Significance of p53-Binding Protein 1 Nuclear Foci in Cervical Squamous Intraepithelial Lesions: Association With High-Risk Human Papillomavirus Infection and P16^INK4a Expression

Abstract

As p53-binding protein 1 (53BP1) localizes to the sites of DNA double-strand breaks and rapidly forms nuclear foci (NF), and its presence may be an indicator of endogenous genomic instability (GIN). We previously showed that 53BP1 NF in cervical cells increase with neoplastic progression, indicating the significance of 53BP1 expression for the estimation of malignant potential during cervical carcinogenesis. This study aimed to further elucidate the impact of 53BP1 expression as a biomarker for cervical squamous intraepithelial lesion (SIL). A total of 81 tissue samples, including 17 of normal cervical epithelium, 22 of cervical intraepithelial neoplasia (CIN) 1, 21 of CIN2, and 21 of CIN3, from patients positive for high-risk human papillomavirus (HR-HPV) were used for double-label immunofluorescence of 53BP1 and Ki-67/p16INK4a expression and HR-HPV in situ hybridization. We analyzed associations between 53BP1 expression type with parameters such as CIN grade, HR-HPV infection status, p16INK4a expression, and CIN prognosis. Expression type of 53BP1 was significantly associated with histological grade of CIN and HR-HPV in situ hybridization signal pattern ( P < .0001). There was a significant correlation between 53BP1 and p16INK4a expression levels ( r = .73, P < .0001). However, there was no association between 53BP1 expression type and CIN prognosis. We propose that 53BP1 expression type is a valuable biomarker for SIL, which can help estimate the grade and GIN of cervical lesions reflecting replication stress caused by the integration of HR-HPV to the host genome.

53BP1 expression as a biomarker to differentiate thyroid follicular tumors

“…With the hypothesis that the presence of 53BP1 NF can be an indicator of endogenous DNA double-strand breaks and DDR activation in individual cells, we previously demonstrated that the type of 53BP1 expression profiles determined by IF may be useful to estimate GIN during a divergent carcinogenesis in thyroid, skin, uterine cervix, bladder, and esophageal cancer ( 7 , 8 , 9 , 10 , 11 ). Classification of 53BP1 expression into the following five categories: (i) stable (no or faint staining); (ii) low DDR (one or two discrete NF); (iii) high DDR (three or more discrete NF); (iv) large focus (discrete NF ≥1 μm and (v) diffuse (intense and heterogenous expression), showed that both the high DDR and large focus types are closely associated with a higher level of cervical carcinogenesis and high-risk human papilloma virus infection ( 9 , 13 ). Instead, both large focus and diffuse types are significantly associated with high-grade urothelial carcinoma showing chromosomal instability and poor prognosis ( 10 ).…”