Genomic Landscape and Clinical Actionability of Skin Adnexal Carcinomas

Purpose Skin adnexal carcinomas (SACs) are rare and heterogeneous tumors with no established systemic treatment options and poor long-term survival rates in the advanced disease setting. Here, we aimed to characterize the genomic landscape and clinically actionable alterations across SAC subtypes. Methods We analyzed next-generation sequencing data from SACs in the American Association for Cancer Research Project GENIE. Mutations, copy number alterations, and structural variants were annotated using OncoKB. Actionable alterations were defined as Level 1-2 alterations or tumor mutational burden (TMB) ≥10 mut/Mb. TMB was compared across subtypes and with melanoma, cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Results A total of 224 SACs were analyzed (49% extramammary Paget disease [EMPD], 33% apocrine/eccrine, 17% sebaceous, 1% follicular). In EMPD, the most frequent actionable alterations were in PIK3CA (25.7%) and ERBB2 (22.9%). In sebaceous carcinoma, actionable alterations were mainly in KRAS (10.3%) and PIK3CA (10.3%). Apocrine/eccrine tumors also presented ERBB2 and PIK3CA alterations, but at lower frequencies (5.5% and 8.2%, respectively). TMB-high occurred in 10.1% of EMPD, 28.2% of sebaceous, and 21.9% of apocrine/eccrine tumors, lower than in melanoma (52.1%), CSCC (64.4%), and BCC (63.3%). SAC drivers showed important heterogeneity across subtypes. Overall, 48.2% of SACs harbored at least one potentially actionable alteration. Conclusion SACs frequently harbor clinically actionable alterations in a histotype-dependent manner. The identification of lineage-specific genomic differences underscores the clinical and translational relevance of integrating histology with genomic profiling for guiding therapeutic decision making.