Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland.
Mod Pathol. 2022 Nov;35(11):1609-1617. doi: 10.1038/s41379-022-01122-7. Epub 2022 Aug 17.
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.
鼻腔鼻窦黑色素瘤是一种罕见的肿瘤，发生于鼻腔、副鼻窦或鼻咽部（鼻道）。本研究评估了 90 例患者，其中 29 例为男性，61 例为女性，中位年龄为 68 岁。大多数肿瘤累及鼻腔，具有上皮样形态。本分析中使用的研究技术包括靶向 DNA 和 RNA 下一代测序、Sanger 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（38/90，42%）驱动，特别是 NRAS（n=36）突变，很少（4/90，4%）显示 BRAF 致病性变异。BRAF/RAS 突变体在副鼻窦（10/14，71%）比鼻腔（26/64，41%）肿瘤更常见。BRAF/RAS 野生型肿瘤偶尔会发生 Ras-MAPK 信号通路的关键成分和调节剂的改变：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。这些突变经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%）。在超过 50%的病例中，观察到 TP53 的核积累增加，反映出核 MDM2 表达升高。此外，包括 RAS/BRAF 野生型肿瘤（n=5）在内的鼻腔鼻窦黑色素瘤（n=7）存在经典 WNT 通路的关键成分和调节剂的改变：APC（4/90，4%）、CTNNB1（3/90，3%）和 AMER1（1/90，1%）。均检测到 TERT 启动子突变（5/53，9%）和融合（2/40，5%）。后者发生在 BRAF/RAS 野生型肿瘤中。未检测到以前在皮肤黑色素瘤中报道的致癌融合基因转录本。包括 7 例 BRAF/RAS 野生型病例在内的 8 例肿瘤表达 ADCK4::NUMBL 顺式融合转录本。总之，本研究证明了大多数鼻腔鼻窦黑色素瘤中 NRAS 及其他 Ras-MAPK 信号通路的关键成分和调节剂的突变激活，如 SPRED1。
