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Pathogenesis and Diagnosis of Genitourinary Cancer

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2020) | Viewed by 46264

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Prof. Dr. Jae Y. Ro

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Guest Editor

Department of Pathology and Genomic Medicine, Weill Medical College of Cornell University, Houston, TX 77030, USA
Interests: pathogenesis and diagnosis of genitourinary (prostate; kidney and bladder); lung tumors (including prevention and the identification of prognostic factors)

Prof. Dr. Charles C. Guo

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Guest Editor

Department of Pathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Interests: bladder cancer; prostate cancer; pathology; molecular classification; pathogenesis; immunohistochemistry; genomics

Dr. Steven Shen

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Guest Editor

GU Pathologist, Weill Medical College of Cornell University, Houston Methodist Hospital, Houston, NY, USA
Interests: Cancer; Metastasis; Infectious Disease & Pathology; Molecular Medicine

Special Issue Information

Dear Colleagues,

Genitourinary (GU) cancers are among the most common neoplastic diseases in the Western world, comprising more than 30% of all cancers in men. Prostate cancer is the most common cancer and the second leading cause of cancer death in American men, accounting for 20% of all cancers and 10% of cancer death in men. Bladder and kidney cancers are also among the common cancers in American men, ranking 4th and 6th, respectively. Testicular cancer is uncommon in the general population, but it is the most common cancer in young men in the age group of 15–34. Penile cancers, particularly those associated with HPV infection, have shown an increasing incidence in young men. The high incidence of GU cancers has generated a great interest in studying their diverse clinicopathologic features and exploring the sophisticated molecular mechanisms in the development and progression of GU cancers.

GU cancers demonstrate a wide spectrum of histomorphological features, leading to complex pathologic classification systems. These classification systems have been subjected to constant modification, with the frequent addition of newly identified entities. Recent genomic studies have revealed distinct molecular alterations that are involved in the pathogenesis of GU cancers. New classification systems based on distinct gene expression signatures have refined our approach to select patients with GU cancers that can benefit from targeted therapy in personalized medicine.

This Special Issue will provide a state-of-the art review of recent developments in the exciting field of GU cancers. It will serve as a valuable resource for pathologists, clinicians, and researchers with an interest in pathogenesis and newly developed diagnostic techniques in GU cancers.

Prof. Jae Y. Ro
Dr. Charles C. Guo
Dr. Steven Shen
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Prostate cancer
Bladder cancer
Kidney cancer
Testicular cancer
Penile cancer
Pathology
Diagnosis
Molecular classification
Genomics
Pathogenesis
Targeted treatment

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

3 pages, 183 KiB

Open AccessEditorial

Pathogenesis and Diagnosis of Genitourinary Cancer

by Charles C. Guo, Steven S. Shen and Jae Y. Ro

Cancers 2021, 13(2), 347; https://doi.org/10.3390/cancers13020347 - 19 Jan 2021

Cited by 3 | Viewed by 1661

Abstract

Genitourinary (GU) cancers are among the most common malignant diseases in men [...] Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

Research

Jump to: Editorial, Review

15 pages, 1363 KiB

Open AccessArticle

Small Non-Coding RNA Profiling in Plasma Extracellular Vesicles of Bladder Cancer Patients by Next-Generation Sequencing: Expression Levels of miR-126-3p and piR-5936 Increase with Higher Histologic Grades

by Alexandru A. Sabo, Giovanni Birolo, Alessio Naccarati, Mihnea P. Dragomir, Serena Aneli, Alessandra Allione, Marco Oderda, Marco Allasia, Paolo Gontero, Carlotta Sacerdote, Paolo Vineis, Giuseppe Matullo and Barbara Pardini

