1 Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
2 Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Thyroid. 2019 May;29(5):657-665. doi: 10.1089/thy.2018.0548.
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). 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). 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. 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.
甲状腺滤泡癌（FC）的细针穿刺细胞学术前诊断几乎是不可能的。先前的研究表明，基于免疫荧光（IF）的 p53 结合蛋白 1（53BP1）表达可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，其可迅速定位到 DNA 双链断裂部位，形成核焦点（NF）。本研究旨在阐明 53BP1 NF 表达作为一种生物标志物来区分滤泡性肿瘤（FTs）的效用。通过 27 例滤泡性腺瘤（FA）、28 例微小浸润性 FC 和 14 例广泛浸润性 FC，分析了基于 IF 的 53BP1 表达与 FT 组织学类型之间的关系。此外，该研究阐明了基于 array comparative genomic hybridization 的 53BP1 NF 与拷贝数异常（CNA）之间的关系，array comparative genomic hybridization 是基因组不稳定性（GIN）的标志。本研究表明，FA 和 FC 之间 53BP1 NF 的表达存在差异。随着 FT 进展，53BP1 在 NF 中的发生率显著增加，顺序如下：正常滤泡<FA<微小浸润性 FC<广泛浸润性 FC。相比之下，FT 样本中的 CNA 无显著差异。此外，FT 中 CNA 与 53BP1 NF 之间无显著相关性。因此，基于这两种 GIN 指标的比较，53BP1 NF（通过 IF）比 CNA（通过 array comparative genomic hybridization）更能评估 FT 的恶性程度。有趣的是，IF 显示 53BP1 NF 呈异质性分布，在侵袭性或包膜下区域比在肿瘤中心更常见，提示 FT 中存在肿瘤内 GIN 异质性。因此，提出 IF 分析 53BP1 表达可能是一种新的诊断方法，用于评估 FT 的恶性潜能。因为 53BP1 NF 反映了 DNA 双链断裂，所以可以假设 NF 中 53BP1 的发生率可以代表肿瘤细胞中 GIN 的水平。IF 分析 53BP1 表达不仅将成为准确诊断 FT 的辅助组织学技术，而且还将成为使用细针穿刺细胞学进行术前诊断的新技术。
