Recurrent Loss of SMARCA4 in Sinonasal Teratocarcinosarcoma
Recurrent Loss of SMARCA4 in Sinonasal Teratocarcinosarcoma
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DOI：
10.1097/pas.0000000000001508
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发表时间：
2020-10-01
影响因子：
5.6
通讯作者：
Bishop, Justin A.
中科院分区：
文献类型：
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作者：
Rooper, Lisa M.;Uddin, Nasir;Bishop, Justin A.
分子分析通过定义新的实体和识别已建立的肿瘤类型中的复发突变，重塑了高级别鼻窦肿瘤的景观。然而，鼻窦畸胎瘤癌肉瘤（TCS），一种罕见的和积极的肿瘤混合畸胎瘤，癌，肉瘤的元素，仍然知之甚少。TCS的多表型分化引起了关于其组织发生的持续争议，并导致与其他几种恶性肿瘤的诊断重叠。在这项研究中，我们评估了TCS的分子基础，以阐明其发病机制和诊断。我们对22例TCS和153例其他鼻窦肿瘤进行了SMARCA 4免疫组化（IHC）。我们在18例TCS（82%）中发现SMARCA4表达缺失，包括15例（68%）完全缺失和3例（14%）部分缺失。虽然我们也发现8例SMARCB 1缺陷型鼻窦癌中有1例（13%）SMARCA 4部分缺失，但在所有其他鼻窦癌和神经内分泌肿瘤中SMARCA 4均完整。然后，我们选择了3个通过IHC完全丢失SMARCA4的TCS，用于包括1425个癌症相关基因的靶向下一代测序组。我们证实在这3例中SMARCA 4的双等位基因体细胞失活没有其他已知的致癌突变。总的来说，这些发现表明SMARCA 4失活可能是TCS的主要遗传事件，扩大了对该基因在鼻窦肿瘤发生中作用的理解。他们还提出了TCS与新描述的SMARCA 4缺陷型鼻窦癌的诊断谱上的可能性，模糊了已建立和新出现的鼻窦实体之间的界限。此外，SMARCA4 IHC可为在有限材料中确认TCS诊断提供有用的辅助手段。
Molecular analysis has reshaped the landscape of high grade sinonasal tumors by defining novel entities and identifying recurrent mutations in established tumor types. However, sinonasal teratocarcinosarcoma (TCS), a rare and aggressive tumor with intermixed teratomatous, carcinomatous, and sarcomatous elements, remains poorly understood. The multiphenotypic differentiation of TCS has engendered persistent controversy about its histogenesis and leads to diagnostic overlap with several other malignancies. In this study, we evaluated the molecular underpinnings of TCS to clarify its pathogenesis and diagnosis. We performed SMARCA4 immunohistochemistry (IHC) on 22 TCS and 153 other sinonasal tumors. We identified loss of SMARCA4 expression in 18 TCS (82%), including 15 (68%) with complete loss and 3 (14%) with partial loss. Although we also identified partial SMARCA4 loss in 1 of 8 SMARCB1-deficient sinonasal carcinomas (13%), SMARCA4 was intact in all other sinonasal carcinomas and neuroendocrine tumors. We then selected 3 TCS with complete SMARCA4 loss by IHC for a targeted next-generation sequencing panel that included 1425 cancer-related genes. We confirmed biallelic somatic inactivation ofSMARCA4without other known oncogenic mutations in these 3 cases. Overall, these findings suggest thatSMARCA4inactivation may be the dominant genetic event in TCS, expanding understanding of this gene's role in sinonasal tumorigenesis. They also raise the possibility that TCS is on a diagnostic spectrum with the newly described SMARCA4-deficient sinonasal carcinoma, blurring the lines between established and emerging sinonasal entities. In addition, SMARCA4 IHC may provide a useful adjunct for confirming a diagnosis of TCS in limited material.