Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma

Bagrodia, Aditya; Eugene, K.; Sfakianos, John P.; Zabor, Emily C.; Bochner, Bernard H.; Al‐Ahmadie, Hikmat; Solit, David B.; Coleman, Jonathan

doi:10.1016/j.juro.2016.01.006

Cited by 36 publications

(34 citation statements)

References 16 publications

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“…1a, P = 0.89). Somatic FGFR3 mutations, which have previously been associated with a favorable prognostic outcome in UTUC 17 , were only present in luminal subtype. Conversely, there were no significant differences among the two subtypes in the percentage of patients with mutations in TP53 or other driver genes commonly present in UTUC.…”

Section: Integrated Genomic and Transcriptomic Analysis Of Utucmentioning

confidence: 79%

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kim

Audenet

et al. 2020

Nat Commun

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Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of diseasespecific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.

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Section: Integrated Genomic and Transcriptomic Analysis Of Utucmentioning

confidence: 79%

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Kim

Audenet

et al. 2020

Nat Commun

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“…High activity of MDM2 has been observed in different cancers, leading to the reduction or loss of the p53 protein through ubiquitination, nuclear export, and transcriptional regulation 38-39. TP53 mutation and MDM2 amplification were mutually exclusive events in the tumorigenesis of UC, both were correlated with greater recurrence and lower survival rate 40-41. Although the p53-binding glycoprotein RNF128 was shown to function in a similar manner to that of MDM2 in the negative feedback loop, downregulation of RNF128 expression was observed in our present study as well as unpublished data by Chen et al 12, in contrast to the usual overexpression of MDM2 in cancers.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder

Lee¹,

Wang²,

Huang³

et al. 2016

J. Cancer

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Background: The TP53 tumor suppressor gene plays a crucial role in the carcinogenesis of many malignancies, including urothelial carcinoma (UC). Overexpression of p53 is associated with poor prognosis in UC. Recently, RING finger protein 128 (RNF128) was shown to be involved in p53-induced apoptosis, forming a negative feedback loop. However, the significance of RNF128 in patients with UC remains unknown. In this study, our aim was to evaluate the expression of RNF128 in UC and to assess its predictive and prognostic value in a well-established cohort.Methods: Through data mining from a published transcriptome (GSE31684), RNF128 was identified as the most differentially expressed gene in UC among those associated with negative regulation of the cytokine biosynthetic process (GO:0042036). Its immunoexpression was further evaluated using the H-scores of 340 patients with upper urinary tract UC (UTUC) and 295 with urinary bladder UC (UBUC). The scores were correlated with clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MeFS). We also used Western blot analysis to evaluate RNF128 protein expression in human urothelial cell (HUC) lines.Results: Downregulation of RNF128 expression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), nodal metastasis (UTUC, p<0.001; UBUC, p=0.001), vascular invasion (UTUC, p<0.001; UBUC, p=0.008) and high mitotic rate (UTUC, p=0.003; UBUC, p=0.023). Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002). Moreover, low expression was predictive of poor DSS (UTUC, p=0.006; UBUC, p=0.003) and MeFS (UTUC, p=0.009; UBUC, p=0.036) in multivariate comparisons. Western blot analysis showed that the RNF128 protein was downregulated in invasive urothelial cancer cell lines.Conclusion: Our findings showed that downregulation of RNF128 was correlated with cancer invasiveness and metastasis as well as reduced survival in patients with UTUC and UBUC, identifying RNF128 as a prognostic factor in UC.

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“…Luminal‐type MIBC, which is a subtype with favourable clinical outcomes, expresses CK20, GATA3, and FOXA1, similarly to urothelial umbrella cells, possibly reflecting its differentiated phenotype . However, the prognostic significance of IHC biomarkers of molecular subtypes has not been thoroughly evaluated in UTUC …”

Section: Introductionmentioning

confidence: 99%

“…6,17 However, the prognostic significance of IHC biomarkers of molecular subtypes has not been thoroughly evaluated in UTUC. [18][19][20][21] Sikic et al 21 risk-stratified UTUC into subgroups by using CK5 and CK20, which are prognostic in MIBC. However, the prognosis of UTUC subgroups was in opposition to what has been demonstrated in MIBC; UTUC showing both CK5 negativity and CK20 positivity was associated with a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemistry of cytokeratin (CK) 5/6, CD44 and CK20 as prognostic biomarkers of non‐muscle‐invasive papillary upper tract urothelial carcinoma

2018

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Aims Immunohistochemical (IHC) staining for cytokeratin (CK) 5/6, CD44 and CK20 has been significantly associated with the prognosis of urinary bladder urothelial carcinoma, and probably reflects its molecular characteristics. We aimed to investigate the IHC‐based subgroups and their prognostic effects on non‐muscle‐invasive papillary upper tract urothelial carcinoma (UTUC). Methods and results IHC staining for CK5/6, CK20 and CD44 was analysed in 211 patients with non‐muscle‐invasive papillary UTUC. Staining was classified as showing a negative, positive or normal pattern. We found that CK5/6‐negative, CD44‐negative and CK20‐positive tumours were distinctly high‐risk subgroups that were associated with high grade (CK5/6‐negative, P < 0.001; CD44‐negative, P < 0.001; CK20‐positive, P = 0.017) and frequent intravesical recurrence (CK5/6‐negative, P = 0.002). Using survival analysis with Kaplan–Meier and log‐rank tests, we found that these IHC subgroups were correlated with poor progression‐free (CK5/6‐negative, P = 0.001; CD44‐negative, P = 0.009; CK20‐positive, P = 0.031) and cancer‐specific (CK5/6‐negative, P = 0.009) survival. Furthermore, CK5/6 negativity was an independent prognostic factor for shorter progression‐free (P = 0.009) and cancer‐specific (P = 0.045) survival. CK5/6 improved Harrell's C‐indices for progression‐free (0.68–0.77, P = 0.029) and cancer‐specific (0.59–0.77, P < 0.001) survival. When markers were combined, luminal‐like subtypes showed poor prognoses. Conclusions We demonstrated that IHC staining for CK5/6, CD44 and CK20 was significantly associated with the clinicopathological characteristics and prognoses of patients with non‐muscle‐invasive papillary UTUC. The IHC subgroups may be correlated with the molecular characteristics of non‐muscle‐invasive papillary UTUC.

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Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma

Cited by 36 publications

References 16 publications

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Modeling biological and genetic diversity in upper tract urothelial carcinoma with patient derived xenografts

Downregulation of RNF128 Predicts Progression and Poor Prognosis in Patients with Urothelial Carcinoma of the Upper Tract and Urinary Bladder

Immunohistochemistry of cytokeratin (CK) 5/6, CD44 and CK20 as prognostic biomarkers of non‐muscle‐invasive papillary upper tract urothelial carcinoma

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