Mucosal malignant melanoma (MMM) is a rare and aggressive tumor. Despite effective local therapies, tumor recurrence and metastasis remain frequent. The genetics of MMM remain incompletely understood. This study is aimed to identify actionable genetic alterations by next-generation sequencing. Fifteen MMM samples were analyzed by next-generation and Sanger sequencing. Gene copy number alterations were analyzed by MLPA. Mutation status was correlated with pERK, pAKT, and Ki-67 expression and follow-up data. Inactivating mutations and intragenic deletions in neurofibromatosis type-1 (NF1) were identified in 3 and 2 cases, respectively, (in total 5/15, 33%) and activating mutations in NRAS and KRAS (3/15, 20%) cases. Other mutated genes included CDKN2A, APC, ATM, MITF, FGFR1, and FGFR2. BRAF and KIT mutations were not observed. Cases with NF1 alterations tended to have worse overall survival. The mutational status was not associated with pERK, pAKT, or Ki-67 immunostaining. MMM carries frequent gene mutations activating the MAPK pathway, similar to cutaneous melanoma. In contrast, NF1 is the most frequently affected gene. Intragenic NF1 deletions have not been described before and may go undetected by sequencing studies. This finding is clinically relevant as NF1-mutated melanomas have worse survival and could benefit from therapy with immune checkpoint and MEK inhibitors.

中文翻译：

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鼻窦黏膜恶性黑色素瘤中的基因内 NF1 缺失

黏膜恶性黑色素瘤（MMM）是一种罕见的侵袭性肿瘤。尽管局部治疗有效，但肿瘤复发和转移仍然频繁。MMM的遗传学仍然不完全清楚。本研究旨在通过下一代测序确定可操作的基因改变。通过下一代和 Sanger 测序分析了 15 个 MMM 样品。通过 MLPA 分析基因拷贝数改变。突变状态与 pERK、pAKT 和 Ki-67 表达和随访数据相关。分别在 3 例和 2 例（总共 5/15，33%）和NRAS和KRAS（3/15，20%）病例中发现了 1 型神经纤维瘤病（ NF1）的失活突变和基因内缺失。其他突变基因包括CDKN2A、APC、ATM、MITF、FGFR1和FGFR2。未观察到BRAF和KIT突变。具有NF1改变的病例往往具有较差的总体生存率。突变状态与 pERK、pAKT 或 Ki-67 免疫染色无关。MMM 携带激活 MAPK 通路的频繁基因突变，类似于皮肤黑色素瘤。相比之下，NF1是最常受影响的基因。之前没有描述过基因内 NF1缺失，并且可能无法通过测序研究检测到。这一发现具有临床意义，因为NF1突变的黑色素瘤存活率较差，并且可能受益于免疫检查点和 MEK 抑制剂的治疗。