 cases there were at least two high risk markers, while the remaining 7 cases showed EGFR amplification (= 1) or gain of chromosome 7 (= 6). Thus, according to the genetic profile, all cases were re-classified into the following bio-molecular subgroups: 1) IDH-wt/cIMPACT 3+ (n = 276); 2) IDH-mut/cIMPACT 3- (n = 14); 3) IDH-mut/cIMPACT 3+ (n = 20); and 4) IDH-wt/cIMPACT 3- (= 4).
While the cIMPACT 3 signature, the IDH status and age, were all strong predictors of outcome, histopathology and immunohistochemistry lost their prognostic significance (Supplementary Table S1). As expected, the IDH status was confirmed to be a robust prognostic marker (IDH-wt, HR 2.91 95%, CI 1.40–6.05) distinguishing two relevant risk subgroups. We also validated the cIMPACT 3 + signature as an additional prognostic marker which improved the stratification of IDH-wt tumours (cIMPACT 3+, HR 2.96 95%, CI 1.18–7.4). Indeed, the probability of overall survival was significantly lower in cIMPACT 3+ (high risk subgroup) than in IDH-wt cIMPACT 3- tumours (low risk subgroup) (Fig. 1B). Notably, all the 13 IDH-wt DA/AA belonged to the cIMPACT 3 + high risk subgroup and showed a median overall survival (8.8 months; range 10–47), which was similar to GBM cases. Therefore, as indicated by the 5th edition of the WHO classification, regardless of histopathological characteristics, these cases should be all classified as glioblastoma IDH-wt CNS entity of WHO grade 4. Instead, according to the overall survival, the cIMPACT 3- GBM cases (either IDH-wt or IDH-mut) could be probably relocated into a more favorable risk subgroup (median overall survival: 28 months (10.2–47.8). Lastly, the cIMPACT 3 signature did not appear to be prognostically relevant in IDH-mut cases.