Abstract

ABSTRACT Background Digital papillary adenocarcinoma (DPAC) is a rare but aggressive cutaneous malignant sweat gland neoplasm that occurs on acral sites. Despite its clinical significance, the cellular and genetic characteristics of DPAC remain incompletely understood. Methods We conducted a comprehensive genomic and transcriptomic analysis of DPAC ( n = 14) using targeted next‐generation DNA and RNA sequencing, along with gene expression profiling employing the Nanostring Technologies nCounter IO 360 Panel. Gene expression in DPAC was compared to that in hidradenoma ( n = 10). Immunohistochemistry was employed to validate gene expression. Results Two out of eight DPACs showed fusion gene rearrangements ( CRTC3 :: MAML2 and TRPS1 :: PLAG1 ). No uniform mutational signature was detected in DPAC. Comparative gene expression analysis revealed an enrichment of genes related to matrix remodeling, metabolism, and DNA damage repair. Hallmark pathway analysis demonstrated significant upregulation of E2F target genes in DPAC compared to hidradenoma ( p = 0.00710). Human papillomavirus‐42 was found to be positive in all of our tested DPAC cases. Immunohistochemistry confirmed increased protein expression of CD56, CDC20, and SOX10 in DPAC. Notably, most DPAC tumors also exhibited B‐cell infiltration, as indicated by CD20 staining. Conclusions Our findings reveal novel fusions and validate altered replication pathways related to HPV42 in DPAC.