HER2 and TOP2A Gene Amplification and Protein Expression in Upper Tract Urothelial Carcinomas

Abstract

HER2, a potential target for therapy, has been described to be amplified in urothelial carcinomas. As the topoisomerase II alpha (TOP2A) gene is located close to the HER2 gene on chromosome 17q12-q21, it is frequently either co-amplified or deleted with HER2 amplification. The purpose of this study was to assess the impact HER2 and TOP2A gene amplification as well as protein expression on outcomes of upper tract urothelial carcinoma (UTUC). HER2 and TOP2A gene amplification and protein expression were assessed in 81 patients with radical nephroureterectomy for UTUC. Immunohistochemistry and chromogenic in-situ hybridization was performed on formalin-fixed, paraffin-embedded samples. HER2 protein expression was observed in 27/81 (33%) cases, of which 8 cases exhibited amplification of HER2. One of them had an additional polysomy 17, whereas 6/67 HER2 non-amplified cases revealed a polysomy 17. Coamplification of HER2 and TOP2A was found in 4 cases, whereas 3 cases showed only HER2 amplification and 20 cases only TOP2A amplification. HER2 IHC overexpression was associated with higher-grade tumors (p = 0.001), non-organ confined carcinomas (p = 0.017), HER2 amplification (p < 0.00001) and TOP2A amplification (p = 0.016). HER2 amplification was association with higher tumor grade (p = 0.001) and lymphnode metastasis (p = 0.003). TOP2A IHC positivity was significantly associated with higher tumor grade (p = 0.0004), TOP2A amplification (p = 0.0003), polysomy 17 (p = 0.035) and HER2 IHC overexpression (p = 0.28), whereas all categories of tumor stage and HER2 amplification remained not related. TOP2A amplification was significantly more frequent in tumors with higher grade, higher tumor stage, polysomy 17 and distant metastasis (p = 0.015; p = 0.042; p = 0.032; p = 0.011), respectively. In univariate analyses HER2 IHC positivity, TOP2A amplification, and polysomy 17 were associated with poor clinical outcome after surgery. HER2 IHC overexpression and TOP2A amplification are associated with features of biologically aggressive UTUC. Overexpression and/or amplification of HER2 and TOP2A could help identify patients who may benefit from targeted therapy.

Screening Hub Genes as Prognostic Biomarkers of Hepatocellular Carcinoma by Bioinformatics Analysis

“…Yang et al demonstrated that PBK promotes the metastasis of hepatocellular carcinoma by activating the ETV4-uPAR signaling pathway 40 . In addition, TOP2A contributes to the early detection and targeted therapy of a variety of cancers [41][42][43] , including HCC 44 . However, the relationship between some of these genes, such as NEK2, and HCC remains unclear.…”

Identification and Integrated Analysis of Key Biomarkers for Diagnosis and Prognosis of Non-Small Cell Lung Cancer

“…TOP2A (DNA Topoisomerase II Alpha) amplification was associated with the characteristics of biologically invasive epithelial carcinoma of the urinary tract. Overexpression and/or amplification of TOP2A can help identify whether patients will benefit from targeted therapy [33]. de Resende et al demonstrated that the evaluation of TOP2A protein is of prognostic importance, and because of its relationship with inferior prognosis, the evaluation of TOP2A immunohistochemistry in biopsies can be an meaningful tool for selecting the most appropriate surgical and clinical approaches for prostate cancer patients [34].…”

DNA topoisomerase IIα and RAD21 cohesin complex component are predicted as potential therapeutic targets in bladder cancer

“…Previous studies have demonstrated that TOP2α was frequently amplified in bladder tumors (1.5%), particularly in advanced stage tumors (3.4%) (18,33). A recent study also indicated that TOP2α amplification was associated with the biological aggressiveness of upper tract urothelial carcinoma (34). Meanwhile, TOP2α amplification was also observed in a number of other types of cancer, including colorectal cancer (35), breast cancer (36,37), leukemia (38) and prostate cancer (39).…”