Cancers

Editorial

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5 pages, 230 KiB

Open AccessEditorial

Updating Clear Cell Renal Cell Carcinoma (a Tribute to Prof. Ondrej Hes)

by Claudia Manini and José I. López

Cancers 2022, 14(16), 3990; https://doi.org/10.3390/cancers14163990 - 18 Aug 2022

Cited by 1 | Viewed by 1152

Abstract

This Special Issue provides an insight into critical issues concerning clear cell renal cell carcinomas (CCRCCs), reflecting the recent level of intricacy reached by renal oncology [...] Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

Research

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13 pages, 3098 KiB

Open AccessArticle

Prognostic Gene Expression-Based Signature in Clear-Cell Renal Cell Carcinoma

by Fiorella L. Roldán, Laura Izquierdo, Mercedes Ingelmo-Torres, Juan José Lozano, Raquel Carrasco, Alexandra Cuñado, Oscar Reig, Lourdes Mengual and Antonio Alcaraz

Cancers 2022, 14(15), 3754; https://doi.org/10.3390/cancers14153754 - 1 Aug 2022

Cited by 10 | Viewed by 2649

Abstract

The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and [...] Read more.

The inaccuracy of the current prognostic algorithms and the potential changes in the therapeutic management of localized ccRCC demands the development of an improved prognostic model for these patients. To this end, we analyzed whole-transcriptome profiling of 26 tissue samples from progressive and non-progressive ccRCCs using Illumina Hi-seq 4000. Differentially expressed genes (DEG) were intersected with the RNA-sequencing data from the TCGA. The overlapping genes were used for further analysis. A total of 132 genes were found to be prognosis-related genes. LASSO regression enabled the development of the best prognostic six-gene panel. Cox regression analyses were performed to identify independent clinical prognostic parameters to construct a combined nomogram which includes the expression of CERCAM, MIA2, HS6ST2, ONECUT2, SOX12, TMEM132A, pT stage, tumor size and ISUP grade. A risk score generated using this model effectively stratified patients at higher risk of disease progression (HR 10.79; p < 0.001) and cancer-specific death (HR 19.27; p < 0.001). It correlated with the clinicopathological variables, enabling us to discriminate a subset of patients at higher risk of progression within the Stage, Size, Grade and Necrosis score (SSIGN) risk groups, pT and ISUP grade. In summary, a gene expression-based prognostic signature was successfully developed providing a more precise assessment of the individual risk of progression. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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19 pages, 41122 KiB

Open AccessArticle

Molecular Subtypes Based on Genomic and Transcriptomic Features Correlate with the Responsiveness to Immune Checkpoint Inhibitors in Metastatic Clear Cell Renal Cell Carcinoma

by ByulA Jee, Eunjeong Seo, Kyunghee Park, Yi Rang Kim, Sun-ju Byeon, Sang Min Lee, Jae Hoon Chung, Wan Song, Hyun Hwan Sung, Hwang Gyun Jeon, Byong Chang Jeong, Seong Il Seo, Seong Soo Jeon, Hyun Moo Lee, Se Hoon Park, Woong-Yang Park and Minyong Kang

Cancers 2022, 14(10), 2354; https://doi.org/10.3390/cancers14102354 - 10 May 2022

Cited by 6 | Viewed by 2693

Abstract

Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been [...] Read more.

Clear cell renal cell carcinoma (ccRCC) has been reported to be highly immune to and infiltrated by T cells and has angiogenesis features, but the effect of given features on clinical outcomes followed by immune checkpoint inhibitors (ICIs) in ccRCC has not been fully characterized. Currently, loss of function mutation in PBRM1, a PBAF-complex gene frequently mutated in ccRCC, is associated with clinical benefit from ICIs, and is considered as a predictive biomarker for response to anti-PD-1 therapy. However, functional mechanisms of PBRM1 mutation regarding immunotherapy responsiveness are still poorly understood. Here, we performed targeted sequencing (n = 60) and whole transcriptomic sequencing (WTS) (n = 61) of patients with metastatic ccRCC treated by ICIs. By integrating WTS data from the CheckMate 025 trial, we obtained WTS data of 177 tumors and finally identified three molecular subtypes that are characterized by distinct molecular phenotypes and frequency of PBRM1 mutations. Patient clustered subtypes 1 and 3 demonstrated worse responses and survival after ICIs treatment, with a low proportion of PBRM1 mutation and angiogenesis-poor, but were immune-rich and cell-cycle enriched. Notably, patients clustered in the subtype 2 showed a better response and survival after ICIs treatment, with enrichment of PBRM1 mutation and metabolic programs and a low exhausted immune phenotype. Further analysis of the subtype 2 population demonstrated that GATM (glycine amidinotransferase), as a novel gene associated with PBRM1 mutation, plays a pivotal role in ccRCC by using a cell culture model, revealing tumor, suppressive-like features in reducing proliferation and migration. In summary, we identified that metastatic ccRCC treated by ICIs have distinct genomic and transcriptomic features that may account for their responsiveness to ICIs. We also revealed that the novel gene GATM can be a potential tumor suppressor and/or can be associated with therapeutic efficacy in metastatic ccRCC treated by ICIs. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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12 pages, 2732 KiB

