Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.
Primary mucosal melanomas of the head and neck are characterised by overexpression of the DNA mutating enzyme APOBEC3B.
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原发性头颈部粘膜黑色素瘤（MM）很少见，表现出侵袭性生物学行为和升高的突变负荷。在头/颈椎间盘中观察到的高基因组不稳定性的分子机制仍然难以捉摸。DNA胞嘧啶脱氨酶APOBEC 3B（A3 B）构成了人类癌症中主要的内源性突变来源。A3 B相关突变通过5′-TCA/T基序中的C至T/−G碱基取代来鉴定。在此，我们提出的免疫组化和基因组数据支持的作用，A3 B在头/颈椎间盘突出症。使用定制兔α-A3 B mAb（5210 - 87 - 13），通过免疫组织化学评估口腔（n = 13）和鼻窦（n = 13）黑色素瘤以及口腔黑色素细胞痣（n = 13）中的A3 B蛋白水平。在13例口腔黑色素瘤中的12例（92.3%）（H评分范围= 9-72，中位数= 40）和13例鼻窦黑色素瘤中的8例（62%）（H评分范围= 1-110，中位数= 24）中观察到异质性、选择性至弥漫性、仅细胞核、A3 B免疫阳性。2例A3 B阴性病例显示与A3 G一致的显著胞浆染色。口腔和鼻窦痣的A3 B蛋白水平显著高于口内黑色素细胞痣（分别为P < 0.0001和P = 0.0022），后者为A3 B阴性（H评分范围= 1-8，中位数= 4）。然而，A3 B水平在口腔和鼻窦肿瘤之间没有显著差异（P > 0.99）。在10例鼻窦炎中进行的NGS显示，50%的研究病例中存在错义NRAS突变，KIT和HRAS突变各1例。公开可用的全基因组测序（WGS）数据显示，头颈部肿瘤（n = 2）中C至T突变的数量和APOBEC 3富集评分显著升高。上述数据有力地表明了诱变酶A3 B在头颈部黑色素瘤形成中的可能作用，而不是良性黑色素细胞肿瘤。核APOBEC 3B（A3 B）上调表征头颈部粘膜黑色素瘤，燃料突变负荷，并促进肿瘤间和肿瘤内异质性。
Primary head/neck mucosal melanomas (MMs) are rare and exhibit aggressive biologic behaviour and elevated mutational loads. The molecular mechanisms responsible for high genomic instability observed in head/neck MMs remain elusive. The DNA cytosine deaminase APOBEC3B (A3B) constitutes a major endogenous source of mutation in human cancer. A3B‐related mutations are identified through C‐to‐T/−G base substitutions in 5′‐TCA/T motifs. Herein, we present immunohistochemical and genomic data supportive of a role for A3B in head/neck MMs. A3B protein levels were assessed in oral (n = 13) and sinonasal (n = 13) melanomas, and oral melanocytic nevi (n = 13) by immunohistochemistry using a custom rabbit α‐A3B mAb (5210‐87‐13). Heterogeneous, selective‐to‐diffuse, nuclear only, A3B immunopositivity was observed in 12 of 13 (92.3%) oral melanomas (H‐score range = 9–72, median = 40) and 8 of 13 (62%) sinonasal melanomas (H‐score range = 1–110, median = 24). Two cases negative for A3B showed prominent cytoplasmic staining consistent with A3G. A3B protein levels were significantly higher in oral and sinonasal MMs than intraoral melanocytic nevi (P < 0.0001 and P = 0.0022, respectively), which were A3B‐negative (H‐score range = 1–8, median = 4). A3B levels, however, did not differ significantly between oral and sinonasal tumours (P > 0.99). NGS performed in 10 sinonasal MMs revealed missense NRAS mutations in 50% of the studied cases and one each KIT and HRAS mutations. Publicly available whole‐genome sequencing (WGS) data disclosed that the number of C‐to‐T mutations and APOBEC3 enrichment score were markedly elevated in head/neck MMs (n = 2). The above data strongly indicate a possible role for the mutagenic enzyme A3B in head/neck melanomagenesis, but not benign melanocytic neoplasms. Nuclear APOBEC3B (A3B) upregulation characterizes head/neck mucosal melanomas, fuels mutational load, and promotes inter‐ and intratumoral heterogeneity.
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