Targeted Sequencing Revealed Distinct Mutational Profiles of Ocular and Extraocular Sebaceous Carcinomas

SIMPLE SUMMARY: The molecular pathogenesis of sebaceous carcinoma is largely unknown so far. The main aim of our study was to investigate genetic alterations in ocular and extraocular sebaceous carcinoma in Korean patients. By applying targeted next-generation sequencing, we demonstrated a distinct mutational profile in ocular and extraocular sebaceous carcinoma. In addition, clinically actionable variants involving tyrosine kinase genes and homologous recombination deficiency-associated genes were detected, suggesting the possibility of targeted therapeutic trials in intractable sebaceous carcinoma cases. ABSTRACT: The biological behavior of sebaceous carcinoma (SeC) is relatively indolent; however, local invasion or distant metastasis is sometimes reported. Nevertheless, a lack of understanding of the genetic background of SeC makes it difficult to apply effective systemic therapy. This study was designed to investigate major genetic alterations in SeCs in Korean patients. A total of 29 samples, including 20 ocular SeCs (SeC-Os) and 9 extraocular SeCs (SeC-EOs), were examined. Targeted next-generation sequencing tests including 171 cancer-related genes were performed. TP53 and PIK3CA genes were frequently mutated in both SeC-Os and SeC-EOs with slight predominance in SeC-Os, whereas the NOTCH1 gene was more commonly mutated in SeC-EOs. In clinical correlation, mutations in RUNX1 and ATM were associated with development of distant metastases, and alterations in MSH6 and BRCA1 were associated with inferior progression-free survival (all p < 0.05). In conclusion, our study revealed distinct genetic alterations between SeC-Os and SeC-EOs and some important prognostic molecular markers. Mutations in potentially actionable genes, including EGFR, ERBB2, and mismatch repair genes, were noted, suggesting consideration of a clinical trial in intractable cases.