Comprehensive integrative profiling of upper tract urothelial carcinomas

Abstract

Background Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. Conclusions Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions

“…Consistent with previous studies, we recently observed similar findings. In addition, we found that FGFR3 mutated UTUC were hypomethylated compared to FGFR3 wild-type tumors, suggesting crosstalk between genetic and epigenetic phenotypes of these tumors [12]. Notably, FGFR3 wild-type tumors harbored a high rate of SWI/SNF genetic tumor alterations and were associated with a higher level of tumor infiltrated lymphocytes (TILs) [12].…”

“…In the past few years, several studies have focused on the molecular characterization of UTUC using next-generation sequencing [4][5][6][11][12][13][17][18][19][20][21][22][23][24]. The most frequently mutated genes were FGFR3 (40-80%), KMT2D (35-56%), KMT2A (32-47%), and TP53 (18-26%) [4,5,11,13,22].…”

“…Recently, we reported the UTUC methylation profiles and identified 2 epigenetic subtypes, namely EpiC-low and EpiC-high. While the earlier one was hypomethylated, immune depleted, and enriched for FGFR3 mutations, the latter was hypermethylated, immune infiltrated, and associated with SWI/SNF genes somatic mutations [12] (Figure 1). Moreover, we identified for the first time a high rate of mutations in the ZFP36 family in almost one-quarter of UTUC.…”

“…Moreover, we identified for the first time a high rate of mutations in the ZFP36 family in almost one-quarter of UTUC. Further mechanistic studies showed that ZFP36L1 loss of function experiments in urothelial cell lines led to increased cell migration and epithelial-mesenchymal transition [12]. More recently, Fujii et al conducted a comprehensive molecular study of 198 UTUC patients through whole-exome sequencing (WES), single nucleotide polymorphism (SNP) array, RNA sequencing, and methylation analysis [37].…”

“…UTUC has a different behavior as compared to bladder UC [10], and while molecular alterations of urothelial bladder carcinoma have been widely studied by The Cancer Genome Atlas, data about such alterations in UTUC remain scarce [4,11,12]. However, the novel molecular insights provided by these studies led to a better understanding of this aggressive disease and provided a rationale for new therapeutic approaches.…”