Abstract：
Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.
摘要：
鼻窦粘膜黑色素瘤是一种罕见的鼻腔内肿瘤，鼻旁窦,或鼻咽（鼻窦）。这项研究评估了90例确诊病例，其中29名男性和61名女性，中位年龄68岁。大多数肿瘤累及鼻腔，并具有上皮样形态。该分析中使用的研究技术包括靶向DNA和RNA下一代测序，桑格测序,荧光原位杂交和免疫组织化学。鼻腔鼻窦黑色素瘤通常由RAS引起（38/90，42%），尤其是NRAS（n=36）突变，很少（4/90，4％）显示BRAF致病性变异。BRAF/RAS突变体在鼻旁窦肿瘤中（10/14，71％）比鼻肿瘤（26/64，41％）更频繁。BRAF/RAS野生型肿瘤偶尔携带Ras-MAPK信号通路的关键成分和调节因子的改变：NF1突变（1/17，6%）或NF1基因座缺失（1/25，4%），SPRED1(3/25,12%),PIK3CA(3/50,6%),PTEN(4/50,8%)和mTOR(1/50,2%)突变。这些突变通常以相互排斥的方式发生。在一些肿瘤中，其中一些是NRAS突变体，TP53缺失(6/48,13%)和/或突变(5/90,6%)。在>50%的病例中观察到由升高的核MDM2表达反映的TP53的可变核积累。此外，鼻窦黑色素瘤（n=7），包括RAS/BRAF野生型肿瘤（n=5），具有典型WNT途径的关键成分和调节因子的改变：APC（4/90，4％），CTNNB1(3/90，3%)和AMER1(1/90，1%)。两者,鉴定了TERT启动子突变(5/53,9%)和融合体(2/40,5%)。后者发生在BRAF/RAS野生型肿瘤中。未检测到先前在皮肤黑素瘤中报道的致癌融合基因转录本。包括7例BRAF/RAS野生型病例的8个肿瘤表达ADCK4::NUMBL顺式融合转录本。总之,这项研究记录了NRAS和Ras-MAPK信号通路的其他关键成分和调节因子如SPRED1在大多数鼻腔鼻窦黑色素瘤中的突变激活.
