Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple non muscle-invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression. The tumors were subtyped by gene expression profiling and analyzed for hotspot mutations in FGFR3, PIK3CA, and TERT, the most frequent early driver mutations in this tumor type. TP53 alterations, frequent in advanced UBC, were inferred from p53 staining pattern, and potential genomic alterations were inferred by gene expression patterns at regions harboring frequent copy number alterations. We show that early driver mutations were largely preserved in UBC recurrences. Changes in FGFR3, PIK3CA, or TERT mutation status were not linked to changes in molecular subtype and aggressive behavior. Instead, changes into a more aggressive molecular subtype seem to be associated with p53 alterations. We analyze changes in gene expression from primary tumors, to recurrences, and progression tumors, and identify two modes of progression: Patients for whom progression is preceded by or coincides with a radical subtype shift, and patients who progress without any systematic molecular changes. For the latter group of patients, progression may be either stochastic, or depending on factors already present at primary tumor initiation. This article is protected by copyright. All rights reserved.

International journal of cancer. 2019 Oct 14 [Epub ahead of print]

Gottfrid Sjödahl, Pontus Eriksson, Oliver Patschan, Nour-Al-Dain Marzouka, Lovisa Jakobsson, Carina Bernardo, Kristina Lövgren, Gunilla Chebil, Ellen Zwarthoff, Fredrik Liedberg, Mattias Höglund

Department of Translational Medicine, Division of Urological Research, Lund University and Department of Urology, Skåne University Hospital, Sweden., Division of Oncology and Pathology, Clinical Sciences, Lund University, Lund, Sweden., Department of Pathology, Erasmus MC Cancer Institute, Erasmus Medical Center, Rotterdam, The Netherlands.