Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

Goux, C.; Vacher, Sophie; Schnitzler, Anne; Delongchamps, Nicolas Barry; Zerbib, Marc; Peyromaure, Michaël; Sibony, Mathilde; Allory, Yves; Bièche, Ivan; Damotte, Diane; Pignot, G.

doi:10.1038/s41598-020-73642-8

Cited by 12 publications

(13 citation statements)

References 36 publications

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“…Both EGFs and FGFRs have reported prognostic and therapeutic value in human UC. Abnormal expression of the EGFR pathway was associated with muscle-invasive bladder cancer and indicated a poor prognosis, and FGFR3 mutations or overexpression indicated a more favorable prognosis ( 55 , 56 ). Moreover, anti-EGFR treatment has shown promise in treating metastatic urothelial carcinoma in humans ( 57 ), as well as antitumor activity in canine iUC ( 58 ).…”

Section: Discussionmentioning

confidence: 99%

The miRNome of canine invasive urothelial carcinoma

et al. 2022

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Urothelial carcinoma (UC) comprises up to 2% of all naturally occurring neoplasia in dogs and can be challenging to diagnose. MicroRNAs (miRNAs) have been reported to be dysregulated in numerous diseases, including neoplasia. MiRNA expression has been evaluated in human UC, but there is limited information regarding the miRNA transcriptome of UC in dogs. Our study aimed to evaluate differential miRNA expression in bladder tissue collected from normal canine urothelium and canine invasive UC (iUC) to elucidate the dysregulated pathways in canine UC. Next-Generation RNA sequencing (RNA-Seq) was performed for dogs with UC (n = 29) and normal canine urothelium (n = 4). Raw RNA data were subjected to normalization, and pairwise comparison was performed using EdgeR with Benjamini-Hochberg FDR multiple testing correction (p < 0.05; >2-fold change) comparing tissue samples of normal urothelium to canine iUC samples. Principal component analysis and hierarchical cluster analysis were performed. MiRNA of FFPE tissue samples of separate iUC (n = 5) and normal urothelium (n = 5) were used to evaluate five miRNAs using RT-qPCR. Pathway analysis was performed utilizing miRWalk, STRING database, and Metascape utilizing KEGG pathways and GO terms databases. Twenty-eight miRNAs were differentially expressed (DE) by RNA-Seq. RT-qPCR confirmed that four miRNAs are significantly downregulated in UC compared to healthy urothelial samples (miR-105a, miR-143, miR-181a, and miR-214). Principal component analysis and hierarchical cluster analysis showed separation between miRNAs in iUC and the control group. The DE miRNAs are most often associated with gene silencing by miRNA, miRNAs in cancer, and miRNAs involved in DNA damage responses. Proteins involved include HRAS, KRAS, ARAF, RAF1, MAPK1, MAP2K1, MAPK3, FGFR3, EGFR, HBEGF, RASSF1, E2F2, E2F3, ERBB2, SRC, MMP1, and UP3KA. The differential expression of miRNAs in canine iUC compared to normal canine urothelial tissue indicates that these markers should be further evaluated for their potential role as diagnostic and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

The miRNome of canine invasive urothelial carcinoma

et al. 2022

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“…These genes encode regulatory proteins. Among these, the homeobox A cluster gene family (HOXA), specifically HOXA13, a member of HOX13 paralogous genes, are involved in controlling the spatial expression patterns of target genes 1 , 2 , 18 , 19 and in mediating urogenital system formation. 20 , 21 , 22 However, many of them are still active in adult human organs and tissues 23 and are frequently deregulated in human cancers.…”

Section: Discussionmentioning

confidence: 99%

“…We set a semiquantitative scoring system based on the coalition of the expansion of positively stained tumor cells (Score [ 1 ]: 0: <1%, 1: 1%–30%, 2: 30%–70% and 3: >70%) and the intensity of staining reaction (score [ 2 ]: 0 = absent; 1 = weak; 2 = moderate; 3 = strong). The final immunostaining score was the product of score 1 multiplied by score 2 in each individual slide.…”

Section: Methodsmentioning

confidence: 99%

An insight into the diagnostic and prognostic value of HOX A13’s expression in non‐muscle invasive bladder cancer