Open AccessArticle

PBRM1 Immunohistochemical Expression Profile Correlates with Histomorphological Features and Endothelial Expression of Tumor Vasculature for Clear Cell Renal Cell Carcinoma

by Kazuho Saiga, Chisato Ohe, Takashi Yoshida, Haruyuki Ohsugi, Junichi Ikeda, Naho Atsumi, Yuri Noda, Yoshiki Yasukochi, Koichiro Higasa, Hisanori Taniguchi, Hidefumi Kinoshita and Koji Tsuta

Cancers 2022, 14(4), 1062; https://doi.org/10.3390/cancers14041062 - 20 Feb 2022

Cited by 4 | Viewed by 2403

Abstract

Loss of the polybromo-1 (PBRM1) protein has been expected as a possible biomarker for clear cell renal cell carcinoma (ccRCC). There is little knowledge about how PBRM1 immunohistochemical expression correlates with the histomorphological features of ccRCC and the endothelial expression of tumor vasculature. [...] Read more.

Loss of the polybromo-1 (PBRM1) protein has been expected as a possible biomarker for clear cell renal cell carcinoma (ccRCC). There is little knowledge about how PBRM1 immunohistochemical expression correlates with the histomorphological features of ccRCC and the endothelial expression of tumor vasculature. The present study evaluates the association of architectural patterns with the PBRM1 expression of cancer cells using a cohort of 425 patients with nonmetastatic ccRCC. Furthermore, we separately assessed the PBRM1 expression of the endothelial cells and evaluated the correlation between the expression of cancer cells and endothelial cells. PBRM1 loss in cancer cells was observed in 148 (34.8%) patients. In the correlation analysis between architectural patterns and PBRM1 expression, macrocyst/microcystic, tubular/acinar, and compact/small nested were positively correlated with PBRM1 expression, whereas alveolar/large nested, thick trabecular/insular, papillary/pseudopapillary, solid sheets, and sarcomatoid/rhabdoid were negatively correlated with PBRM1 expression. PBRM1 expression in vascular endothelial cells correlated with the expression of cancer cells (correlation coefficient = 0.834, p < 0.001). PBRM1 loss in both cancer and endothelial cells was associated with a lower recurrence-free survival rate (p < 0.001). Our PBRM1 expression profile indicated that PBRM1 expression in both cancer and endothelial cells may be regulated in an orchestrated manner. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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15 pages, 2575 KiB

Open AccessArticle

LiKidMiRs: A ddPCR-Based Panel of 4 Circulating miRNAs for Detection of Renal Cell Carcinoma

by José Pedro Sequeira, Vera Constâncio, Sofia Salta, João Lobo, Daniela Barros-Silva, Carina Carvalho-Maia, Jéssica Rodrigues, Isaac Braga, Rui Henrique and Carmen Jerónimo

Cancers 2022, 14(4), 858; https://doi.org/10.3390/cancers14040858 - 9 Feb 2022

Cited by 17 | Viewed by 3507

Abstract

Background: Decreased renal cell cancer-related mortality is an important societal goal, embodied by efforts to develop effective biomarkers enabling early detection and increasing the likelihood of curative treatment. Herein, we sought to develop a new biomarker for early and minimally invasive detection of [...] Read more.

Background: Decreased renal cell cancer-related mortality is an important societal goal, embodied by efforts to develop effective biomarkers enabling early detection and increasing the likelihood of curative treatment. Herein, we sought to develop a new biomarker for early and minimally invasive detection of renal cell carcinoma (RCC) based on a microRNA panel assessed by ddPCR. Methods: Plasma samples from patients with RCC (n = 124) or oncocytomas (n = 15), and 64 healthy donors, were selected. Hsa-miR-21-5p, hsa-miR-126-3p, hsa-miR-155-5p and hsa-miR-200b-3p levels were evaluated using a ddPCR protocol. Results: RCC patients disclosed significantly higher circulating levels of hsa-miR-155-5p compared to healthy donors, whereas the opposite was observed for hsa-miR-21-5p levels. Furthermore, hsa-miR-21-5p and hsa-miR-155-5p panels detected RCC with high sensitivity (82.66%) and accuracy (71.89%). The hsa-miR-126-3p/hsa-miR-200b-3p panel identified the most common RCC subtype (clear cell, ccRCC) with 74.78% sensitivity. Conclusion: Variable combinations of plasma miR levels assessed by ddPCR enable accurate detection of RCC in general, and of ccRCC. These findings, if confirmed in larger studies, provide evidence for a novel ancillary tool which might aid in early detection of RCC. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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15 pages, 3764 KiB

