Dataset Information

Transcriptional Analysis of Immunohistochemically Defined Subgroups of Non-Muscle-Invasive Papillary High-Grade Upper Tract Urothelial Carcinoma.

ABSTRACT: Immunohistochemical (IHC) staining for CK5/6 and CK20 was reported to be correlated with the prognosis of early urothelial carcinoma in a way contrary to that of advanced tumors for unknown reasons. We aimed to characterize the gene expression profiles of subgroups of non-muscle-invasive papillary high-grade upper tract urothelial carcinoma (UTUC) classified by CK5/6 and CK20 expression levels: group 1 (CK5/6-high/CK20-low), group 2 (CK5/6-high/CK20-high), and group 3 (CK5/6-low/CK20-high). Expression of group 3 was predictive of worse prognosis of non-muscle-invasive papillary high-grade UTUC. Transcriptional analysis revealed 308 differentially expressed genes across the subgroups. Functional analyses of the genes identified cell adhesion as a common process differentially enriched in group 3 compared to the other groups, which could explain its high-risk phenotype. Late cell cycle/proliferation signatures were also enriched in group 3 and in some of the other groups, which may be used as a prognostic biomarker complementary to CK5/6 and CK20. Group 2, characterized by low levels of genes associated with mitogen-activated protein kinase and tumor necrosis factor signaling pathways, was hypothesized to represent the least cancerous subtype considering its normal urothelium-like IHC pattern. This study would facilitate the application of easily accessible prognostic biomarkers in practice.

SUBMITTER: Jung M

PROVIDER: S-EPMC6386996 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Object: CK14 expression is an important marker of basal/squamous-like (BASQ)-type muscle-invasive bladder carcinoma, and this molecularly defined subtype has a poor prognosis and a distinct response to chemotherapy. However, CK14 expression and its clinicopathological and molecular significance in papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) remain unknown. Herein, we investigated the prognostic implications of immunohistochemical (IHC) staining for CK14 and the transcriptional characteristics associated with CK14 expression in papillary NMIUTUC. Materials and Methods: IHC staining for CK14 was conducted in 204 papillary NMIUTUC specimens. Positive CK14 IHC staining was defined as a positive signal in >0% of tumor cells. RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors. Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003). Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780). Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor α-nuclear factor-κB, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype. In addition, with a p < 0.05 and |fold change| ≥2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors. Functional analysis of these genes revealed several networks and gene ontology terms related to the positive regulation of cellular proliferation in CK14-positive tumors. Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002). Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity. We propose that CK14 IHC staining can be a useful biomarker of BASQ-type papillary NMIUTUC that can be applied in daily practice with the aim of precision oncology.

Project description:Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Dataset Information

Transcriptional Analysis of Immunohistochemically Defined Subgroups of Non-Muscle-Invasive Papillary High-Grade Upper Tract Urothelial Carcinoma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets