Canonical Gene Amplifications and CDKN2A/B Loss Stratify Risk in idh1/2-mutant Astrocytoma Patients

Introduction: Molecular biomarkers have enhanced prognostication of IDH1/2-mutant astrocytomas (IDHmut-astrocytomas). CDKN2A/B homozygous-loss is now sufficient for grade 4 classification, irrespective of tumor histology. However, there are no prognostic biomarkers to distinguish histologically defined grade 2 and 3 IDHmut-astrocytomas. Additionally, grade 2 and 3 cases exhibit negligible survival differences in previous studies. We aimed to identify how other features, such as canonical focal amplifications, could stratify survival amongst grade 2/3 IDHmut-astrocytomas.

Methods: We collected clinicogenomic data from TCGA (n=264) and multi-institutional cohorts (n=734). Cases were classified using molecular guidelines (WHO 2021/cIMPACT-NOW). Focal amplifications were examined in canonically amplified genes: CCND2, CDK4/6, EGFR, MDM2/4, MET, and PDGFRA. Focal amplifications are low prevalence but frequently co-occur; consequently, we considered tumors with ≥1 of these canonical amplifications to be amplified cases. We identified prognostic features and broad molecular patterns using multivariate modeling and unbiased clustering.

Results: We identified 998 IDHmut-astrocytoma patients (median age 37.3yrs; range 19.2-78.1yrs): 250 WHO grade 2, 420 grade 3, and 328 grade 4. Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification were correlated with shorter median overall survival (mOS, q < 0.20). Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived longest (mOS 205.7 months). Grade 2/3 patients with CDKN2A/B hemizygous-loss or canonical focal amplifications (mOS 80.4 and 88.7 months, respectively) faired comparably to grade 4 with CDKN2A/B intact and no amplifications (mOS 91.5 months, p=0.93). Grade 4 patients with any level of CDKN2A/B loss exhibited shortest survival (mOS 31.9 and 32.5 months, respectively), followed by grade 4 patients with intact CDKN2A/B and focal gene amplifications (mOS 55.9 months).

Conclusion : Combining CDKN2A/B hemizygous-loss and canonical focal amplifications revealed groups of IDHmut-astrocytoma patients with intermediate prognosis. These findings can refine risk stratification and inform molecular grading schemes. This study highlights the biological variability amongst IDHmut-astrocytomas and the importance of patient-specific genomics.