Genomic Landscape of Primary and Secondary Cutaneous Angiosarcoma: A Single‐Center Retrospective Cohort Analysis in Japan

ABSTRACT Cutaneous angiosarcoma (cAS) is an aggressive vascular malignancy comprising idiopathic primary cutaneous angiosarcoma (PCAS) and secondary cutaneous angiosarcoma (SCAS) arising after radiation therapy or chronic lymphedema. Comparative genomic analyses delineating these subtypes in Asian populations remain limited. We retrospectively evaluated 15 Japanese cAS patients (10 PCAS, 5 SCAS) who underwent comprehensive genomic profiling (CGP) using FoundationOne CDx or liquid CDx between 2020 and 2026. Variants of unknown significance (VUS) and potential clonal hematopoiesis (CH)‐derived mutations were systematically excluded. The cohort demonstrated a uniformly low tumor mutational burden (median 4 mut/Mb) with no MSI‐H cases. TP53 was the most frequent driver mutation (47%), followed by CDKN2A (33%), MYC (33%), KDR (27%), CDKN2B (27%), MTAP (27%), KIT (27%), and PDGFRA (27%). A molecular separation was observed between the two clinical subtypes, where focal MYC amplification was confined to SCAS cases (5/5, 100%), whereas PCAS lesions were enriched with cell‐cycle pathway alterations via co‐deletions of CDKN2A , CDKN2B , and MTAP , alongside variable receptor tyrosine kinase (RTK) gains ( KIT/PDGFRA ). RAS pathway mutations presented only as three cases of missense variants across both subtypes. Although limited by sample size, these findings suggest subtype‐associated genomic patterns in Japanese cAS and may serve as preliminary observations that warrant validation in larger East Asian cohorts.