Simultaneous DNA Testing and RNA Fusion Testing Improves Diagnosis of NUT Carcinoma

NUT carcinoma is a rare and aggressive squamous cell cancer primarily affecting the lungs, head, and neck, with a median survival of just 6.7 months. It is typically suspected in younger patients with little to no history of smoking and a poorly differentiated tumor. Early and accurate diagnosis is crucial for initiating appropriate treatment and enrolling patients in clinical trials. Now, a new study has found that the diagnosis of suspected NUT carcinoma should include additional testing capable of detecting gene fusions that are definitive markers of the disease. The study found that more than 75% of patients with NUT carcinoma may not receive an immediate diagnosis due to the limitations of standard DNA-based testing, which often fails to detect the NUTM1 gene fusions that define the disease.

The study was conducted by investigators at Dana-Farber Cancer Institute (Boston, MA, USA) in collaboration with Brigham and Women’s Hospital (Boston, MA, USA) to evaluate the best strategies for definitively diagnosing NUT carcinoma. Researchers analyzed the diagnostic results of 116 tumors using various molecular panel tests, including next-generation DNA sequencing, circulating tumor DNA (ctDNA) testing, and gene fusion detection methods. They specifically assessed the effectiveness of NUT immunohistochemistry (IHC), RNA fusion testing, and NUTM1 fluorescence in situ hybridization (FISH) as more targeted diagnostic tools. The research aimed to determine how these techniques perform in identifying NUTM1 gene fusions, which occur when genetic errors cause two genes to fuse, producing a malfunctioning protein characteristic of this cancer.

Image: The diagnosis of NUT carcinoma should include additional testing capable of detecting gene fusions specific to the disease (Nephron, CC BY-SA 3.0, via Wikimedia Commons)

The findings, published in Clinical Cancer Research, revealed that standard DNA sequencing and circulating tumor DNA (ctDNA) testing detected NUTM1 gene fusions in fewer than 25% of cases. In contrast, NUT IHC detected these fusions in 100% of cases, RNA fusion testing in 84%, and NUTM1 FISH in 92%. The study also found that more than half of the analyzed tumors did not contain additional cancer-associated mutations, but when present, these mutations involved epigenetic, cell cycle, or DNA repair pathways. The researchers emphasized that these results call for an immediate revision of diagnostic workflows to include both DNA and RNA fusion testing for suspected NUT carcinoma cases. They are now initiating laboratory studies to explore whether targeting the secondary mutations could lead to effective combination treatments.

“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,” said co-senior author Dr. Jia Luo, a thoracic oncologist at the Lowe Center for Thoracic Oncology at Dana-Farber. “Early accurate diagnosis is key to getting patients on the correct treatment and clinical trials.”