Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable -catenin Overexpression and a -catenin Mutation
Pathogenetic Analysis of Sinonasal Teratocarcinosarcomas Reveal Actionable -catenin Overexpression and a -catenin Mutation
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DOI：
10.1055/s-0037-1601320
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发表时间：
2017-08-01
影响因子：
0.9
通讯作者：
Brenner, J. Chad
中科院分区：
文献类型：
--
作者：
Birkeland, Andrew C.;Burgin, Sarah J.;Brenner, J. Chad
目的鼻鼻窦畸胎瘤是一种罕见的颅底侵袭性肿瘤。治疗选择有限，结果很差。关于调节这些肿瘤的遗传因素知之甚少。表征这些肿瘤中可操作的分子改变可能提供潜在的成功治疗选择。方法我们对一个鼻窦畸畸癌肉瘤标本进行了靶向外显子组测序，以确定潜在的驱动突变。我们对指标肿瘤和随后的畸胎癌肉瘤的石蜡包埋组织进行了-catenin免疫组织化学染色。访问了在线癌症突变数据库（癌症体细胞突变目录和癌症基因组图谱）。结果我们在鼻窦畸胎瘤肉瘤中发现了-catenin的活化p.S45F突变。这种突变导致Wnt/-catenin通路中的组成信号。我们通过免疫组化证实了-catenin在第一个肿瘤和第二个患者中的过表达和核定位。在多种实体肿瘤中发现了p.S45F激活突变，占所有已知-catenin突变的3.3%至10.4%。结论：我们在鼻窦畸畸癌肉瘤中发现了-catenin的潜在驱动突变，导致-catenin过表达。这些发现提示Wnt/-catenin通路在鼻窦畸胎瘤发生中的作用以及抗catenin靶向治疗的作用。
Objective Sinonasal teratocarcinosarcomas are rare, aggressive tumors of the skull base. Treatment options are limited and outcomes are poor. Little is known in regard to the genetic factors regulating these tumors. Characterization of actionable molecular alterations in these tumors could provide potentially successful therapeutic options.Methods We performed targeted exome sequencing on an index sinonasal teratocarcinosarcoma specimen to identify potential driver mutations. We performed immunohistochemical stains for -catenin on paraffin-embedded tissue on the index tumor and a subsequent teratocarcinosarcoma. Online databases of cancer mutations (Catalogue of Somatic Mutations in Cancer and The Cancer Genome Atlas) were accessed.Results We identified an activating p.S45F mutation in -catenin in our index sinonasal teratocarcinosarcoma. This mutation results in constitutive signaling in the Wnt/-catenin pathway. We confirmed -catenin overexpression and nuclear localization via immunohistochemistry in the index tumor and a second patient. The p.S45F activating mutation was found in a variety of solid tumors, and accounts for 3.3 to 10.4% of all known -catenin mutations.Conclusion We identified a potential driver mutation in -catenin in a sinonasal teratocarcinosarcoma, resulting in -catenin overexpression. These findings suggest a role for the Wnt/-catenin pathway in sinonasal teratocarcinosarcoma tumorigenesis and a role for anti--catenin targeted therapy.