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Background  Frequent mutations in the nuclear receptor binding SET domain protein 1 ( NSD1 ) gene have been observed in head and neck squamous cell carcinomas (HNSCC).  NSD1  encodes a histone 3 lysine-36 methyltransferase.  NSD1  mutations are correlated with improved clinical outcomes and increased sensitivity to platinum-based chemotherapy agents in human papillomavirus-negative (HPV-) tumors, despite weak T-cell infiltration. However, the role of  NSD1  and related family members  NSD2  and  NSD3  in human papillomavirus-positive (HPV+) HNSCC is unclear.    Methods  Using data from over 500 HNSCC patients from The Cancer Genome Atlas (TCGA), we compared the relative level of mRNA expression of  NSD1 ,  NSD2 , and  NSD3  in HPV+ and HPV- HNSCC. Correlation analyses were performed between T-cell infiltration and the relative level of expression of  NSD1 ,  NSD2 , and  NSD3  mRNA in HPV+ and HPV- HNSCC. In addition, overall survival outcomes were compared for both the HPV+ and HPV- subsets of patients based on stratification by  NSD1 ,  NSD2 , and  NSD3  expression levels.    Results  Expression levels of  NSD1 ,  NSD2  or  NSD3  were not correlated with altered lymphocyte infiltration in HPV+ HNSCC. More importantly, low expression of  NSD1 ,  NSD2 , or  NSD3  correlated with significantly reduced overall patient survival in HPV+, but not HPV- HNSCC.    Conclusion  These results starkly illustrate the contrast in molecular features between HPV+ and HPV- HNSCC tumors and suggest that  NSD1 ,  NSD2 , and  NSD3  expression levels should be further investigated as novel clinical metrics for improved prognostication and patient stratification in HPV+ HNSCC.    Supplementary Information  The online version contains supplementary material available at 10.1186/s13027-021-00347-6.

Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis