Multiomic Characterization and Molecular Profiling of Nuclear Protein in Testis Carcinoma.

Abstract

Nuclear protein in testis carcinoma (NC) is an underdiagnosed and aggressive squamous/poorly differentiated cancer characterized by rearrangement of the gene <i>NUTM1</i> on chromosome 15q14. Co-occurring alternations have not been fully characterized. We analyzed the genomic and immune landscape of 54 cases of NC that underwent DNA- and RNA-based NGS sequencing (Caris). While NC is driven by <i>NUTM1</i> fusion oncoproteins, co-occurring DNA mutations in epigenetic or cell cycle pathways were observed in 26% of cases. There was no significant difference between the fusion partner of <i>NUTM1</i> and co-occurring gene mutations. RNA sequencing analysis showed increased <i>MYC</i> pathway activity in NC compared with head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LUSC), which is consistent with the known pathophysiology of NC. Characterization of the NC tumor microenvironment using RNA sequencing revealed significantly lower immune cell infiltration compared with HNSCC and LUSC. NC was 10× higher in patients with HNSCC and LUSC younger than 50 years than in those older than 70 years. To our knowledge, this is the first series of NC profiled broadly at the DNA and RNA level. We observed fewer intratumoral immune cells by RNA sequencing, which may be associated with anecdotal data of lack of immunotherapy benefit in NC. High <i>MYC</i> pathway activity in NC supports ongoing trials targeting <i>MYC</i> suppression. The incidence of NC among patients younger than 50 years with LUSC/HNSCC supports testing for NC in these patients. The prognosis of NCs remains dismal, and future studies should focus on improving the response to immunotherapy and targeting MYC.