Expression pattern of p53-binding protein 1 as a new molecular indicator of genomic instability in bladder urothelial carcinoma

Katsuya Matsuda,Hisayoshi Kondo,Yuhmi Hasegawa,Masahiro Nakashima,Yuko Akazawa,Masachika Iseki,Keiji Suzuki,Tatsuhiko Kawasaki

doi:10.1038/s41598-018-33761-9

Katsuya Matsuda, Hisayoshi Kondo + Show 6 more

Open Access

https://doi.org/10.1038/s41598-018-33761-9

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Abstract

Copy number alterations and loss of heterozygosity are associated with increasing tumor grade and bladder cancer stage. Our previous study suggested that co-expression of Ki-67 and p53-binding protein 1 (53BP1) could provide an indicator of an abnormal DNA damage response (DDR) pathway. The present study investigated 53BP1 expression as a novel molecular marker in urothelial carcinoma (UC) using bladder tissues with in total of 40 cases including a normal urothelium, urothelial papilloma, low-grade UC, or high-grade UC. Double-label immunofluorescence was used to analyze 53BP1 and Ki-67 expression. This was compared with the level of chromosomal instability and with the expression of other DDR molecules catalytic subunit. This study identified clear differences in the 53BP1 expression patterns in urothelial carcinogenesis, and their close association with genomic instability. 53BP1 abnormal immunoreactivity, particularly with co-localization of Ki-67, was restricted to malignant tissues. Our analyses indicated that a cut-off of >4% of nuclei with 53BP1 abnormal expression plus Ki-67 immunoreactivity distinguished high-grade UC from low-grade UC with 80.0% sensitivity and 100% specificity. We therefore propose that double immunofluorescent analysis of 53BP1 and Ki-67 expression could provide a useful tool to estimate the chromosomal instability and malignant potential of urothelial tumors.

Highlights

Urothelial carcinoma (UC) is a malignant neoplasm derived from the urothelial cells that accounts for more than 90% of bladder tumors
Exposure of the bladder mucosa to various carcinogenic compounds excreted in urine may induce DNA damage in urothelial cells; this leads to genomic instability (GIN), a key carcinogenic mechanism[15,16]
Our results demonstrated that abnormal 53BP1 expression was significantly associated with an abnormal DNA damage response (DDR) pathway and a high level of copy number alteration in HGUC, suggesting that this could provide a new molecular marker to distinguish HGUC from LGUC and to estimate GIN during urothelial carcinogenesis

Summary

Introduction

Urothelial carcinoma (UC) is a malignant neoplasm derived from the urothelial cells that accounts for more than 90% of bladder tumors. UroVysionTM is a promising test that uses multi-colored FISH and has been approved by the USA FDA; this can be used to grade UCs and estimate the malignant potency of urothelial tumors and, importantly, can differentiate between an inverted papilloma and inverted LGUC32 This assay was designed to detect copy number changes for chromosomes 3, 7 and 17, and at the chromosome 9p21 locus. Our results demonstrated that abnormal 53BP1 expression was significantly associated with an abnormal DDR pathway and a high level of copy number alteration in HGUC, suggesting that this could provide a new molecular marker to distinguish HGUC from LGUC and to estimate GIN during urothelial carcinogenesis

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