We report a series of 33 skin tumors harboring a gene fusion of the MAP3K8 gene, which encodes a serine/threonine kinase. The MAP3K8 fusions were identified by RNA sequencing in 28 cases and by break-apart FISH in five cases. Cases in which fusion genes were fully characterized demonstrated a fusion of the 5' part of MAP3K8 comprising exons 1-8 in frame to one of several partner genes at the 3' end. The fusion genes invariably encoded the intact kinase domain of MAP3K8, but not the inhibitory domain at the C-terminus. In 13 (46%) of the sequenced cases, the 3' fusion partner was SVIL. Other recurrent 3' partners were DIP2C and UBL3, with additional fusion partners that occurred only in a single tumor. Clinically, the lesions appeared mainly in young adults (2-59 years of age; median = 18), most commonly involving the lower limbs (55%). Five cases were diagnosed as Spitz nevus, 13 as atypical Spitz tumor, and 15 as malignant Spitz tumor. Atypical and malignant cases more commonly occurred in younger patients. Atypical Spitz tumors and malignant Spitz tumors cases tended to show epidermal ulceration (32%), a dermal component with giant multinucleated cells (32%), and clusters of pigmented cells in the dermis (32%). Moreover, in atypical and malignant cases, a frequent inactivation of CDKN2A (21/26; 77%) was identified either by p16 immunohistochemistry, FISH, or comparative genomic hybridization. Gene expression analysis revealed that MAP3K8 expression levels were significantly elevated compared to a control group of 57 Spitz lesions harboring other known kinase fusions. Clinical follow-up revealed regional nodal involvement in two of six cases, in which sentinel lymph node biopsy was performed but no distant metastatic disease after a median follow-up time of 6 months.

中文翻译：

---

具有 MAP3K8 融合的黑色素细胞肿瘤：33 例具有形态学-遗传相关性的报告。

我们报告了一系列包含 MAP3K8 基因融合的 33 种皮肤肿瘤，该基因编码丝氨酸/苏氨酸激酶。MAP3K8 融合在 28 例中通过 RNA 测序鉴定，在 5 例中通过分离 FISH 鉴定。融合基因得到充分表征的案例表明，包含框内外显子 1-8 的 MAP3K8 的 5' 部分与 3' 端的几个伙伴基因之一融合。融合基因总是编码 MAP3K8 的完整激酶结构域，但不编码 C 末端的抑制结构域。在 13 个 (46%) 的测序病例中，3' 融合伴侣是 SVIL。其他复发性 3' 伙伴是 DIP2C 和 UBL3，以及仅在单个肿瘤中出现的其他融合伙伴。临床上，皮损主要出现在青壮年（2-59岁；中位数=18），最常累及下肢 (55%)。诊断为Spitz痣5例，非典型Spitz瘤13例，恶性Spitz瘤15例。非典型和恶性病例更常见于年轻患者。非典型 Spitz 肿瘤和恶性 Spitz 肿瘤病例往往表现出表皮溃疡 (32%)、具有巨大多核细胞的真皮成分 (32%) 和真皮中的色素细胞簇 (32%)。此外，在非典型和恶性病例中，通过 p16 免疫组织化学、FISH 或比较基因组杂交确定了 CDKN2A 的频繁失活（21/26；77%）。基因表达分析显示，与包含其他已知激酶融合的 57 个 Spitz 病变的对照组相比，MAP3K8 表达水平显着升高。