Metaplastic thymomas are rare biphasic thymic tumors that are characteristically well-circumscribed, confined to the thymus, and follow a benign to indolent clinical course. Their relationship to other thymic neoplasms remains unclear, and their molecular characteristics have not been defined. We report for the first time recurrent translocation events in metaplastic thymomas involving the Yes Associated Protein 1 (YAP1) and Mastermind Like Transcriptional Coactivator 2 (MAML2) genes. Eight metaplastic thymomas were retrieved from two institutions’ archives over a 21-year period. Paraffin-embedded material from all cases underwent targeted DNA-based hybrid capture next-generation sequencing. Cases showing no somatic alterations subsequently underwent targeted RNA sequencing. Allele-specific real-time polymerase chain reaction was performed to detect GTF2I c.74146970T>A (p.L424H) mutations. All cases showed characteristic histologic features of metaplastic thymoma and demonstrated no local recurrence or distant metastatic disease at 1–22 years of follow-up. Six of eight cases were successfully sequenced, all showing YAP1-MAML2 fusions; in four cases the fusions were detected by DNA sequencing and in two cases by RNA sequencing. Two distinct products were identified: 5′ YAP1 exon 1 fused to 3′ MAML2 exons 2–5 or 5′ YAP1 exons 1–5 fused to 3′ MAML2 exons 2–5. All cases underwent allele-specific real-time polymerase chain reaction and demonstrated no GTF2I L424H mutations. Metaplastic thymoma is a distinct, clinically indolent thymic epithelial neoplasm characterized by YAP1-MAML2 fusion and lacking the GTF2I mutations found in Type A and AB thymomas.

化生性胸腺瘤是罕见的双相胸腺肿瘤，其特征是边界清楚，局限于胸腺，并遵循良性至惰性临床过程。它们与其他胸腺肿瘤的关系仍不清楚，其分子特征也未明确。我们首次报告了化生性胸腺瘤中涉及 Yes 相关蛋白 1 ( YAP1 ) 和 Mastermind 样转录辅激活因子 2 ( MAML2 ) 的复发性易位事件）基因。在 21 年的时间里，从两个机构的档案中检索到八个化生性胸腺瘤。来自所有病例的石蜡包埋材料都进行了基于靶向 DNA 的杂交捕获下一代测序。没有显示体细胞改变的病例随后进行了靶向 RNA 测序。进行等位基因特异性实时聚合酶链反应以检测GTF2I c.74146970T>A (p.L424H) 突变。所有病例都表现出化生性胸腺瘤的特征性组织学特征，并且在 1-22 年的随访中没有局部复发或远处转移。8 个案例中有 6 个成功测序，均显示YAP1-MAML2融合; 在四个案例中，融合是通过 DNA 测序检测到的，在两个案例中，融合是通过 RNA 测序检测到的。鉴定了两种不同的产物：5 ' YAP1外显子 1 融合到 3' MAML2外显子 2-5 或 5' YAP1外显子 1-5 融合到 3' MAML2外显子 2-5。所有病例均进行了等位基因特异性实时聚合酶链反应，未显示GTF2I L424H 突变。化生性胸腺瘤是一种独特的、临床惰性的胸腺上皮肿瘤，其特征是YAP1-MAML2融合，并且缺乏A 型和 AB 型胸腺瘤中发现的GTF2I突变。