This single-center retrospective cohort study compared tumor mutational burden (TMB), UV mutational signature, and single-nucleotide and pathway-level mutational profiles of pleomorphic dermal sarcoma (PDS) to metastatic cutaneous squamous cell carcinoma (CSCC) and soft-tissue sarcoma (STS) using a 447-gene sequencing panel at Dana-Farber/Brigham and Women's Hospital (January 2015–October 2025).
PDS and CSCC shared nearly identical genetic profiles: mean TMB was 44.6 (95% CI, 37.5–51.8) for PDS vs. 54.1 (95% CI, 40.4–67.8) for CSCC (no significant difference), both far above STS at 4.2 (95% CI, 3.2–5.2). All PDSs and CSCCs carried UV signature mutations; no STSs did. Principal component analysis showed completely overlapping PDS/CSCC clusters, distinct from a narrow, separate STS cluster.
Very small sample sizes (9 PDS, 15 CSCC, 25 STS) limit statistical power and generalizability. Single-center design may introduce selection bias. Full text is under embargo, so additional methodological detail could not be reviewed.
PDS appears genetically far closer to cutaneous squamous cell carcinoma than to other soft-tissue sarcomas — clinicians should consider whether cutaneous cancer treatment protocols (including immunotherapy strategies targeting high TMB and UV-driven tumors) may be more appropriate than standard sarcoma regimens for PDS.
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