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CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making.

ABSTRACT: Deletions of the cell cycle control gene CDKN2A are described as progression markers of non-muscle invasive bladder cancer and to be associated with fibroblast growth factor 3 (FGFR3) mutations. The prognostic role of CDKN2A RNA expression in muscle invasive bladder cancer (MIBC) is under discussion. In 80 MIBC patients (m/f 60/20) who underwent radical cystectomy the expression of CDKN2A and FGFR3 was examined with qRT-PCR (test cohort). The MDA cohort (n?=?57) and the TCGA cohort (n?=?365) served for validation. The expression of drug target genes and TCGA molecular subtypes was correlated with CDKN2A expression. In the test cohort CDKN2Ahigh patients (n?=?8; 10.0%) had a significantly shorter recurrence-free (p?=?0.018) and disease-specific (p?=?0.006) survival compared to the rest of the cohort. A similar stratification was seen in the validation cohorts (CDKN2Ahigh: n?=?7, 12.3%, p?=?0.001; n?=?46, 12.6%, p?=?0.011). In the TCGA cohort these patients had a comparably low expression of drug target genes. The expression of CDKN2A significantly differed among TGCA molecular subtypes. 71.7% of CDKN2Ahigh were TCGA basal squamous tumours but also show divergent molecular features compared to this group. In summary CDKN2A RNA expression-based risk stratification of MIBC allows the identification of a CDKN2Ahigh poor prognosis group with low expression of drug target genes.

SUBMITTER: Worst TS

PROVIDER: S-EPMC6158275 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making.

Worst Thomas S TS Weis Cleo-Aron CA Stöhr Robert R Bertz Simone S Eckstein Markus M Otto Wolfgang W Breyer Johannes J Hartmann Arndt A Bolenz Christian C Wirtz Ralph M RM Erben Philipp P

Scientific reports 20180926 1

Deletions of the cell cycle control gene CDKN2A are described as progression markers of non-muscle invasive bladder cancer and to be associated with fibroblast growth factor 3 (FGFR3) mutations. The prognostic role of CDKN2A RNA expression in muscle invasive bladder cancer (MIBC) is under discussion. In 80 MIBC patients (m/f 60/20) who underwent radical cystectomy the expression of CDKN2A and FGFR3 was examined with qRT-PCR (test cohort). The MDA cohort (n = 57) and the TCGA cohort (n = 365) ser ...[more]

PMID: 30258198

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Project description:Background:Muscle-invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice. Methods:This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t-test and fold change methods were used to perform the differential expression analysis. The hypergeometric test was used to test the enrichment of the differentially expressed genes in GO terms or KEGG pathways. Results:In the present study, we identified three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle-invasive bladder cancer (MIBC) risk prediction. The validation of this stratification method on two datasets demonstrated that the stratified patients exhibited significant difference in overall survival, and our stratification was superior to three other stratifications. Consistently, the high-risk group exhibited worse prognosis than low-risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high-risk MIBC were significantly enriched in several cancer-related pathways. Notably, PDGFRB, a receptor for platelet-derived growth factor of PI3K-Akt signaling pathway, and TUBA1A were identified as two targets of multiple drugs. In addition, the angiogenesis-related genes, as well as two marker genes of M2 macrophage, CD163 and MRC1, were highly upregulated in high-risk MIBC. Conclusions:In summary, this study investigated the underlying molecular mechanism and potential therapeutic targets associated with worse prognosis of high-risk MIBC, which could improve our understanding of progression of MIBC and provide new therapeutic strategies for the MIBC patients.

Dataset Information

CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making.

Publications

CDKN2A as transcriptomic marker for muscle-invasive bladder cancer risk stratification and therapy decision-making.

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