Open AccessArticle

Nivolumab Reduces PD1 Expression and Alters Density and Proliferation of Tumor Infiltrating Immune Cells in a Tissue Slice Culture Model of Renal Cell Carcinoma

by Philipp J. Stenzel, Nina Hörner, Sebastian Foersch, Daniel-Christoph Wagner, Igor Tsaur, Anita Thomas, Axel Haferkamp, Stephan Macher-Goeppinger, Wilfried Roth, Stefan Porubsky and Katrin E. Tagscherer

Cancers 2021, 13(18), 4511; https://doi.org/10.3390/cancers13184511 - 8 Sep 2021

Cited by 6 | Viewed by 2830

Abstract

Background: In the treatment of clear cell renal cell carcinoma (ccRCC), nivolumab is an established component of the first-line therapy with a favorable impact on progression free survival and overall survival. However, treatment-related adverse effects occur and, to date, there is no approved [...] Read more.

Background: In the treatment of clear cell renal cell carcinoma (ccRCC), nivolumab is an established component of the first-line therapy with a favorable impact on progression free survival and overall survival. However, treatment-related adverse effects occur and, to date, there is no approved predictive biomarker for patient stratification. Thus, the aim of this study was to establish an ex vivo tissue slice culture model of ccRCC and to elucidate the impact of nivolumab on tumor infiltrating immune cells. Methods: Fresh tumor tissue of ccRCC was treated with the immune checkpoint inhibitor nivolumab using ex vivo tissue slice culture (TSC). After cultivation, tissue slices were formalin-fixed, immunohistochemically stained and analyzed via digital image analysis. Results: The TSC model was shown to be suitable for ex vivo pharmacological experiments on intratumoral immune cells in ccRCC. PD1 expression on tumor infiltrating immune cells was dose-dependently reduced after nivolumab treatment (p < 0.01), whereas density and proliferation of tumor infiltrating T-cells and cytotoxic T-cells were inter-individually altered with a remarkable variability. Tumor cell proliferation was not affected by nivolumab. Conclusions: This study could demonstrate nivolumab-dependent effects on PD1 expression and tumor infiltrating T-cells in TSC of ccRCC. This is in line with results from other scientific studies about changes in immune cell proliferation in peripheral blood in response to nivolumab. Thus, TSC of ccRCC could be a further step to personalized medicine in terms of testing the response of individual patients to nivolumab. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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21 pages, 4328 KiB

Open AccessArticle

Integrated mRNA and miRNA Transcriptomic Analyses Reveals Divergent Mechanisms of Sunitinib Resistance in Clear Cell Renal Cell Carcinoma (ccRCC)

by María Armesto, Maitane Marquez, María Arestin, Peio Errarte, Ane Rubio, Lorea Manterola, Jose I. López and Charles H. Lawrie

Cancers 2021, 13(17), 4401; https://doi.org/10.3390/cancers13174401 - 31 Aug 2021

Cited by 11 | Viewed by 2636

Abstract

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic [...] Read more.

The anti-angiogenic therapy sunitinib remains the standard first-line treatment for meta static clear cell renal cell carcinoma (ccRCC). However, acquired resistance develops in nearly all responsive patients and represents a major source of treatment failure. We used an integrated miRNA and mRNA transcriptomic approach to identify miRNA:target gene interactions involved in sunitinib resistance. Through the generation of stably resistant clones in three ccRCC cell lines (786-O, A498 and Caki-1), we identified non-overlapping miRNA:target gene networks, suggesting divergent mechanisms of sunitinib resistance. Surprisingly, even though the genes involved in these networks were different, they shared targeting by multiple members of the miR-17~92 cluster. In 786-O cells, targeted genes were related to hypoxia/angiogenic pathways, whereas, in Caki-1 cells, they were related to inflammatory/proliferation pathways. The immunotherapy target PD-L1 was consistently up-regulated in resistant cells, and we demonstrated that the silencing of this gene resulted in an increase in sensitivity to sunitinib treatment only in 786-O-resistant cells, suggesting that some ccRCC patients might benefit from combination therapy with PD-L1 checkpoint inhibitors. In summary, we demonstrate that, although there are clearly divergent mechanisms of sunitinib resistance in ccRCC subtypes, the commonality of miRNAs in multiple pathways could be targeted to overcome sunitinib resistance. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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15 pages, 3727 KiB

