Abstract B03: Identification of PTEN p.W274C as a potential biomarker to predict inferior survival in patients with limited-stage small-cell bladder cancer
Authors: Earle F. Burgess, Nury Steuerwald, James Symanowski, Chad Livasy, Carol Farhangfar, Claud Grigg, Zoran Gatalica, David Arguello, Peter E. Clark, Derek Raghavan
Journal: Clinical Cancer Research (2020)

Abstract Background: Small-cell bladder cancer (SCBC) is a rare histologic subtype that confers a poor prognosis and lacks predictive biomarkers. Because mutations in the PTEN/AKT pathway are important in urothelial tumor biology, we sought to characterize PTEN mutational status and association with clinical outcome in a cohort of patients with limited-stage (LS) SCBC. Methods: 23 LS-SCBC cases treated at our institution were identified. PTEN gene variants were assessed using comprehensive next-generation sequencing on diagnostic transurethral bladder tumor resection or cystectomy specimens containing SCBC histology. Detected variants were filtered using bioinformatic algorithms predicting for deleterious impact on protein function. Variants in the PTEN gene were assessed for association with relapse-free survival (RFS) and overall survival (OS) using Kaplan-Meier techniques and Cox proportional hazards models. Results: Deleterious PTEN mutations were observed in 9/23 (39.1%) patients. p.W274C was the most common PTEN variant and was detected in 5 (21.7%) patients. Median follow-up for the cohort was 3.4 years. 14/23 (60.9%) patients have died. All five patients with PTEN p.W274C have died, whereas 9 deaths occurred among the 18 patients without the variant [OS HR = 3.20 [(1.04, 9.89), p = 0.033]]. In the 19 patients with known relapse history, all 3 patients with PTEN p.W274C relapsed, and 6 of the 16 patients without the variant relapsed [RFS HR = 4.01 [(0.94, 17.06), p = 0.043]]. Based on the adverse prognostic value of PTEN p.W274C in this cohort, we performed in silico characterization of the potential impact of this variant on protein function, which jointly predicted for deleterious effect. Because this variant occurs within the C2 domain of the PTEN gene, it is suspected to result in impaired membrane binding and improper positioning of the catalytic portion of the protein onto the cellular membrane. Conclusions: PTEN p.W274C was associated with inferior survival in this cohort of patients with LS-SCBC, suggesting this undescribed gene variant may play an important role in the progression of small-cell bladder cancer. In silico analysis suggests this variant impairs wild-type PTEN activity, though formal characterization is warranted. Efforts to validate the prognostic value of PTEN p.W274C in an expanded cohort of SCBC patients are under way. Citation Format: Earle F. Burgess, Nury Steuerwald, James Symanowski, Chad Livasy, Carol Farhangfar, Claud Grigg, Zoran Gatalica, David Arguello, Peter E. Clark, Derek Raghavan. Identification of PTEN p.W274C as a potential biomarker to predict inferior survival in patients with limited-stage small-cell bladder cancer [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 B03.