Cancers 2020, 12(6), 1507; https://doi.org/10.3390/cancers12061507 - 09 Jun 2020

Cited by 33 | Viewed by 3353

Abstract

Bladder cancer (BC) is the tenth most frequent cancer worldwide. Due to the need for recurrent cystoscopies and the lack of non-invasive biomarkers, BC is associated with a high management burden. In this respect, small non-coding RNAs (sncRNAs) have been investigated in urine as possible biomarkers for BC, but in plasma their potential has not yet been defined. The expression levels of sncRNAs contained in plasma extracellular vesicles (EVs) from 47 men with BC and 46 healthy controls were assessed by next-generation sequencing. The sncRNA profiles were compared with urinary profiles from the same subjects. miR-4508 resulted downregulated in plasma EVs of muscle-invasive BC patients, compared to controls (adj-p = 0.04). In World Health Organization (WHO) grade 3 (G3) BC, miR-126-3p was upregulated both in plasma EVs and urine, when compared to controls (for both, adj-p < 0.05). Interestingly, two sncRNAs were associated with the risk class: miR-4508 with a downward trend going from controls to high risk BC, and piR-hsa-5936 with an upward trend (adj-p = 0.04 and adj-p = 0.05, respectively). Additionally, BC cases with low expression of miR-185-5p and miR-106a-5p or high expression of miR-10b-5p showed shorter survival (adj-p = 0.0013, adj-p = 0.039 and adj-p = 0.047, respectively). SncRNAs from plasma EVs could be diagnostic biomarkers for BC, especially in advanced grade. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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17 pages, 2905 KiB

Open AccessArticle

Moesin (MSN) as a Novel Proteome-Based Diagnostic Marker for Early Detection of Invasive Bladder Urothelial Carcinoma in Liquid-Based Cytology

by Jeong Hwan Park, Cheol Lee, Dohyun Han, Jae Seok Lee, Kyung Min Lee, Min Ji Song, Kwangsoo Kim, Heonyi Lee, Kyung Chul Moon, Youngsoo Kim, Minsun Jung, Ji Hye Moon, Hyebin Lee and Han Suk Ryu

Cancers 2020, 12(4), 1018; https://doi.org/10.3390/cancers12041018 - 21 Apr 2020

Cited by 12 | Viewed by 3493

Abstract

Bladder urothelial carcinoma (BUC) is the most lethal malignancy of the urinary tract. Treatment for the disease highly depends on the invasiveness of cancer cells. Therefore, a predictive biomarker needs to be identified for invasive BUC. In this study, we employed proteomics methods on urine liquid-based cytology (LBC) samples and a BUC cell line library to determine a novel predictive biomarker for invasive BUC. Furthermore, an in vitro three-dimensional (3D) invasion study for biological significance and diagnostic validation through immunocytochemistry (ICC) were also performed. The proteomic analysis suggested moesin (MSN) as a potential biomarker to predict the invasiveness of BUC. The in vitro 3D invasion study showed that inhibition of MSN significantly decreased invasiveness in BUC cell lines. Further validation using ICC ultimately confirmed moesin (MSN) as a potential biomarker to predict the invasiveness of BUC (p = 0.023). In conclusion, we suggest moesin as a potential diagnostic marker for early detection of BUC with invasion in LBC and as a potential therapeutic target. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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11 pages, 425 KiB

Open AccessArticle

Comparative Analysis of Urine Fractions for Optimal Bladder Cancer Detection Using DNA Methylation Markers

by Anouk E. Hentschel, Jakko A. Nieuwenhuijzen, Judith Bosschieter, Annina P. van Splunter, Birgit I. Lissenberg-Witte, J. Patrick van der Voorn, Loes I. Segerink, R. Jeroen A. van Moorselaar and Renske D.M. Steenbergen

Cancers 2020, 12(4), 859; https://doi.org/10.3390/cancers12040859 - 02 Apr 2020

Cited by 34 | Viewed by 3510

Abstract

DNA methylation analysis of full void urine and urine pellet seems promising for bladder cancer (BC) detection and surveillance. Urinary cell-free DNA from urine supernatant is now gaining interest for other molecular tests in BC. This study aims to evaluate which urine fraction is preferred for BC diagnosis using methylation markers: full void urine, urine pellet or supernatant. Methylation levels of nine markers were determined in the three urine fractions and correlated with their respective tumor tissues in BC patients and compared to controls. For all markers and marker panel GHSR/MAL, diagnostic performance was determined by calculating the area under the curve (AUC) of the respective receiver operating characteristic curves. For most of the markers, there was a significant correlation between the methylation levels in each of the urine fractions and the matched tumor tissues. Urine pellet was the most representative fraction. Generally, AUCs for BC diagnosis were comparable among the fractions. The highest AUC was obtained for GHSR/MAL in urine pellet: AUC 0.87 (95% confidence interval: 0.73–1.00), corresponding to a sensitivity of 78.6% and a specificity of 91.7%. Our results demonstrate that cellular and cell-free DNA in urine can be used for BC diagnosis by urinary methylation analysis. Based on our comparative analysis and for practical reasons, we recommend the use of urine pellet. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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12 pages, 2700 KiB

