Introduction – NUT carcinoma is an aggressive cancer, originally described in midline structures of adolescents and young adults but now known to occur in a variety of anatomic sites with growing numbers of variant histologies being reported. As such, NUT immunoreactivity and/or demonstration of the NUTM1 fusion is required for definitive diagnosis.

Methods – We identified patients within the Tempus multimodal real-world database who had either a diagnosis of NUT carcinoma based on clinically abstracted diagnosis fields or via the presence of a NUTM1 fusion, as detected either by Tempus xT (targeted DNA panel) or Tempus xR (whole-exome capture RNA-seq).

Results – There were 59 patients in the Tempus database with NUT carcinoma annotated as their primary diagnosis. Tempus NGS testing confirmed the presence of a NUTM1 fusion for 48 (81%). Of the remaining 11 patients, none underwent RNA-seq testing at Tempus and only 2 had solid-tissue DNA-seq performed at Tempus. Additionally, there were 106 patients with a NUTM1 fusion based on NGS evidence that did not have an initial NUT diagnosis, including: non-small cell lung cancer (n=33), head and neck (n=10), cancer of unknown primary (n=10), thyroid cancer (n=11), soft tissue sarcoma (n=11), and several other cancer types. Eight out of 31 sweat gland adenocarcinomas/porocarcinomas in the cohort had a NUTM1 rearrangement. Several other NUTM1 fusion rearrangements with partners not previously associated with NUT carcinoma were identified, the clinical significance of which is unclear.Among the 154 patients where we detected a NUTM1 rearrangement, the most common fusion events were BRD4-NUTM1 (n = 55), NSD3-NUTM1 (n = 31), BRD3-NUTM1 (n = 17), SLC12A6-NUTM1 (n=11), YAP1-NUTM1 (n = 11), MXD4-NUTM1 (n=3), and CIC-NUTM1 (n=3)other fusion partners occurred in only one or two patients. The overall potential underdiagnosis rate (patients with the detected fusion but not an annotated formal NUT carcinoma diagnosis) was 69% (106/154); including BRD4-NUTM1 51% (28/55), BRD3-NUTM1 47% (8/17), NSD3-NUTM1 81% (25/31), and 91% for YAP1-NUTM1 (10/11).Some cancer types were enriched for specific fusion gene partners. Eleven of 12 patients (92%) that were diagnosed with thyroid cancer had a NSD3-NUTM1 fusion. Of the 8 sweat gland adenocarcinomas/porocarcinomas, 6 had a YAP1-NUTM1 fusion.The median overall survival was 5.29 months (n = 72) and the median age was 51 (n = 114) at diagnosis. The median age at diagnosis for patients annotated with NUT carcinoma was 41 years compared to 58.5 years for patients with a NUTM1 fusion but lacking the diagnosis.

Conclusions – NUT carcinomas may be underdiagnosed the majority of the time. Certain cancer types with a high enrichment of NUTM1 fusions, such as sweat gland adenocarcinomas/porocarcinomas, thyroid cancers, and sarcomas, may benefit from universal NGS sequencing to ensure correct diagnosis.

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