Genetic mutations in neuroendocrine carcinomas of unknown primary

Introduction: Although genetic mutations have been reported in neuroendocrine carcinomas of unknown primary (NECs-UP), no scientifically validated targeted therapies are currently available. Moreover, cancer genomic profiling tests remain underutilized in clinical practice. These issues highlight the urgent need to elucidate the genomic landscape of NECs-UP and its potential therapeutic relevance. Aim: This study aimed to characterize the mutational profile of recurrent and/or metastatic NEC-UP. Materials and methods: Data were analyzed for 122 consecutive patients with NECs-UP registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C-CAT) between June 2019 and August 2025. Genetic mutations were determined by next-generation sequencing. Survival of patients was determined by log-rank test and a Cox proportional hazards model. Results: The top 10 mutations in NECs-UP were TP₅₃ (71.3%), RB₁ (49.2%), KMT₂D (24.6%), NOTCH₁ (20.5%), CDKN₂A (18.0%), SPEN (15.6%), ARID₁A (15.6%), RICTOR (15.6%), CIC (14.8%), SDHA (14.8%), with 16.3 7.1 (mean SD) mutations/individual. Mutation in TP53 (p = 0.0474) and CIC (p = 0.0322) were associated with a significantly worse prognosis, as determined by log-rank test. The hazard ratios for cases with this mutation was 2.0550 (95% CI, 1.0540-4.006, p = 0.03455) for CIC. Conclusions: This study delineated the mutational spectrum of recurrent and/or metastatic NECs-UP. Even in advanced disease, prognostically relevant mutations were identified, emphasizing the clinical importance of cancer genomic profiling tests. .