Boubaker

Gurtner

Trabelsi

et al. 2022

Clinical Laboratory Analysis

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Background Several studies have interrogated the molecular pathways and their interacting genes underlying bladder cancer (BCa) tumorigenesis, yet, the role of homeobox genes is still poorly understood. Specifically, HOXA13, which plays an important role as a major actor in the urogenital tract's development. Methods Immunohistochemical (IHC) staining was performed to inspect the differential expression of HOXA13 protein in non‐muscle‐invasive bladder cancer (NMIBC) and non‐tumoral tissues. A semiquantitative scoring system was adopted to evaluate the IHC labeling. Correlation to clinical parameters was performed by descriptive statistics. Overall survival was estimated by the Kaplan–Meier method and Cox regression model. The functional HOX A13 protein association networks (PPI) were obtained using String 11.0 database. Results HOX A13 exhibited cytoplasmic and nuclear staining. Its expression levels were lower in high‐grade NMIBC (HG NMIBC) compared to low‐grade ones (LG NMIBC). The expression of HOX A13 was correlated to tumor grade (LG/HG) ( p = 0.036) and stage (TA/T1) ( p = 0.036). Nevertheless, its expression was not correlated to clinical parameters and was not able to predict the overall survival of patients with HG NMIBC. Finally, PPI analysis revealed that HOX A13 seems to be a part of a molecular network holding mainly PBX1, MEIS, ALDH1A2, HOX A10, and HOX A11. Conclusion The deregulation of HOX A13 is not associated with the prognosis of BCa. It seems to be rather implicated in the early initiation of urothelial tumorigenesis and thus may serve as a diagnostic marker in patients with NMIBC. Further experimentations on larger validation sets are mandatory.

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“…В частности, в работе отечественных коллег экспрессию гена FGFR3 определяли вместе с экспрессией PD-L1 для оценки риска прогрессирования НМИРМП [32]. В работе других авторов с использованием данных TCGA и результатов собственного исследования был составлен прогностический классификатор НМИРМП, в котором экспрессия FGFR3 и еще группы генов указывает на тот или иной подтип НМИРМП [33].…”

Section: Discussionunclassified

<i>FGFR3, TERT, ТР53</i> mutations and the <i>FGFR3</i> gene expression in bladder cancer as prognostic markers

et al. 2021

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Background. Bladder cancer (BC) is a common urological cancer, 75 % of which are non-muscle invasive BC. After removal of the primary tumor, the adequate classification of malignancy and the defining of tumor progression risk remains an important issue, since it is associated with frequency of cystoscopy and choice of the BCG- or chemotherapy management.Objective: improve the algorithms of prognosis in intermediate-risk patients with non-muscle-invasive bladder cancer with the consideration of molecular characteristics of the primary tumor.Materials and methods. We studied 125 BC samples; mutations in the FGFR3, PIK3CA, TERT, and TP53 genes were determined by polymerase chain reaction and Sanger sequencing, as well as the expression of the FGFR3, EGFR, ERBB2, FOXA1, and GATA3 genes using realtime polymerase chain reaction.Results. Somatic mutations in the studied loci were detected in 65.6 % of the samples, five new mutations were identified. A decrease of the mutation frequency in the FGFR3 and TERT genes was shown, an increase — TP53 in order (Ta—T1/low G) > (T1/high G) > (>T2/any G). The largest area under the ROC curve (0.807 ± 0.092, р = 0.004) was demonstratedfor the prognostic classifier with the independent variables: mutation in FGFR3 and/or TERT; mutation TP53; overexpression of the FGFR3 gene. The FGFR3, TERT mutations and/or FGFR3 overexpression in the absence of TP53 mutation indicates minimally invasive primary tumor. On the contrary, harboring TP53 mutation indicate the features of muscle-invasive BC at the genetic level. Using this algorithm, we reclassified 21 of T1G3 BC cases as having characteristics associated with non-invasive tumor in 43 %, and invasive BC in 57 % of patients.Conclusion. The aforementioned prognostic model could be used as additional laboratory test in assessing the malignancy and progression risk of non-muscle invasive BC.

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Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

Cited by 12 publications

References 36 publications

The miRNome of canine invasive urothelial carcinoma

The miRNome of canine invasive urothelial carcinoma

An insight into the diagnostic and prognostic value of HOX A13’s expression in non‐muscle invasive bladder cancer

<i>FGFR3, TERT, ТР53</i> mutations and the <i>FGFR3</i> gene expression in bladder cancer as prognostic markers

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