New Study Reveals Limitations of Standard DNA Tests for NUT Carcinoma

In a groundbreaking study published in the *Clinical Cancer Research* journal, investigators from the Dana-Farber Cancer Institute have highlighted significant shortcomings in standard DNA tests used to diagnose NUT carcinoma, a rare and aggressive form of cancer affecting the lungs, head, and neck. The study, released on July 24, 2025, indicates that over 75% of patients with NUT carcinoma may not receive an accurate diagnosis due to the inability of conventional DNA testing to detect the specific gene fusions that are characteristic of this cancer.

NUT carcinoma is defined by the fusion of the NUTM1 gene with other genes, leading to the production of malfunctioning proteins that drive tumor growth. According to Dr. Jia Luo, co-senior author and thoracic oncologist at the Lowe Center for Thoracic Oncology, early and accurate diagnosis is critical for effective treatment and participation in clinical trials. "If a diagnosis of NUT carcinoma is being considered, standard of care DNA-based testing is insufficient," stated Dr. Luo. Instead, he recommends that clinicians consult pathology colleagues for advanced testing methods such as NUT immunohistochemistry (IHC) or RNA fusion testing.

The study included diagnostic results from 116 tumors diagnosed with NUT carcinoma, which underwent various molecular tests including next-generation DNA sequencing and circulating tumor DNA (ctDNA) testing. The results were stark: standard DNA sequencing and ctDNA testing detected NUT fusions in less than 25% of cases. In contrast, NUT IHC, RNA fusion testing, and NUTM1 fluorescence in situ hybridization (FISH) detected these fusions with rates of 100%, 84%, and 92%, respectively. These findings suggest an urgent need to revise diagnostic protocols for NUT carcinoma to prevent misdiagnosis.

Dr. Christopher French, co-senior author and oncologist at Brigham and Women’s Hospital, emphasized that the study’s findings should prompt immediate changes in clinical practice. "This approach of performing DNA testing and RNA fusion testing simultaneously is already employed in other cancers where gene fusion identification is crucial for diagnosis," he said.

NUT carcinoma, often seen in younger patients with minimal smoking history, has a grim prognosis, with a median survival rate of only 6.7 months. The lack of early detection contributes significantly to this poor outcome. The study's implications extend beyond diagnosis; the researchers also identified that many tumors did not harbor additional cancer-associated gene mutations, while some did, which could be targeted for future therapies.

The researchers are now initiating laboratory studies to explore whether targeting these additional mutations could provide new therapeutic avenues for NUT carcinoma patients. As Dr. Luo noted, "This study characterized the common mutations seen in NUT carcinoma, which will help researchers develop future effective combination treatments." The findings from this research not only underline the necessity for improved diagnostic protocols but also open new pathways for potential treatment strategies in managing this aggressive cancer.

### Conclusion

The revelations from the Dana-Farber Cancer Institute underscore the critical need for advancement in diagnostic testing for NUT carcinoma. With a substantial proportion of cases going undetected by standard testing methods, clinicians must adapt their diagnostic workflows to incorporate more sensitive testing techniques. This shift could significantly improve patient outcomes and provide a foundation for developing targeted therapies for this life-threatening disease.