Comprehensive genetic profiling of six pulmonary NUT carcinomas with a novel micropapillary histological subtype in two cases

Abstract Nuclear protein in testis (NUT) carcinoma (NC) is a rare and aggressive neoplasm associated with a rearrangement of the NUT gene on chromosome 15q14. To date, genomic alterations of NCs, especially those in the lung are poorly understood. In this study, immunohistochemistry staining, fluorescence in situ hybridization, and two next-generation sequencing panels (NGS) of 56 and 701 genes were utilized to explore the clinical, pathological, and genetic profiling of pulmonary NCs. Six pulmonary NCs were confirmed with a mean age of 41 years (range: 22–69 years) and a median survival time of 6.5 months (range: 2–19 month). Morphologically, typical abrupt keratinization was observed in four out of six cases (67%), and two patients presented a mixed pattern of classical squamous component and micropapillary adenocarcinoma morphology. We also identified a case with NUT gene amplification instead of rearrangement. Further, NGS analysis demonstrated the following fusions: BRD4-NUTM1 (2/4 cases) and NSD3-NUTM1 (2/4 cases), and highlighted 53 gene mutations, including 50 (94.3%, 50/53) single nucleotide variations (SNVs) and three (5.7%, 3/53) long insertions/deletions. SNVs of MUC16 were the most common, and occurred in three cases (75%). Moreover, SNVs of EPHA8, FANCA, TRIO, and USP6 were detected in two out of four cases (50%). These 53 mutated genes were involved in 13 functional pathways based on enrichment analysis, especially in the PI3K-Akt signaling pathway. Finally, none of the cases showed obvious copy number variations, and had low tumor mutational burden and stable microsatellite sites.