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Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer.

ABSTRACT: Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal and luminal, with 12% of basal tumours exhibiting epithelial-to-mesenchymal transition (EMT). Levels of immune cell infiltration have been shown to be subtype-specific. Here, we performed immunohistochemistry (IHC) for 11 antibodies relating to molecular subtypes or EMT in 26 cases of HGT1 urothelial carcinoma cases with 6 matched samples subsequently obtained at cystectomy (n = 6; 1 muscle-invasive, 5 non-muscle-invasive; 3 = pTis, 1 = pT1, 1 = pTa) and at recurrence (n = 2, pT2). RNAScope was also conducted in a subset. Expression patterns in HGT1 specimens versus MIBC (pT2+) were examined, and correlated with disease-specific survival (DSS). Levels of stromal tumour-infiltrating lymphocytes (sTILs) were assessed manually to determine whether lymphocyte infiltration was associated with DSS and whether differences existed between HGT1 and MIBC. Molecular subtype markers demonstrated increased prognostic potential compared to the EMT markers assessed. Increased expression of the luminal markers FOXA1 and SCUBE2, were found to be significantly associated with better DFS. No EMT markers were significantly associated with DFS. In areas of non-invasive papillary urothelial carcinoma, but not invasive carcinoma, sTIL levels were found to be significantly associated with DFS. While differences were observed between HGT1 cases that progressed versus those that did not, a larger cohort study is required for validation of these findings. Taken together, an emphasis on molecular subtype markers, rather than EMT markers, may be preferable when studying biomarkers of HGT1 urothelial carcinoma in the future.

SUBMITTER: Ottley EC

PROVIDER: S-EPMC7578305 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer.

Ottley Edward C EC Pell Robert R Brazier Benedict B Hollidge Julianne J Kartsonaki Christiana C Browning Lisa L O'Neill Eric E Kiltie Anne E AE

The journal of pathology. Clinical research 20200506 4

Approximately 75% of bladder cancers are non-muscle invasive (NMIBC). Of these, up to 53% of cases progress to life-threatening muscle-invasive bladder cancer (MIBC). Patients with high-grade stage T1 (HGT1) NMIBC frequently undergo radical cystectomy (RC), although this represents overtreatment for many. Identification of progressors versus non-progressors could spare unnecessary treatment. Recent studies have confirmed that urothelial carcinoma is composed of two main molecular subtypes, basal ...[more]

PMID: 32374509

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Project description:BackgroundA growing number of investigations have suggested a close link between cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and the tumor microenvironment (TME). However, the relationships between these physiological processes in bladder urothelial carcinoma (BLCA) remain unclear.MethodsWe first explored biomarkers of tumor stemness (TS) by single-cell sequencing analysis. Then, subtypes of bladder urothelial carcinoma (BLCA) were identified using clustering analysis based on TS biomarkers. The TS score was constructed using principal component analysis to quantify tumor stemness in BLCA. Then, meta-analysis was performed to measure the hazard ratio of the TS score in BLCA cohorts. Moreover, we evaluated the clinical value of the TS score for predicting the response to tumor immunotherapy using immunotherapy cohorts. Finally, we built an EMT cell model by treating T24 cells with TGF-β and validated the relationship between the TS score and the EMT process in tumors by real-time quantitative PCR, cell invasion assays, and RNA-seq. In total, 3846 BLCA cells, 6 cell lines, 1627 BLCA samples, and 9858 samples from 32 other types of tumors were included in our study.ResultsThree TS clusters and two TS-related gene clusters were identified with differential EMT activity status, CSC features, and TME characteristics in BLCA. Then, a TS scoring system was established with 61 TS-related genes to quantify the TS. The prognostic value of the TS score was then confirmed in multiple independent cohorts. A high TS score was associated with high EMT activity, CSC characteristics, high stromal cell content, high TP53 mutation rate, poor prognosis, and high tumor immunotherapy tolerance. The cell line experiment and RNA-seq further validated that our TS score can reflect the EMT and CSC characterization of tumor cells.ConclusionOverall, this research provides a better understanding of tumor invasion and metastasis mechanisms through an analysis of TS patterns with different EMT processes and CSC characteristics. The TS score provides an index for EMT and CSC research and helps clinicians develop treatment plans and predict outcomes for patients.

Dataset Information

Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer.

Publications

Greater utility of molecular subtype rather than epithelial-to-mesenchymal transition (EMT) markers for prognosis in high-risk non-muscle-invasive (HGT1) bladder cancer.

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