Molecular Characterization of NUT Carcinoma: A Report from the NUT Carcinoma Registry

作者：Justin J. Kim, Sara A. Walton, Navin R. Mahadevan, Jessica Haradon, Francesco Paoloni, Paul K. Paik, Jamie E. Chaft, Robert C. Hsu, Sarina Anne Piha-Paul, Pasi Antero Janne, David Allen Barbie, Lynette Marie Sholl, Steven G. DuBois, Glenn J. Hanna, Geoffrey Ira Shapiro, Christopher Alexander French, Jia Luo · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-1071 · 被引用次数：14 · 研究领域：Protein Degradation and Inhibitors、FOXO transcription factor regulation、PARP inhibition in cancer therapy

PURPOSE: NUT carcinoma (NC) is an underdiagnosed, poorly differentiated squamous cell cancer with a median survival of 6.7 months. Defined by NUTM1 fusions, NC enhances oncogene transcription, including MYC. We investigated the ability of standard next-generation sequencing (NGS) to identify NUTM1 fusions and describe additional molecular features of NC. EXPERIMENTAL DESIGN: This study included 116 patients with NC whose tumors underwent broad-panel NGS (>80 genes) of DNA, ctDNA, and/or RNA fusion sequencing between 2013 and 2024. NGS reports and medical records were manually reviewed. RESULTS: Of 116 patients (median age, 38; 40.5% female), 84.5% had DNA, 12.1% had ctDNA, and 51.7% had RNA fusion testing. In a subset of 100 patients with DNA/ctDNA testing, 92.9% (n = 79/85) had <10 pack-years/never-smoking history, and 58.8% (n = 47/80) had a BRD4::NUTM1 fusion. The median tumor mutational burden was 1.0 mut/Mb (range 0.0-16.0; n = 71 known), and 19.7% (n = 13/66) had PD-L1 expression ≥1%. DNA, ctDNA, RNA fusion, NUT IHC, and NUTM1 FISH detected NC fusions in 21.6%, 21.4%, 83.9%, 100.0%, and 91.9% of tests, respectively. Co-occurring pathogenic mutations included oncogenes PIK3CA, RET, and FGFR3 and tumor suppressors ATM and BRCA1 (n = 1 each). Secondary genes altered in >5% of NCs included LDL receptor-related protein 1B (LRP1B; 10.4%), histone-lysine N-methyltransferase 2D (KMT2D; 8.0%), and FAT atypical cadherin 1 (FAT1; 5.5%); common pathways with mutated genes were epig...