Open AccessArticle

Pure Large Nested Variant of Urothelial Carcinoma (LNUC) Is the Prototype of an FGFR3 Mutated Aggressive Urothelial Carcinoma with Luminal-Papillary Phenotype

by Veronika Weyerer, Markus Eckstein, Eva Compérat, Hendrik Juette, Nadine T. Gaisa, Yves Allory, Robert Stöhr, Bernd Wullich, Morgan Rouprêt, Arndt Hartmann and Simone Bertz

Cancers 2020, 12(3), 763; https://doi.org/10.3390/cancers12030763 - 24 Mar 2020

Cited by 23 | Viewed by 3452

Abstract

Since 2016, large nested urothelial carcinoma (LNUC) has been included within the WHO classification of urothelial tumors. Limited reports with mainly small case series have confirmed the malignant behavior of LNUC despite its bland morphological appearance. We evaluated, for the first time, markers for new immunooncological or targeted therapies including FGFR3 mutational status and PD-L1 status, the frequency of TERT-promoter mutations and the molecular subtype in a cohort of 25 LNUC using SNaPshot analysis and immunohistochemistry. Of the 25 cases, 17 were pure LNUC, with 13 showing an additional exophytic papillary/papillary-like component. Seven mixed LNUCs presented areas of classical nested variant urothelial carcinoma (NVUC) and one showed a component of conventional urothelial carcinoma. Of the 17 evaluable pure LNUCs, 16 were FGFR3-mutated with identical mutations in their concomitant papillary/papillary-like components. An FGFR3 mutation was found in 1/7 evaluable mixed LNUCs combined with NVUC. TERT-promoter mutations were detected in 86.7% pure and 83.3% mixed tumors. Immunohistochemistry revealed a luminal phenotype; PD-L1 was negative in the majority of tumor cells and tumor-associated immune cells. Pure LNUC is a prime example of a luminal, FGFR3-mutated, mostly PD-L1-negative tumor. In contrast, FGFR3 mutations seem to be rare in mixed LNUC, which may indicate a different pathway of tumor development. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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14 pages, 3344 KiB

Open AccessArticle

Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implications on Adult Bladder Cancer

by Sun-Wha Im, Chang Ohk Sung, Kun Suk Kim, Nam Hoon Cho, Young Min Kim, Ghee Young Kwon, Kyung Chul Moon, Song-Yi Choi, Jae Sung Lim, Yeong Jin Choi, Soo Jin Jung, So Dug Lim, Sung Hyun Paick, Ok-Jun Lee, Ho Won Kang, Seo Hee Rha, Hee Sang Hwang, Ja-Min Park, Sun Young Yoon, Jeesoo Chae, Jaeyong Choi, Jong-Il Kim and Yong Mee Cho Show full author list Hide full author list

Cancers 2020, 12(2), 307; https://doi.org/10.3390/cancers12020307 - 28 Jan 2020

Cited by 3 | Viewed by 3281

Abstract

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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12 pages, 2127 KiB

Open AccessArticle

Independent Evaluation of the Respective Predictive Values for High-Grade Prostate Cancer of Clinical Information and RNA Biomarkers after Upfront MRI and Image-Guided Biopsies

by Mathieu Roumiguié, Guillaume Ploussard, Léonor Nogueira, Eric Bruguière, Olivier Meyrignac, Marine Lesourd, Sarah Péricart and Bernard Malavaud

