When a NUT carcinoma is detected, standard-of-care DNA next-generation sequencing (NGS) may be unable to detect upward of 75% of incidences of the disease, according to findings published in Clinical Cancer Research. The study authors suggested that to correctly detect and diagnosis NUT carcinomas, RNA-based fusion testing, NUT immunohistochemistry, and NUTM1 fluorescence in situ hybridization (FISH) should become a routine part of testing.
“If a diagnosis of NUT carcinoma is being considered, standard of care DNA-based testing is insufficient and clinicians should consult with pathology colleagues about ordering a better gold standard test such as NUT immunohistochemistry or RNA-based mutation sequencing,” stated co-senior study author Jia Luo, MD, a thoracic oncologist at the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute. “Early accurate diagnosis is key to getting patients on the correct treatment and clinical trials.”
Study Methods and Rationale
NUT carcinomas are aggressive, poorly differentiated squamous cell cancers that are typically found in midline structures and are characterized by NUTM1 fusions. The study authors believed that NUT carcinomas are often underdiagnosed and sought to determine the ability of standard NGS for detecting NUTM1 fusions. They also explored other molecular features of NUT carcinomas to aid in future diagnosis.
The researchers analyzed NGS reports and medical records from 116 patients with NUT carcinoma who underwent broad-panel NGS (> 80 genes) between 2013 and 2024.
Key Study Findings
Of the 116 patients, 84.5% had DNA testing completed, 12.1% had circulating tumor DNA (ctDNA) testing completed, and 51.7% had RNA fusion testing. Of the 100 patients with DNA or ctDNA testing, 92.9% had less than a 10 pack-year or never-smoker history, and 58.8% had a BRD4:NUTM1 fusion. The median tumor mutational burden was 1.0 mutation/megabase, and 19.7% had PD-L1 expression ≥ 1%.
DNA, ctDNA, RNA fusion, NUT immunohistochemistry, and NUTM1 FISH detected NUT carcinoma fusions in 21.6%, 21.4%, 83.9%, 100.0%, and 91.9% of tests, respectively. “These findings warrant immediate change to the diagnostic workflow for patients with suspected NUT carcinoma,” Dr. Luo said, recommending simultaneous testing of both DNA and RNA fusions.
Other co-occurring pathogenic mutations were found in the PIK3CA, RET, and FGFR3 genes as well as in the tumor suppressor ATM and BRCA1 genes. Secondary altered genes included LRP1B, MLL2/KMT2D, and FAT1, which were found in more than 5% of all NUT carcinomas. The most common pathways with mutated genes were epigenetic (57%), cell cycle (26%), and DNA repair pathways (24%).
“This study characterized the common mutations seen in NUT carcinoma, which will help researchers develop future effective combination treatments,” stated Dr. Luo.
Disclosure: For full disclosures of the study authors, visit aacrjournals.org.
