Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma

Abstract

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 nonmuscle 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.

The Interplay Between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression in Vitro and in Vivo

“…Urine is an optimal bio uid to perform these measurements, given the non-invasive sample collection and the direct contact with the tumor. Our results comparing the urine lactate/alanine ratio show that the mean value of MIBC patients is twice that of NMIBC patients, which can be the consequence of the higher abundance of cells with TP53 alteration in the MIBC [15]. In addition, 70% of patients with NMIBC showed a low value, in agreement with the estimate that only 10-30% of NMIBC will progress to MIBC [3].…”

“…For example, mutations in FGFR3 were mostly observed in patients with the lowest risk of progression among those showing NMIBC [16], and FGFR3, PIK3CA, or TERT alterations were not associated with progression [15]. On the contrary, mutations in TP53 is common in advanced tumors and a key factor that triggers NMIBC progression [15,17]. Considering this information, we have chosen the cell lines RT4 and 5637, which show mutations in FGFR3 or TP53 [5], as good representatives of tumor cells with low-and high-risk of progression, respectively.…”

“…The main objective of this work was to investigate the connection between the metabolism of UBC cells and the risk of progression of the disease, that ultimately can lead to new prognostic markers based on metabolomics. Genomics has recently made great advances in relating alterations in cellular genes to the propensity to convert NMIBC into MIBC [15]. For example, mutations in FGFR3 were mostly observed in patients with the lowest risk of progression among those showing NMIBC [16], and FGFR3, PIK3CA, or TERT alterations were not associated with progression [15].…”

“…Genomics has recently made great advances in relating alterations in cellular genes to the propensity to convert NMIBC into MIBC [15]. For example, mutations in FGFR3 were mostly observed in patients with the lowest risk of progression among those showing NMIBC [16], and FGFR3, PIK3CA, or TERT alterations were not associated with progression [15]. On the contrary, mutations in TP53 is common in advanced tumors and a key factor that triggers NMIBC progression [15,17].…”

Identification of Key Biomarkers in Bladder Cancer: Evidence from a Bioinformatics Analysis

“…Ras activation is coupled to the Wnt signaling β-catenin pathway, driving bladder tumorigenesis [8]. P53 alterations are involved in tumor progression to more aggressive forms [9] and the RB1 pathway plays a critical role in the regulation of the cell cycle and cell death [10,11]. Until now, there has been no consensus about the use of urinary markers or tests for non-muscle-invasive bladder cancer (NMIBC) from the international panels on bladder cancer [12][13][14].…”