Genomic landscape of sweat gland carcinomas: Clinical applications and future directions

Sweat gland carcinomas (SGC) are rare tumors frequently driven by somatic mutations. More than 20 distinct SGC entities are recognized, many of which exhibit overlapping histopathological features, making accurate diagnosis challenging. This review provides a comprehensive overview of SGC entities and summarizes current knowledge of their mutational landscapes to improve understanding of their biology and identify potential therapeutic targets, particularly for aggressive tumors lacking treatment options in advanced stages. Key oncogenic driver mechanisms include high mutational burden, mutational signatures consistent with ultraviolet (UV)-induced DNA damage, dysregulation of the epidermal growth factor receptor (EGFR) signaling pathway, and defects in homologous recombination-mediated DNA double-strand break repair. Recurrent, functionally significant somatic alterations have been identified in genes such as TP53, PIK3CA and CDKN2A/B, consistent with their roles in genomic stability, cell signaling and epigenetic regulation. Fusion genes represent a further key feature of SGC. Some fusion genes are entity-specific and serve as molecular hallmarks. Notably, some fusions partners have been identified in several SGC entities, suggesting shared underlying biology. Interestingly, digital papillary adenocarcinoma is the only SGC entity in which oncogenic transformation is mainly driven by a virus (HPV42). This review highlights the need for comprehensive molecular characterization of SGC and discusses the implications for prognosis, risk stratification and therapeutic decision-making. Ongoing case reporting and molecular characterization will be essential to further elucidate the molecular landscape, biological behavior, and therapeutic vulnerabilities of these rare tumors, particularly in carcinomas for which surgical excision alone is unlikely to achieve a curative outcome. Integrating broad molecular profiling with clinicopathological data and establishing systematic registries for rare cancers will be critical to advancing both biological understanding and clinical management of SGC.