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Simple Summary  This in silico study aimed to investigate associations between dipeptidyl peptidase (DPP) 9 mRNA expression, survival and gene signature in human hepatocellular carcinoma (HCC).  DPP9  loss-of-function exonic variants were mostly associated with cancers. In HCC patients, DPP9 and the closely related genes  DPP4  and  DPP8  were upregulated in liver tumors. High co-expression of genes that were positively correlated with  DPP4 ,  DPP8  and  DPP9  was associated with poor survival in HCC patients. These findings strongly implicate the  DPP4  gene family, especially  DPP9 , in the pathogenesis of human HCC and therefore encourages future functional studies.    Abstract  Dipeptidyl peptidase (DPP) 9, DPP8, DPP4 and fibroblast activation protein (FAP) are the four enzymatically active members of the S9b protease family. Associations of DPP9 with human liver cancer, exonic single nucleotide polymorphisms (SNPs) in  DPP9  and loss of function (LoF) variants have not been explored. Human genomic databases, including The Cancer Genome Atlas (TCGA), were interrogated to identify  DPP9  LoF variants and associated cancers. Survival and gene signature analyses were performed on hepatocellular carcinoma (HCC) data. We found that  DPP9  and  DPP8  are intolerant to LoF variants.  DPP9  exonic LoF variants were most often associated with uterine carcinoma and lung carcinoma. All four  DPP4 -like genes were overexpressed in liver tumors and their joint high expression was associated with poor survival in HCC. Increased  DPP9  expression was associated with obesity in HCC patients. High expression of genes that positively correlated with overexpression of  DPP4 ,  DPP8 , and  DPP9  were associated with very poor survival in HCC. Enriched pathways analysis of these positively correlated genes featured Toll-like receptor and SUMOylation pathways. This comprehensive data mining suggests that DPP9 is important for survival and that the DPP4 protease family, particularly DPP9, is important in the pathogenesis of human HCC.

DPP9: Comprehensive In Silico Analyses of Loss of Function Gene Variants and Associated Gene Expression Signatures in Human Hepatocellular Carcinoma