Nuclear protein in testis midline carcinoma (NMC) is a very rare, aggressive subset of poorly differentiated squamous cell malignancy with a dismal 6.7-month median survival and usually occur in the midline anatomical structures of Head & neck, mediastinum. BRD4–NUT rearrangement is pathognomonic. BRD4 can up-regulate the expression of PD-L1 and Bromodomain inhibitors (BETi) currently in trials suppress PDL1 expression and tumor growth (Zhu, Cell Rep; 2016). We, therefore, attempted to study the comprehensive landscape of genomic alterations and PDL1 expression pattern.
We investigated three NMC cases that underwent molecular profiling using a commercial multiplatform profiling service (Caris Life Sciences, Phoenix, AZ). We sequenced genomic DNA isolated from a formalin-fixed paraffin embedded tumor sample using the Illumina NextSeq platform (NextGen), protein expression (IHC) and gene amplification (CISH or FISH), antibody used for PD-L1 is SP142 (tumor cell). ArcherDx FusionPlex Assay was used for gene fusions.
All three cases were identified with NUTM1 fusions (BRD3-NUTM1 fusion in one case and BRD4-NUTM1 fusion in 2). Patients aged between 34-44. High PDL1 Expression (3+, 100%) was seen in one tumor, median tumor mutational load was 5 mutations/megabase (low; range: 2-6). ERCC1 expression was low in all (3/3), while high TOPO1 expression in (2/3) and TOP2A in 2/2. RRM1 expression was negative in (2/3) High expression of TUBB3 was seen in (2/3). 592 genes were analyzed and no additional pathogenic alterations were identified using a 592-gene mutation panel.
High PDL1 expression may be present in some NMC tumors despite simple molecular karyotype and low tumor mutational burden. Anthracyclines, platinum compounds, TOPO1 inhibitors, taxanes and gemcitabine may be useful for inducing brief rapid responses based on biomarker expression. (BETi) and histone deacetylase inhibitors (HDACi), currently in clinical trials can induce differentiation and growth arrest of NMC cells. BETi combined with PD-1/PD-L1 targeted therapy may be a promising future for NMC by suppressing PDL1 to increase the activity of anti-tumor cytotoxic T cells and restore anti-tumor immunity.
Clinical trial identification
Legal entity responsible for the study
Kymera Independent Physicians
All authors have declared no conflicts of interest.