Cancers 2020, 12(2), 285; https://doi.org/10.3390/cancers12020285 - 24 Jan 2020

Cited by 12 | Viewed by 2237

Abstract

Upfront MRI is taking the lead in the diagnosis of clinically significant prostate cancer, while few image-guided biopsies (IGBs) fail to demonstrate clinically significant prostate cancer. The added value of innovative biomarkers is not confirmed in this context. We analysed SelectMDx-v2 (MDx-2) in a cohort of upfront MRI and image-guided biopsy patients. Participants included patients who received a trans-rectal elastic-fusion registration IGB on the basis of DRE, PSA, PCA3, and PCPT-2.0 risk evaluation. Pre-biopsy MRI DICOM archives were reviewed according to PI-RADS-v2. Post-massage first-void urine samples stored in the institutional registered bio-repository were commercially addressed to MDxHealth to obtain MDx-2 scores. Univariate and multivariate analyses were conducted with the detection on IGB of high-grade (ISUP 2 and higher) as the dependent variable. High-grade cancer was demonstrated in 32/117 (27.4%) patients (8/2010–8/2018). Age, prostate volume, biopsy history, MDx-2, and PI-RADS-v2 scores significantly related to the detection of high-grade cancer. MDx-2 scores and the clinical variables embedded into MDx-2 scores were analysed in multivariate analysis to complement PI-RADS-v2 scores. The two combinations outperformed PI-RADS-v2 alone (AUC-ROC 0.67 vs. 0.73 and 0.80, respectively, p < 0.05) and calibration curves confirmed an adequate prediction. Similar discrimination (C-statistics, p = 0.22) was observed in the prediction of high-grade cancer, thereby questioning the respective inputs and added values of biomarkers and clinical predictors in MDx-2 scores. Based on the results of this study, we can conclude that instruments of prediction developed for systematic prostate biopsies, including those that incorporate innovative biomarkers, must be reassessed and eventually confirmed in the context of upfront MRI and IGB. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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16 pages, 3337 KiB

Open AccessArticle

Long Pentraxin-3 Follows and Modulates Bladder Cancer Progression

by Sara Matarazzo, Laura Melocchi, Sara Rezzola, Elisabetta Grillo, Federica Maccarinelli, Arianna Giacomini, Marta Turati, Sara Taranto, Luca Zammataro, Marianna Cerasuolo, Mattia Bugatti, William Vermi, Marco Presta and Roberto Ronca

Cancers 2019, 11(9), 1277; https://doi.org/10.3390/cancers11091277 - 30 Aug 2019

Cited by 23 | Viewed by 3387

Abstract

Bladder tumors are a diffuse type of cancer. Long pentraxin-3 (PTX3) is a component of the innate immunity with pleiotropic functions in the regulation of immune response, tissue remodeling, and cancer progression. PTX3 may act as an oncosuppressor in different contexts, functioning as an antagonist of the fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) system, rewiring the immune microenvironment, or acting through mechanisms not yet fully clarified. In this study we used biopsies and data mining to assess that PTX3 is differentially expressed during the different stages of bladder cancer (BC) progression. BC cell lines, representative of different tumor grades, and transgenic/carcinogen-induced models were used to demonstrate in vitro and in vivo that PTX3 production by tumor cells decreases along the progression from low-grade to high-grade advanced muscle invasive forms (MIBC). In vitro and in vivo data revealed for the first time that PTX3 modulation and the consequent impairment of FGF/FGR systems in BC cells have a significant impact on different biological features of BC growth, including cell proliferation, motility, metabolism, stemness, and drug resistance. PTX3 exerts an oncosuppressive effect on BC progression and may represent a potential functional biomarker in BC evolution. Moreover, FGF/FGFR blockade has an impact on drug resistance and stemness features in BC. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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Review

Jump to: Editorial, Research

15 pages, 719 KiB

Open AccessReview

The Role of Steroid Hormone Receptors in Urothelial Tumorigenesis

by Hiroki Ide and Hiroshi Miyamoto

Cancers 2020, 12(8), 2155; https://doi.org/10.3390/cancers12082155 - 04 Aug 2020

Cited by 10 | Viewed by 2440

Abstract

Preclinical and/or clinical evidence has indicated a potential role of steroid hormone-mediated signaling pathways in the development of various neoplastic diseases, while precise mechanisms for the functions of specific receptors remain poorly understood. Specifically, in urothelial cancer where sex-related differences particularly in its incidence are noted, activation of sex hormone receptors, such as androgen receptor and estrogen receptor-β, has been associated with the induction of tumor development. More recently, glucocorticoid receptor has been implied to function as a suppressor of urothelial tumorigenesis. This article summarizes and discusses available data suggesting that steroid hormone receptors, including androgen receptor, estrogen receptor-α, estrogen receptor-β, glucocorticoid receptor, progesterone receptor and vitamin D receptor, as well as their related signals, contribute to modulating urothelial tumorigenesis. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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25 pages, 788 KiB

Open AccessReview

Clinical Applications of Molecular Biomarkers in Prostate Cancer

by Felipe Couñago, Fernando López-Campos, Ana Aurora Díaz-Gavela, Elena Almagro, Esaú Fenández-Pascual, Iván Henríquez, Rebeca Lozano, Estefanía Linares Espinós, Alfonso Gómez-Iturriaga, Guillermo de Velasco, Luis Miguel Quintana Franco, Ignacio Rodríguez-Melcón, José López-Torrecilla, Daniel E. Spratt, Luis Leonardo Guerrero, Juan Ignacio Martínez-Salamanca and Elia del Cerro

