Pathogenic variants in PTEN to predict for increased risk of relapse and death in patients with limited stage small cell bladder cancer


Earle Frederick Burgess, Nury Steuerwald, James Thomas Symanowski, Chad Livasy, Carol J. Farhangfar, Zoran Gatalica, David Arguello, Jason Zhu, Claud Grigg, Peter E. Clark, Derek Raghavan


Small cell bladder cancer (SCBC) is a rare histologic subtype with insufficient genomic characterization. Patients with limited stage (LS) SCBC have a poor prognosis, and no biomarker exists to optimize treatment selection. We sought to identify genomic aberrations in patients with LS-SCBC using a comprehensive next generation sequencing (NGS) platform. Mutations in the PTEN/AKT pathway are important in urothelial tumor biology but have an undefined role in SCBC.


23 LS-SCBC cases were identified. NGS was performed on diagnostic transurethral bladder tumor resection or cystectomy specimens containing SCBC. Detected variants were filtered by in silico algorithms predicting for a deleterious impact on protein function. Variant allele frequencies (VAF) greater than 2% were permitted in this analysis. 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.


Median follow up for the cohort was 4.02 years. 14/23 (60.9%) patients have died. Six unique 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. Three variants were detected at > 10% VAF. All 9 patients with a deleterious PTEN variant died. The presence of deleterious PTEN variants [HR = 4.68 [(1.54, 14.27), p = 0.003]] predicted for inferior OS. In the 19 patients with known relapse history, 6/7 (85.7%) with and 3/12 (25%) without any deleterious PTEN mutation relapsed. The presence of deleterious PTEN variants [HR = 9.41 [(2.32, 38.23), p < 0.001]] also predicted for inferior RFS.


Pathogenic variants in tumor suppressor PTEN were associated with inferior RFS and OS in this pilot cohort of patients with LS-SCBC, suggesting that disruption of PTEN function may be a critical genomic event underlying the progression of small cell bladder cancer. Our findings also support prior reports that pathogenic gene variants detected at low allele frequencies may be clinically important.

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