Current Knowledge on Genomic Profiling of Upper Tract Urothelial Carcinoma

Abstract

Recent research in next-generation sequencing characterized the genomic landscape of urothelial cancer. However, the majority of the studies focused on bladder cancer (BC). Upper urinary tract urothelial carcinomas (UTUC) and BC share some histological characteristics, but, considering the differences in terms of embryologic precursors, epidemiology, genetics, medical and surgical management and response to therapy, UTUC and BC should be considered as two distinct diseases. Our objective is to analyze through a literature search the latest updates and the current knowledge about the genomics of UTUC. We also evaluate genetic differences between BC and UTUC and the potential implications for systemic therapy. Molecular subtyping and variant histology and their correlation with response to chemotherapy were also explored. In summary, the most frequent genomic variations in UTUC included FGFR3, chromatin remodeling genes, TP53/MDM2 and other tumor suppressors/oncogenes. The genomics of UTUC, integrated with clinical data, could drive the selection of patients who could benefit from targeted therapy or off-label treatment. Routine implementation of tumor genomic characterization in UTUC patients should therefore be contemplated and evaluated prospectively.

Expression Analysis and Mutational Status of Histone Methyltransferase KMT2D at Different Upper Tract Urothelial Carcinoma Locations

“…The KMT2 family member KMT2D, which regulates the H3K4me methylation landscapes predominantly at enhancers, has been implicated in the development of cancer by dysregulation of enhancer activity and subsequent disruption of normal development programs [23][24][25][26]. In urothelial carcinoma, KMT2D has been found among the top mutated genes in several genomic characterization studies; it seems to be an early event in the pathogenesis of UTUC rather than a driver of disease progression [18,19,27,28]. Indeed, in our study, KMT2D alterations were not significantly associated with clinical variables such as stage or grade of the disease.…”

Genetic Interference of FGFR3 Impedes Invasion of Upper Tract Urothelial Carcinoma Cells by Alleviating RAS/MAPK Signal Activity

“…Accumulating evidence indicates that gain-of-function mutations in the FGFR3 gene may give rise to constitutive receptor activation and have been identified in bladder cancer and UTUC [ 25 , 26 , 27 , 28 , 29 ]. Accordingly, the FGFR3/RAS/MAPK signaling axis has long been proposed as a target for UC treatment [ 5 , 30 ]. Despite intensive discussion regarding the application of targeting FGFR3 using receptor kinase inhibitors or ligand-trapping antibodies in UC treatment [ 31 , 32 , 33 ], little is known about the efficacy of the FGFR3 genetic interference strategy in UTUC treatment.…”

The Predictive Value of Systemic Immune-Inflammation Index on Bladder Recurrence on Upper Tract Urothelial Carcinoma Outcomes after Radical Nephroureterectomy

“…These models are based on age, tumor grade, pathologic tumor grade, lymph node metastasis, lymph vascular invasion, tumor multifocality, and tumor architecture [3][4][5][6]. With the development of current genomics studies of UTUC [7], physicians can integrate the clinical pathologic characteristics with genetic and molecular subtyping of UTUC. Knowing the different genotype and phenotype features can lay the groundwork for a deeper understanding of UTUC biology [8].…”