hERG1 potassium channel expression predicts survival in clear-cell renal cell carcinoma: A pilot study with a long-term follow up

Aim of the study: Clear-cell renal carcinoma (ccRCC) is highly dependent on angiogenesis and several angiogenesis-related biomar- kers have been identified. hERG1 potassium channels are involved in the angiogenesis pathway and are overexpressed in several cancers. Aim of this study was to evaluate the expression and prognostic role of classical angiogenesis-related biomarkers (VEGF-A, PDGFRb, KDR and Flt1) along with markers of hypoxia (CA-IX and GLUT1), in association with the uncanonical biomarker hERG1. Materials and methods: Tissue samples were obtained from patients who underwent partial or radical nephrectomy with curative intent for RCC from October 2005 to October 2006 at our institution. None of the patients received neoadjuvant chemotherapy or immunotherapy. Immunohistochemistry was performed using the following antibodies on 7 mcm sections on positively charged slides: anti-hERG1, anti- VEGF-A, anti-CA-IX, anti-GLUT1, anti-PDGFRb, anti-KDR and anti-Flt1. For all the aforementioned markers, the immunoreactivity score (IS) (estimated as the percentage of positive cells) allowed to distinguish four groups: 0% (addressed as “0”), 1–25% (addressed as “1”), 26–50% (addressed as “2”) and 51–100% (“3”) positive cells, respectively. Fisher’s exact test assessed the association between hERG1 and other angiogenic markers expression. Kaplan-Meier curves were built to assess recurrence-free survival (RFS) and cancer specific survival (CSS) according to hERG1 expression. Multivariable Cox regression analyses were fitted to estimate the hazard of disease recurrence. Results: 30 patients who had a histological diagnosis of ccRCC were included. Pre-operative, intraoperative and pathological features of patients are shown in Table 1. A significant association between hERG1 and CA-IX expression was found ( p = 0.04). No significant association between hERG1 and VEGF expression ( p = 0.19) emerged. At a median follow up of 123.5 months, 14 (46.7%) patients were free from disease, 4 (13.3%) and 8 (26.7%) patients patients experienced local and systemic recurrence, respectively while 4 (13.3%) patients experienced both local and systemic recurrence. 11 (36.7%) patients died from RCC. RFS was 100% in patients with low hERG1 expression (IS = 0–1), 19.3% (SE + 12.2%) in patients with IS = 2 and 12.5% (SE + 11.7%) in patients with IS = 3 ( p = 0.04). CSS was 100% in patients with low hERG1 expression (IS = 0–1) and 65.8% (SE + 13.6%) in case of high hERG1 expression (IS = 2–3), respectively ( p = 0.13). At Cox regression ana- lysis, a high hERG1 expression was significantly associated with disease recurrence (HR: 3.44; 95%CI: 1.33–8.93; p = 0.011). Conversely, CA-IX and VEGF expression had no significant impact on recurrence ( p = 0.49 and p = 0.15, respectively).