Abstract
Abstract BACKGROUND Astrocytoma, IDH-mutant is currently characterized by both histological and molecular features according to the WHO CNS5 classification. However, there were still patients with IDH-mutant lower-grade astrocytomas (LGAs, CNS WHO grade 2 and 3) who suffered poor survival. Our previous research demonstrated the enrichment and predictive role of MET fusions and/or splicing variations (MET F/SVs) in previously classified secondary IDH-mutant glioblastoma, which could be a potential complement to the existing grading system. MATERIALS We herein presented descriptive, Kaplan-Meier, multivariable Cox regression outcome analyses, and DNA methylation profiling cluster analysis in a large cohort of astrocytomas, IDH-mutant. RESULTS A total of 427 astrocytomas, IDH-mutant were included. 28/427 (6.56%) patients were defined as carrying MET F/SVs, including 9/261 (3.45%) LGAs and 19/166 (11.45%) IDH-mutant high-grade astrocytomas (HGAs, CNS WHO grade 4). The distribution of MET F/SVs was significantly different between LGAs and HGAs (p = 0.0011). Kaplan-Meier analysis of PFS and OS confirmed MET F/SVs was significantly associated with inferior survival irrespective of CNS WHO grade. Multivariable Cox regression analysis with PFS and OS as the endpoint showed MET F/SVs were independently associated with worse survival (p = 0.006 for PFS and p < 0.0001 for OS). Moreover, we collected 159 astrocytomas, IDH-mutant with DNA methylation profiles for further analysis. The included patients were classified into the methylation class MC astrocytoma, IDH-mutant in version 12.5 of the Heidelberg brain tumor classifier. On the t-distributed stochastic neighbor embedding (t-SNE) projection, the IDH-mutant astrocytoma with MET F/SVs was more clustered in high-grade astrocytoma (p = 0.017). CONCLUSION Collectively, we demonstrated the utmost relevance of MET F/SVs as an adverse prognostic factor in IDH-mutant astrocytoma independent of the current WHO CNS grading system. We proposed that the LGAs with MET F/SVs should be designated into CNS WHO grade 4.
Published Version
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