Cancers 2020, 12(6), 1550; https://doi.org/10.3390/cancers12061550 - 12 Jun 2020

Cited by 22 | Viewed by 5110

Abstract

There is clinically relevant molecular heterogeneity in prostate cancer (PCa), but this biological diversity has had only a minimal impact on clinical practice. Treatment outcomes in patients with localised PCa are often highly variable, even among patients stratified to the same risk group or disease state based on standard clinical and pathological parameters. In recent years, the development of gene panels has provided valuable data on the differential expression of genes in patients with PCa. Nevertheless, there is an urgent need to identify and validate prognostic and predictive biomarkers that can be applied across clinical scenarios, ranging from localised disease to metastatic castration-resistant PCa. The availability of such tools would allow for precision medicine to finally reach PCa patients. In this review, we evaluate current data on molecular biomarkers for PCa, with an emphasis on the biomarkers and gene panels with the most robust evidence to support their application in routine clinical practice. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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30 pages, 1580 KiB

Open AccessReview

Urinary Biomarkers in Bladder Cancer: Where Do We Stand and Potential Role of Extracellular Vesicles

by Manuel Castanheira de Oliveira, Hugo R. Caires, Maria J. Oliveira, Avelino Fraga, M. Helena Vasconcelos and Ricardo Ribeiro

Cancers 2020, 12(6), 1400; https://doi.org/10.3390/cancers12061400 - 29 May 2020

Cited by 38 | Viewed by 7577

Abstract

Extracellular vesicles (EVs) are small membrane vesicles released by all cells and involved in intercellular communication. Importantly, EVs cargo includes nucleic acids, lipids, and proteins constantly transferred between different cell types, contributing to autocrine and paracrine signaling. In recent years, they have been shown to play vital roles, not only in normal biological functions, but also in pathological conditions, such as cancer. In the multistep process of cancer progression, EVs act at different levels, from stimulation of neoplastic transformation, proliferation, promotion of angiogenesis, migration, invasion, and formation of metastatic niches in distant organs, to immune escape and therapy resistance. Moreover, as products of their parental cells, reflecting their genetic signatures and phenotypes, EVs hold great promise as diagnostic and prognostic biomarkers. Importantly, their potential to overcome the current limitations or the present diagnostic procedures has created interest in bladder cancer (BCa). Indeed, cystoscopy is an invasive and costly technique, whereas cytology has poor sensitivity for early staged and low-grade disease. Several urine-based biomarkers for BCa were found to overcome these limitations. Here, we review their potential advantages and downfalls. In addition, recent literature on the potential of EVs to improve BCa management was reviewed and discussed. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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20 pages, 8697 KiB

Open AccessReview

Renal Tumors of Childhood—A Histopathologic Pattern-Based Diagnostic Approach

by Ariadne H.A.G. Ooms, Gordan M. Vujanić, Ellen D’Hooghe, Paola Collini, Aurore L’Herminé-Coulomb, Christian Vokuhl, Norbert Graf, Marry M. van den Heuvel-Eibrink and Ronald R. de Krijger

Cancers 2020, 12(3), 729; https://doi.org/10.3390/cancers12030729 - 19 Mar 2020

Cited by 25 | Viewed by 5652

Abstract

Renal tumors comprise approximately 7% of all malignant pediatric tumors. This is a highly heterogeneous group of tumors, each with its own therapeutic management, outcome, and association with germline predispositions. Histopathology is the key in establishing the correct diagnosis, and therefore pathologists with expertise in pediatric oncology are needed for dealing with these rare tumors. While each tumor shows different histologic features, they do have considerable overlap in cell type and histologic pattern, making the diagnosis difficult to establish, if based on routine histology alone. To this end, ancillary techniques, such as immunohistochemistry and molecular analysis, can be of great importance for the correct diagnosis, resulting in appropriate treatment. To use ancillary techniques cost-effectively, we propose a pattern-based approach and provide recommendations to aid in deciding which panel of antibodies, supplemented by molecular characterization of a subset of genes, are required. Full article

(This article belongs to the Special Issue Pathogenesis and Diagnosis of Genitourinary Cancer)

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