Genomic profiles of patients with skin melanoma in the era of immune checkpoint inhibitors.

The use of immune checkpoint inhibitors (ICIs) for treating melanoma has dramatically improved patient prognosis. The genomic profiles of patients receiving ICI therapy would provide valuable information for disease management and treatment. We investigated the genomic profiles of patients with melanoma who had received ICI therapy and explored associations with clinical features and outcomes via a large-scale nationwide database in Japan (the C-CAT database). We identified 339 patients eligible for this study. The most frequent genetic mutations were found in the BRAF (27%), TERT (24%), and NRAS (19%) genes, and the most common copy number variations (CNVs) were in the CDKN2A (36%), CDKN2B (26%), and MTAP (19%) genes. Associations with high tumor mutational burden (TMB-high) status were significant for TERT (p < 0.001), NF1 (p < 0.001), ROS1 (p = 0.015), POLE (p = 0.045), and POLD1 (p = 0.008) mutations, along with older age (≥65 years, p = 0.036). Patients with multiple metastases (two or more) were more likely to have NOTCH3 mutations (p = 0.017) and be younger than 65 years (p = 0.024). In particular, as well as younger age, patients with brain metastases were more likely to harbor BRAF mutations (p < 0.001), while those with liver metastases were more likely to harbor NOTCH3 mutations (p < 0.001) but not CDKN2B CNVs (p = 0.041). Patients with NRAS mutations were less likely to respond to ICI therapy (p = 0.014) and exhibited shorter overall survival (p = 0.006). In this population, the frequency of BRAF mutations was lower than that in fair-skinned populations, but the associations between genomic profiles, clinical features, and outcomes were similar to those previously reported in fair-skinned populations.