Abstract B21: PTRF promotes cell survival and predicts disease progression in upper tract urothelial carcinoma

Abstract

Abstract Urothelial carcinoma (UC) arises from epithelial lining of pyelocaliceal cavities, ureter, bladder, and urethra and is the sixth most common cancer in the United States. UC of bladder (UCB) accounts for 90–95% of UCs, and upper tract UC (UTUC) is substantially less common (5–10%). Clinical implication is generally extrapolated to UTUC from biologic studies in UCB due to the rarity of this disease. Although UTUC and UCB share similar histologic appearances and some common gene alterations, UTUC exhibits distinct epidemiologic and clinical features. For example, UTUC patients tend to have high risk of tumor recurrence and poor prognosis compared with UCB, especially in advanced disease. These observations suggest that some unique molecular pathways underlie UTUC progression. Polymerase I and transcript release factor (PTRF) known as Cavin-1 was initially discovered as a protein involved in the dissociation of transcription complexes. PTRF has been associated with tumor progression in a number of human cancers, but its role in UTUC remains undefined. Based on microarray screening data from 48 Taiwanese UTUC patients, PTRF was significantly associated with pT stage (p = 0.009). Next, we surveyed a multi-institutional cohort of UTUC (457 Caucasian patients) using immunohistochemical (IHC) staining of PTRF on tissue microarrays for validation. The percentage and intensity of IHC staining was evaluated to determine the expression level of PTRF; the high expression was defined as H-score > 100. PTRF expression was compared with clinicopathologic parameters, and the impact of PTRF on progression-free survival (PFS) and cancer-specific survival (CSS) was examined by Kaplan-Meier and Cox proportional hazards analyses. Overall, 30 (6.6%) patients had high expression of PTRF, which was significantly associated with advanced pT status (p < 0.0001), nodal metastasis (p = 0.031), lymphovascular invasion (p = 0.001), and tumor differentiation (p = 0.009). Patients with high PTRF expression had apparently worse PFS and CSS than those with low expression from Kaplan-Meier analysis (both p <0.00001). After adjusting various clinicopathologic factors in multivariate analysis, PTRF represented an independent predictor for PFS and CSS (HR 1.782, 95% CI 1.021–3.111, p = 0.042 and HR 2.057, 95% CI 1.148–3.684, p = 0.015, respectively). Furthermore, to decipher the functional role of PTRF in UTUC, specific short hairpin RNAs were employed to knockdown (KD) endogenous PTRF and results showed that the cell viability was diminished in PTRF-KD UTUC cell line BFTC909. In summary, we believe that elevated PTRF in UTUC can increase cell survival underlying disease progression and overexpression of PTRF correlated with adverse pathologic features can be an independent prognostic marker. Citation Format: Hsin-Chih Yeh, Nirmish Singla, Elizabeth Hernandez, Vandana Panwar, Vitaly Margulis, Payal Kapur, Shahrokh F. Shariat, Wen-Jeng Wu, Jer-Tsong Hsieh. PTRF promotes cell survival and predicts disease progression in upper tract urothelial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B21.