Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression

Sanguedolce, Francesca; Zanelli, Magda; Palicelli, Andrea; Ascani, Stefano; Zizzo, Maurizio; Cocco, Giorgia; Björnebo, Lars; Lantz, Anna; Falagario, Ugo Giovanni; Cormio, Luigi; Carrieri, Giuseppe

doi:10.3390/ijms23147819

Cited by 7 publications

(7 citation statements)

References 148 publications

(315 reference statements)

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“…The biological and clinical heterogeneity of BC has led several researchers to develop classification schemes able to mirror this variability and translate it into distinct subtypes according to their mRNA expression profiles in the last decade. The next steps were to combine these findings into a consensus classification and to implement such molecular subtyping as a risk-stratification tool in routine practice, using IHC in order to assess subtype-specific biomarkers at the protein level [ 7 , 8 ].…”

Section: Her2 and Bc Molecular Subtypesmentioning

confidence: 99%

“…As far as we know, BC is a heterogeneous disease from a molecular standpoint as well, resulting from a complex multi-step carcinogenesis that includes several changes involving genes and molecular pathways with specific functions in tumor development and progression. In an attempt to catch this biological variability, several efforts have been made over the last decade to develop of a molecular classification encompassing a discrete category of BC harboring different clinical and prognostic features, matching their DNA and RNA profiles [ 6 , 7 , 8 , 9 ]. In routine practice, current risk assessment models in NMIBC, as well as predictive/prognostic systems in MIBC, are based on clinical and histopathological features [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

Sanguedolce

Zanelli

Palicelli

et al. 2023

IJMS

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Bladder cancer (BC) is a heterogeneous disease from a molecular, morphological, and clinical standpoint. HER2 is a known oncogene involved in bladder carcinogenesis. Assessing HER2 overexpression as a result of its molecular changes in a routine pathology practice using immunohistochemistry might be a useful adjunct in several scenarios, namely (1) to correctly identify flat urothelial lesions and inverted urothelial lesions in the diagnostic setting; (2) to provide prognostic hints in both non-muscle invasive (NMI) and muscle invasive (MI) tumors, thus supplementing risk stratification tools, especially when evaluating higher-risk tumors such as those with variant morphology; (3) to improve antibody panels as a surrogate marker of BC molecular subtyping. Furthermore, the potential of HER2 as a therapeutic target has been only partly explored so far, in light of the ongoing development of novel target therapies.

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Section: Her2 and Bc Molecular Subtypesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

Sanguedolce

Zanelli

Palicelli

et al. 2023

IJMS

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“…GATA3 has been recognized as a marker of urothelial lineage due to its commonly high expression rates in UC, and it is widely used in the distinction between primary and secondary tumors of the bladder [ 17 ]. Nevertheless, the range of GATA3 positivity in UC is definitely wide, spanning from less than 5% to 100% [ 14 ]. Consistently lower CK20 staining rates have been described in BCs (up to 70%) [ 18 , 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…The latter has activated PPAR-γ and FGFR3 mutations, with enriched epithelial markers, and a good clinical prognosis, whereas basal tumors are associated with EGFR regulon activity, usually present at an advanced stage, and have the worst clinical prognosis [ 10 ]; nevertheless, they seem to be more sensitive to neoadjuvant cisplatin-based chemotherapy than luminal MIBCs [ 11 , 12 ]. The routine performance of molecular analysis in current practice is undermined by technical and economic issues; thus, immunohistochemical (IHC) surrogates for molecular profiling have been identified by validating the consistency between mRNA expression profiles and the expression of immunohistochemical markers [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological Features and Survival Analysis in Molecular Subtypes of Muscle-Invasive Bladder Cancer

Sanguedolce

Falagario

Zanelli

et al. 2023

IJMS

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Molecular subtyping of bladder cancer (BC) aims to capture the biological heterogeneity of this complex disease in order to provide better patient risk stratification. Immunohistochemical (IHC) markers are regarded as promising surrogates to classify BCs into luminal and basal subtypes in routine practice. We investigated the correlation between the molecular subclassification, assessed through IHC, and the conventional prognostic variables of a cohort of 93 muscle-invasive BCs (MIBCs), with a focus on the pattern of muscularis propria (MP) invasion, and evaluated their association with outcome. Basal, luminal, double-positive (DP), and double-negative (DN) phenotypes were identified according to the coordinate expression of 1 basal (CK5/6) and 2 luminal (CK20, GATA3) markers, and accounted for 33.3%, 32.3%, 3.2%, and 31.2% (Scheme #1) and 9.7%, 60.2%, 26.9%, and 3.2% (Scheme #2). There was a significant association between the pattern of MP invasion and the molecular subtypes according to Scheme #2, in that all 8 basal and DN cases, as well as 83% of DP cases, had a non-infiltrative invasion pattern. No consistent differences were observed in terms of OS and CSS between the molecular subtypes obtained through surrogate IHC markers. In keeping with previous studies, we report the correlation between the identification of BC subtypes and the presence of morphological prognostic factors, supporting the need for a comprehensive pathological evaluation, including clinicopathological and molecular parameters, in order to improve the diagnosis and management of MIBC.

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“…Luminal and basal molecular subtypes also emerged from early TCGA studies and served as the bases for subsequently reported taxonomic studies of bladder cancer [ 8 ]. Furthermore, the deregulation of the major signaling pathways and the molecular subtypes show implications in bladder cancer therapy and variable impact on the prognostic stratification of patients [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. In addition to these mostly transcriptomic-derived classifications, a novel molecular classification of bladder cancer with prognostic and therapeutic implications, including luminal/basal/double negative (null) categories, recently emerged but using NanoString nCounter gene expression analysis instead [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype

Blanca

López-Beltrán

Lopez-Porcheron

et al. 2023

Cancers

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This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2–4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0–2] vs. high [score 3–7], model A) or three (low [score 0–2] vs. intermediate [score 3–4] vs. high [score 5–7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer.

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Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 1: General Issues and Marker Expression

Cited by 7 publications

References 148 publications

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

HER2 Expression in Bladder Cancer: A Focused View on Its Diagnostic, Prognostic, and Predictive Role

Clinicopathological Features and Survival Analysis in Molecular Subtypes of Muscle-Invasive Bladder Cancer

Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype

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