Riobello Cristina, Casanueva Muruais Rodrigo, Suárez-Fernández Laura, García-Marín Rocío, Cabal Virginia N, Blanco-Lorenzo Verónica, Franchi Alessandro, Laco Jan, López Fernando, Llorente José Luis, Hermsen Mario A
Department Head and Neck Cancer, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Centro de Investigación Biomédica en Red (CIBER-ONC), Oviedo, Spain.
Department Otolaryngology, Hospital Universitario Central de Asturias, Oviedo, Spain.
Pigment Cell Melanoma Res. 2022 Jan;35(1):88-96. doi: 10.1111/pcmr.13015. Epub 2021 Oct 8.
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.
黏膜恶性黑色素瘤（MMM）是一种罕见且侵袭性强的肿瘤。尽管有有效的局部治疗方法，但肿瘤复发和转移仍很常见。MMM的遗传学仍未完全了解。本研究旨在通过下一代测序确定可操作的基因改变。对15份MMM样本进行了下一代测序和桑格测序分析。通过多重连接探针扩增技术（MLPA）分析基因拷贝数改变。将突变状态与磷酸化细胞外信号调节激酶（pERK）、磷酸化蛋白激酶B（pAKT）和Ki-67表达以及随访数据进行关联分析。分别在3例和2例（共5/15，33%）中鉴定出1型神经纤维瘤病（NF1）的失活突变和基因内缺失，在3例（3/15，20%）中鉴定出NRAS和KRAS的激活突变。其他突变基因包括细胞周期蛋白依赖性激酶抑制剂2A（CDKN2A）、腺瘤性息肉病基因（APC）、共济失调毛细血管扩张症突变基因（ATM）、小眼畸形相关转录因子（MITF）、成纤维细胞生长因子受体1（FGFR1）和成纤维细胞生长因子受体2（FGFR2）。未观察到BRAF和KIT突变。发生NF1改变的病例总体生存率往往较差。突变状态与pERK、pAKT或Ki-67免疫染色无关。与皮肤黑色素瘤相似，MMM频繁发生激活丝裂原活化蛋白激酶（MAPK）途径的基因突变。相比之下，NF1是最常受影响的基因。此前尚未描述过基因内NF1缺失，测序研究可能无法检测到。这一发现具有临床相关性，因为NF1突变的黑色素瘤生存率较差，可能受益于免疫检查点和丝裂原活化蛋白激酶激酶（MEK）抑制剂治疗。
