Small cell bladder carcinoma (SCBC) represents a rare histologic variant with a poor prognosis and for which no routine biomarkers exist. Limited reports of genomic sequencing in SCBC have demonstrated a high prevalence of TP53 and RB1 gene mutations, though the prognostic value of these and other gene variants in SCBC remains undefined. In this study, we performed targeted genomic sequencing on a cohort of SCBC patients and correlated genomic findings with clinical outcomes to identify potential novel biomarkers.
Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort.
The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, P = 0.122) and RB1 (HR 0.481, P = 0.182), while LS patients with TP53 mutations (HR 2.730, P = 0.056), and MCL1 gene amplification (HR 4.183, P = 0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (P = 0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]).
These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.
Urologic oncology. 2022 May 31 [Epub ahead of print]
Earle F Burgess, J Alexa Sanders, Chad Livasy, James Symanowski, Zoran Gatalica, Nury M Steuerwald, David Arguello, Cory R Brouwer, W Michael Korn, Claud M Grigg, Jason Zhu, Justin T Matulay, Peter E Clark, Elisabeth I Heath, Derek Raghavan
Levine Cancer Institute, Atrium Health, Charlotte, NC. Electronic address: ., Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, NC., Carolinas Pathology Group, Charlotte, NC., Levine Cancer Institute, Atrium Health, Charlotte, NC., Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK., Caris Life Sciences, Irving, TX., Karmanos Cancer Institute, Wayne State University, Detroit, MI.