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e21594 Background: NRAS wildtype melanoma account for 80-85% melanoma patients and have been reported had a better response for immunotherapy. Although PD-L1 expression and tumor mutation burden (TMB) have been considered as important biomarkers for immunotherapy in many types of tumors, the predictive efficacy of them in melanoma is controversial. Since evidences showed NOTCH pathway mutation was a potential predictive biomarker for immune checkpoint inhibitors in some types of tumors. Here we explored the relationship between NOTCH family genes mutations and efficacy of NRAS wildtype melanoma immunotherapy. Methods: 265 NRAS wildtype ICI-pretreatment melanomas from cBioPortal (https://www.cbioportal.org), which is divided to discovery (N = 76) and validation (N = 189) cohort to analyze the association between NOTCH family genes (NOTCH1-4) mutation and efficacy of ICIs therapy. All nonsynonymous somatic mutations, including nonsense, missense, nonstop, frameshift deletion and insertion, in-frame deletion and insertion, and splice site mutations were considered for inclusion in our study. The potential mechanism was subsequently explored through RNA expression in immunotherapy treated population. Results: Patients with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in discovery (HR: 0.30, 95%CI: 0.11-0.83, P = 0.01) and validation cohort (HR: 0.21, 95%CI: 0.07-0.68, P = 0.003). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P < 0.05). RNA data revealed that enhanced anti-tumor immunity was observed in NOTCH4-Mut tumors. Activated CD4 memory T cell, CD8 T cell, follicular helper T cell (Tfh) and Neutrophils were more abundant in NOTCH4-Mut tumors. In addition, the results of enrichment analysis showed that several immune-related pathways varied significantly between NOTCH4-Mut and NOTCH4-Wt tumors, including Interferon γ response, DNA repair, epithelial mesenchymal transition (EMT), angiogenesis. Conclusions: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guiding immunotherapeutic responsiveness.

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e14032 Background: The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, which indicated that all IDH mutant diffuse astrocytic tumors are considered a single type (Astrocytoma, IDH-mutant) and are then graded as CNS WHO grade 2, 3, or 4. Besides, the guideline eliminates the term “Glioblastoma (GBM), IDH-mutant”. Moreover, grading is no longer entirely histological, since the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis. Therefore, more clinical and genomic characteristics of IDH-mutant astrocytoma under molecular typing need to be further studied. Methods: Adults pathological diagnosed with diffuse astrocytoma and glioblastoma in our Chinese dataset were identified retrospectively. All patients included in the analysis were tested for 131 CNS tumor-related genes (including IDH1/2), chromosomes 1p/19q and chromosomes 7/10. Results: 63 initial diagnosed IDH-mutant diffuse astrocytomas including 46 patients with grade 2-3 and 17 patients with uncertain grade. While, 5.2% of GBM (9/174) harbored IDH1/2 mutation which should be redefined as diffuse astrocytoma, IDH-mutant, WHO 4 grade. And these patients had a high frequency of CDKN2A/B homozygous deletion (88.9%, 8/9). In patients with 2-3 grade and unclear grade, CDKN2A/B homozygous deletion accounted for 18.7% (9/48) and 27.8% (5/18), respectively, which meant the grade of these diffuse astrocytomas should be revised to WHO 4 grade according to guideline. While mutation frequency of crucial prognosis factors in glioma, including chromosomes 7 loss, chromosomes 10 gain, EGFR amplification, PIK3CA/R1, PDGFRA amplification, CDK4 amplification, were 9.7%, 2.8%, 5.6%, 13.9%, 6.9% and 8.3% in all 72 astrocytomas, respectively. In addition, we found 83.3% (5/6) KDR copy number variant were occurred in which initially pathological diagnosed as IDH-mutant GBM. Conclusions: we conducted comprehensive analysis of IDH mutant diffuse astrocytoma. CDKN2A/B homozygous deletion as a specific grade-classified molecular marker could better re-distinguish about 20%-30% 2-3 grade and uncertain grade astrocytoma. KDR copy number variant may be a marker in IDH-mutant astrocytoma to identify the tumor which pathology is closer to GBM.