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Sebaceous carcinoma (SC) represents a rare, aggressive eyelid malignancy with poor prognosis and is a possible component of Muir-Torre syndrome. However, genetic features as driver mutations or potential therapeutic targets are not fully elucidated. Recent a few studies have shown that SCs have concurrently multiple mutations including RAS/RAF/MAPK and PI3K/Akt pathways via next-generation sequencing in western population. Because we recently demonstrated absence of KRAS mutations in Korean eyelid SCs, we extended our previous study to the analysis of NRAS , BRAF , PIK3CA , and CTNNB1 mutations, and the examination of related protein expressions in 15 eyelid SCs. Repeated molecular analysis by peptide nucleic acid-mediated PCR clamping method, PNA clamping-assisted fluorescence melting curve analysis, and direct sequencing revealed that all eyelid SCs had wild type alleles of NRAS , BRAF , and PIK3CA in hotspot exon locations. Only silent mutations in the CTNNB1 gene (p.Q61Q) were identified. Using immunohistochemistry and microsatellite instability analysis, they harbored all intact mismatch repair gene proteins with microsatellite stability. Membranous and cytoplasmic β-catenin staining was found in all tumors, whereas the one third of those tumors showed cyclin D1 overexpression, of which 40% and 80% showed p53 expression and p16 expression, respectively. The lack of KRAS , NRAS , BRAF , and PIK3CA mutation in our study may suggest that a subset of eyelid SCs is unlike that of eyelid SCs of western countries. The mismatch repair gene proteins and microsatellite instability analysis as a screening test for Muir-Torre syndrome may be limited in the Korean eyelid SCs. [ABSTRACT FROM AUTHOR]

Cutaneous malignant melanomas (CMMs) are rare but are the cause of the highest skin cancer-related mortality in Korea. Very few studies have investigated the associations between KRAS , NRAS , BRAF , and PIK3CA mutations and TICs, as well as their prognostic impact on Korean CMMs. Peptide nucleic acid-mediated polymerase chain reaction clamping and Mutyper and immunohistochemistry were used to detect these mutations in 47 paraffinized CMMs. BRAF and NRAS mutations were detected in 21.3% and 12.8% of CMMs, respectively. No KRAS or PIK3CA mutations were identified. NRAS mutations correlated with low FOXP3 (regulatory T lymphocyte marker) and indoleamine 2,3-dioxygenase (IDO) (activated dendritic cell marker) TICs in CMMs, which is consistent with the negative correlation of regulatory T cells with NRAS mutations in TCGA data, while BRAF mutations were not associated with any TICs. In gene set enrichment analysis, BRAF and NRAS mutations were enriched in decreased CD8 (suppressor/cytotoxic T lymphocyte marker) T cell-linked and increased CD4 (helper/inducer T lymphocyte marker) T cell-linked gene signatures, respectively, confirming the trend in our cohort of associations only with NRAS. BRAF or NRAS mutations alone did not affect any prognosis. In the subgroup analyses, BRAF mutations, as well as high CD4, CD8, FOXP3, and IDO TICs, caused worse overall survival in NRAS -mutated melanoma. No correlation of CD163 (monocyte–macrophage-specific marker) was detected. We found that approximately one-third of our cohort had BRAF and NRAS mutations, none had KRAS or PIK3CA mutations, and most displayed decreased anti-tumor immunity. These findings may warrant further study on combined immunotherapeutic and molecular targeted therapy in Korean CMMs. Subgroup analyses according to TICs and BRAF / NRAS mutations may help to identify high-risk patients with worse prognoses. [ABSTRACT FROM AUTHOR]