Genetic mutations in neuroendocrine carcinomas of unknown primary
Hiromi Nagano1, Satoshi Kiyama1, Kyutoku Takayuki1
1Department of Otolaryngology Head and Neck Surgery, Kagoshima University Graduate School of Medical and Dental Sciences.
Abstract:
<p><strong>Introduction: </strong>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.</p><p><strong>Aim:</strong> This study aimed to characterize the mutational profile of recurrent and/or metastatic NEC-UP.</p><p><strong>Materials and methods: </strong>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.</p><p><strong>Results: </strong>The top 10 mutations in NECs-UP were <em>TP<sub>53</sub></em> (71.3%), <em>RB<sub>1</sub></em> (49.2%), <em>KMT<sub>2</sub>D</em> (24.6%),<em> NOTCH<sub>1</sub></em> (20.5%), <em>CDKN<sub>2</sub>A</em> (18.0%), <em>SPEN</em> (15.6%), <em>ARID<sub>1</sub>A</em> (15.6%), RICTOR (15.6%), <em>CIC</em> (14.8%), <em>SDHA</em> (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 <em>CIC</em>.</p><p><strong>Conclusions: </strong>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.</p>.
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