Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with BRAF wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E–negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1–mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92–1.00; P = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, P = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.

中文翻译：

---

基于下一代测序的panel在BRAF野生型晚期黑色素瘤中的临床应用确定了关键的致癌改变和治疗策略

使用新一代测序 (NGS) 进行的分子分析已应用于多种实体癌，以发现潜在的治疗靶点。在这里，我们描述了晚期黑色素瘤患者的临床 NGS 小组的结果。来自首尔国立大学医院（SNUH；首尔，韩国）的 BRAF 野生型黑色素瘤患者的 36 个肿瘤组织被收集并使用 SNUH FIRST-Cancer NGS panel 进行深度测序，以评估单核苷酸变异、小插入/ 缺失、拷贝数变异和结构变异以估计肿瘤突变负荷 (TMB)。我们发现了 106 个致癌改变，大多数患者（n = 33, 92%）至少有一个致癌改变，包括 2 名最初被诊断为 BRAF V600E 阴性但后来被证实为阳性的患者。共，36 个样本被分为 RAS/BRAF/NF1 突变型（n = 14, 39%）或三重野生型（n = 22, 61%）黑色素瘤亚型。估计的中位 TMB 为每 Mb 8.2 个突变，范围为每 Mb 0 到 146.67 个突变。在 36 名患者中，25 名 (70%) 使用当前开发的药物进行了可操作的改变，7 名 (19.4%) 参加了使用 RAF 抑制剂、多受体酪氨酸激酶抑制剂和抗程序性细胞死亡-1 (PD) 的临床试验-1) 抗体。TMB 倾向于与抗 PD-1/PDL-1 抗体治疗的无进展生存期 (PFS) 相关（HR，0.96；95% 置信区间，0.92–1.00；P = 0.07）。与低 TMB 组相比，高 TMB (≥13) 组与更长的 PFS 相关（中位 34.0 周 vs. 11.0 周，P = 0.04）。全面的，