A Novel Diagnostic Method for Thyroid Follicular Tumors Based on Immunofluorescence Analysis of p53-Binding Protein 1 Expression: Detection of Genomic Instability
A Novel Diagnostic Method for Thyroid Follicular Tumors Based on Immunofluorescence Analysis of p53-Binding Protein 1 Expression: Detection of Genomic Instability
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DOI：
10.1089/thy.2018.0548
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发表时间：
2019-05-01
期刊：
影响因子：
6.6
通讯作者：
Nakashima, Masahiro
中科院分区：
文献类型：
--
作者：
Otsubo, Ryota;Matsuda, Katsuya;Nakashima, Masahiro
背景：术前细针穿刺细胞学诊断甲状腺滤泡癌（FC）几乎是不可能的。先前证明，基于免疫荧光（IF）的p53结合蛋白1（53BP1）表达可以作为评估各种癌症恶性潜能的有价值的生物标志物。53BP1属于一类DNA损伤反应分子，其快速定位于DNA双链断裂位点，形成核灶（NF）。本研究旨在阐明53BP1 NF表达作为区分滤泡性肿瘤（FT）的生物标志物的效用。研究方法：使用27个滤泡性腺瘤（FA）、28个微创FC和14个广泛浸润FC分析基于IF的53BP1表达与FT组织学类型之间的关联。此外，该研究基于阵列比较基因组杂交（基因组不稳定性（GIN）的标志）阐明了53BP1 NF和拷贝数畸变（CNA）之间的关系。结果：本研究证实了FA和FC中53BP1 NF表达的差异。NF中53BP1的表达率随FT进展而显著增加，其顺序为：正常卵泡< FA <微创FC <广泛浸润FC。相比之下，在FT样品中未观察到CNA的显著差异。此外，在FT中，CNAs与NF处的53BP1之间没有显著相关性。因此，基于GIN的这两个指标的比较，与CNA（通过阵列比较基因组杂交）相比，53BP1 NF（通过IF）能够更好地估计FT的恶性程度。有趣的是，IF揭示了53BP1 NF的异质性分布，其在侵袭性或包膜下区域比在肿瘤中心更频繁地发生，表明FT中GIN的瘤内异质性。结论：53BP1表达的IF分析可能是评估FT恶性潜能的新诊断方法。由于53BP1 NF反映DNA双链断裂，因此假设53BP1在NF的发生率可以代表肿瘤细胞中GIN的水平。IF分析53BP1表达不仅可作为准确诊断FT的辅助组织学技术，而且可作为细针穿刺细胞学术前诊断的新技术。
Background: The preoperative diagnosis of thyroid follicular carcinomas (FCs) by fine-needle aspiration cytology is almost impossible. It was previously demonstrated that p53-binding protein 1 (53BP1) expression, based on immunofluorescence (IF), can serve as a valuable biomarker to estimate the malignant potential of various cancers. 53BP1 belongs to a class of DNA damage response molecules that rapidly localize to the site of DNA double-strand breaks, forming nuclear foci (NF). This study aimed to elucidate the utility of 53BP1 NF expression as a biomarker to differentiate follicular tumors (FTs). Methods: Associations between 53BP1 expression based on IF and histological types of FTs were analyzed using 27 follicular adenomas (FAs), 28 minimally invasive FCs, and 14 widely invasive FCs. Furthermore, the study clarified the relationship between 53BP1 NF and copy number aberrations (CNAs) based on array comparative genomic hybridization, a hallmark of genomic instability (GIN). Results: This study demonstrates differences in 53BP1 NF expression between FA and FC. The incidence of 53BP1 at NF significantly increased with FT progression in the following order: normal follicle < FA < minimally invasive FCs < widely invasive FCs. In contrast, no significant differences were observed in CNAs among the FT samples. Furthermore, there was no significant correlation between CNAs and 53BP1 at NF in FTs. Thus, based on a comparison of these two indicators of GIN, 53BP1 NF (by IF) was better able to estimate the malignancy of FTs compared to CNA (by array comparative genomic hybridization). Interestingly, IF revealed a heterogenous distribution of 53BP1 NF, which occurred more frequently in the invasive or subcapsular area than in the center of the tumor, suggesting intratumoral heterogeneity of GIN in FTs. Conclusions: It is proposed that IF analysis of 53BP1 expression could be a novel diagnostic method to estimate the malignant potential of FTs. Because 53BP1 NF reflect DNA double-strand breaks, it is hypothesized that the incidence of 53BP1 at NF can represent the level of GIN in tumor cells. IF analysis of 53BP1 expression will not only be an auxiliary histologic technique to diagnose FTs accurately, but also a novel technique for preoperative diagnosis using fine-needle aspiration cytology.