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Triple-negative, low-grade gliomas: A highly agressive tumor with dismal prognosis.

2023 Background: The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by genetic alterations characteristic in patients treated according to present standards of care. Here we investigate the combined analysis of three molecular alterations according to clinical and radiologic data in a series of 89 LGGs to provide new insights into LGGs pathogenesis.


METHODS
IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 89 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. Also p53 expression and 1p19q deletion status was assessed in all cases.


RESULTS
A total of 74 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 68 R132H (91.9%), 4 R132C (5.4%), 2 R132S (2.7%) and 2 R172M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P =0.027) and p53 expression (P=0.012). The presence (v absence) of IDH mutations was associated with a better outcome (5-year survival rate, 91% v 54%, respectively, P<0.001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio=34.6; 95% CI, 2.72 to 329.32, P =0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P <0.05) and that these tumors involved significantly more frequently the insula (P<0.05), were larger in size (>6cm, P<0.05), displayed an infiltrative pattern on MRI (P<0.05) and were almost all p53 negative with no 1p19q deletion (P <10-6).


CONCLUSIONS
The combined absence of IDH mutations, p53 expression and 1p19 codeletion in LGGs identifies a novel entity coined "Triple negative" tumors with distinctive location, infiltrative behavior, specific molecular alterations and dismal outcome. These findings could significantly modify LGG classification and may represent a new tool to guide patient-tailored therapy.