Targeted RNA sequencing in diagnostically challenging head and neck carcinomas identifies novel MON2::STAT6, NFATC2::NUTM2B, POC5::RAF1, and NSD3::NCOA2 gene fusions

Aims Although molecular tests developed for a growing list of oncogenic alterations have significantly aided in the classification of head and neck carcinomas, tumours in which prototypical histologic and immunophenotypic features are lacking or only partially developed continue to pose diagnostic challenges. Searching for known diagnostic and therapeutic targets by clinical next‐generation sequencing (NGS) assays can often lead to new discoveries. Methods and Results We present our institutional experience in applying targeted RNA NGS in 36 head and neck carcinomas that were morphologically difficult to classify between 2016 and 2023. The patients ranged in age from 5 to 83 years (median, 64), with the majority of tumors occurring in the major salivary glands and the sinonasal tract. Overall, seven (19%) cases showed unusual gene rearrangements, including five novel alterations: MON2 :: STAT6 in a hard palate adenocarcinoma with mucinous features, POC5 :: RAF1 in apocrine intraductal carcinoma of the lacrimal gland, EWSR1 :: CDADC1 fusion in a basaloid carcinoma of the submandibular gland, NFATC2 :: NUTM2B in myoepithelial carcinoma, and NSD3 :: NCOA2 fusion in a peculiar high‐grade carcinoma with a peritheliomatous growth pattern, and focal myogenic differentiation. Potential therapeutic actionability was identified in three cases ( RAF1 and FGFR2 fusions). Conclusion These findings broaden the current spectrum of gene rearrangements in head and neck carcinomas and support the utility of clinical NGS in identifying unusual, actionable alterations in diagnostically challenging cases.