A novel diagnostic method for thyroid follicular tumors based on immunofluorescence analysis of p53-binding protein 1 expression: detection of genomic instability.

BACKGROUND: The preoperative diagnosis of thyroid follicular carcinomas by fine-needle aspiration cytology (FNAC) is almost impossible. We 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 (DSBs), forming nuclear foci (NF). This study aimed to elucidate the utility of 53BP1 NF expression as a biomarker to differentiate follicular tumors (FTs).

METHODS: We analyzed associations between 53BP1 expression based on IF and histological types of FTs using 27 follicular adenomas (FAs), 28 minimally invasive follicular carcinomas (MFCs), and 14 widely invasive FCs (WFCs). Furthermore, our study clarified the relationship between 53BP1 NF and copy number aberrations (CNAs) based on array comparative genomic hybridization (aCGH), a hallmark of genomic instability (GIN).

RESULTS: This study demonstrated 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 < MFC < WFC. 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 aCGH). Interestingly, IF revealed the heterogenous distribution of 53BP1 NF, which occurred more frequently in the invasive or subcapsular area than in the center of the tumor, suggesting intra-tumor heterogeneity of GIN in FTs.

CONCLUSIONS: We propose that IF analysis of 53BP1 expression could be a novel diagnostic method to estimate the malignant potential of FTs. Because 53BP1 NF reflect DNA DSBs, we hypothesize 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 accurately diagnose FTs, but also a novel technique for preoperative diagnosis using FNAC.