A Novel TP53 Mutation Associated with TWIST1 and SIP1 Expression in an Aggressive Adrenocortical Carcinoma
A Novel TP53 Mutation Associated with TWIST1 and SIP1 Expression in an Aggressive Adrenocortical Carcinoma
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DOI：
10.1007/s12022-017-9482-7
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发表时间：
2017-12-01
影响因子：
4.4
通讯作者：
Vieira Neto, Leonardo
中科院分区：
文献类型：
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作者：
Bulzico, Daniel;Torres, Davi Coe;Vieira Neto, Leonardo
肾上腺皮质癌(ACC)是一种罕见的与TP53基因突变相关的肿瘤，多发生在儿童期。上皮-间充质转化(EMT)转录因子Twist1和Smad相互作用蛋白1(SIP1)在其他恶性肿瘤中与不良预后相关，但它们在ACC中的作用尚不清楚。我们描述了一例76岁患者的晚期转移性ACC(Weiss评分为9)。在初次肿瘤切除后，米托坦治疗作为对低容量肝转移的姑息治疗。在经过两年的病情稳定后，患者死于脑转移。体细胞基因测序显示，从石蜡包埋组织中提取的DNA中存在一种新的TP53突变，在人或半合子病中，外显子8(c.811_818del8；GAGGTGCG/-)缺失8bp，导致302位密码子随后发生移码和过早终止。免疫组织化学P53、p-Ser-15、P53均未见肿瘤染色。此外，免疫组织化学分析显示间充质标志物波形蛋白和纤维连接蛋白表达增加。最后，EMT转录因子Twist1和SIP1在肿瘤细胞中也有过表达。本病例报告描述了一例侵袭性ACC，不仅具有新的体细胞突变，而且还具有新的国际癌症研究机构数据库8碱基缺失的TP53外显子8。此外，EMT诱导物Twist1和SIP1在ACC病例中的表达是首次报道。需要进一步的研究来阐明这种新的TP53突变的生物学意义及其在EMT过程中的作用。
Adrenocortical carcinomas (ACC) are very rare tumors related to TP53 mutations mostly in childhood onset cases. Epithelial-mesenchymal transition (EMT) transcription factors TWIST1 and Smad interacting protein 1 (SIP1) are related to poorer outcomes in other malignancies, but their role in ACC is unknown. We describe a case of an advanced metastatic ACC (Weiss-score of 9) in a patient at age 76. After primary tumor resection, mitotane therapy was started as palliation to low-volume liver metastasis. After a 2-year period of stable disease, the patient died due to brain metastasis. Somatic gene sequencing revealed a novel TP53 mutation in DNA extracted from paraffin-embedded tissue, a deletion of 8bp in exon 8 (c.811_818del8; GAGGTGCG/-) in homo or hemizygosis causing a subsequent frameshift and premature stop codon at position 302. Immunohistochemistry of P53 and p-Ser-15 P53 showed absent tumoral staining. In addition, immunohistochemical analysis showed an increased expression of the mesenchymal markers vimentin and fibronectin. At last, EMT transcription factors TWIST1 and SIP1 were also overexpressed in tumoral cells. This case report describes an aggressive ACC with not only a novel somatic mutation, but also a novel International Agency for Research on Cancer database 8 base-pair deletion in TP53 exon 8. In addition, the expression of EMT inducers TWIST1 and SIP1 have been reported for the first time in an ACC case. Further investigation is needed to clarify the biologic significance of this new TP53 mutation and its role in the EMT process.