Open AccessArticle

The Hypoxic Microenvironment Induces Stearoyl-CoA Desaturase-1 Overexpression and Lipidomic Profile Changes in Clear Cell Renal Cell Carcinoma

by Juan Pablo Melana, Francesco Mignolli, Tania Stoyanoff, María V. Aguirre, María A. Balboa, Jesús Balsinde and Juan Pablo Rodríguez

Cancers 2021, 13(12), 2962; https://doi.org/10.3390/cancers13122962 - 13 Jun 2021

Cited by 15 | Viewed by 3393

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype of renal cell carcinoma (RCC). It is characterized by a high cell proliferation and the ability to store lipids. Previous studies have demonstrated the overexpression of enzymes associated with lipid metabolism, including stearoyl-CoA desaturase-1 (SCD-1), which increases the concentration of unsaturated fatty acids in tumor cells. In this work, we studied the expression of SCD-1 in primary ccRCC tumors, as well as in cell lines, to determine its influence on the tumor lipid composition and its role in cell proliferation. The lipidomic analyses of patient tumors showed that oleic acid (18:1n-9) is one of the major fatty acids, and it is particularly abundant in the neutral lipid fraction of the tumor core. Using a ccRCC cell line model and in vitro-generated chemical hypoxia, we show that SCD-1 is highly upregulated (up to 200-fold), and this causes an increase in the cellular level of 18:1n-9, which, in turn, accumulates in the neutral lipid fraction. The pharmacological inhibition of SCD-1 blocks 18:1n-9 synthesis and compromises the proliferation. The addition of exogenous 18:1n-9 to the cells reverses the effects of SCD-1 inhibition on cell proliferation. These data reinforce the role of SCD-1 as a possible therapeutic target. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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11 pages, 479 KiB

Open AccessEditor’s ChoiceArticle

Association between Immune Related Adverse Events and Outcome in Patients with Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors

by Agnese Paderi, Roberta Giorgione, Elisa Giommoni, Marinella Micol Mela, Virginia Rossi, Laura Doni, Andrea Minervini, Marco Carini, Serena Pillozzi and Lorenzo Antonuzzo

Cancers 2021, 13(4), 860; https://doi.org/10.3390/cancers13040860 - 18 Feb 2021

Cited by 42 | Viewed by 4034

Abstract

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world [...] Read more.

Background: It has been reported that the occurrence of immune-related adverse events (irAEs) in oncological patients treated with immune-checkpoint inhibitors (ICIs) may be associated with favorable clinical outcome. We reported the clinical correlation between irAEs and the efficacy of ICIs in a real-world cohort of metastatic renal cell cancer (mRCC) patients. Methods: We retrospectively evaluated 43 patients with mRCC who were treated with nivolumab or with nivolumab plus ipilimumab. We considered seven specific classes of irAEs including pulmonary, hepatic, gastrointestinal, cutaneous, endocrine, rheumatological, and renal manifestations. We assessed progression-free survival (PFS) of specific irAEs classes compared to the no-irAEs group. Results: Twenty-nine out of 43 patients (67.4%) experienced a total of 49 irAEs registered. The most frequent irAE was thyroid dysfunction (n = 14). The median PFS after the beginning of therapy was significantly longer in patients with thyroid dysfunction and cutaneous reactions. In multivariate analysis, thyroid dysfunction was an independent factor for favorable outcome [HR: 0.29 (95% CI 0.11–0.77) p = 0.013]. Moreover, experiencing ≥2 irAEs in the same patient correlated in multivariate analysis with better outcome compared with none/one irAE [HR: 0.33 (95% CI 0.13–0.84) p = 0.020]. Conclusions: This retrospective study suggests an association between specific irAES (thyroid dysfunction and skin reaction) and efficacy of ICIs in metastatic RCC. Notably, multiple irAEs in a single patient were associated with better tumor response. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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17 pages, 3954 KiB

Open AccessEditor’s ChoiceArticle

Soluble PD-L1 Is an Independent Prognostic Factor in Clear Cell Renal Cell Carcinoma

by Gorka Larrinaga, Jon Danel Solano-Iturri, Peio Errarte, Miguel Unda, Ana Loizaga-Iriarte, Amparo Pérez-Fernández, Enrique Echevarría, Aintzane Asumendi, Claudia Manini, Javier C. Angulo and José I. López

Cancers 2021, 13(4), 667; https://doi.org/10.3390/cancers13040667 - 7 Feb 2021

Cited by 37 | Viewed by 3436

Abstract

(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort [...] Read more.

(1). Background: Immunohistochemical (IHC) evaluation of programmed death-1 (PD-1) and its ligand (PD-L1) is being used to evaluate advanced malignancies with potential response to immune checkpoint inhibitors. We evaluated both plasma and tissue expression of PD-1 and PD-L1 in the same cohort of patients, including non-metastatic and metastatic clear cell renal cell carcinoma (CCRCC). Concomitant plasma and tissue expression of PD-1 and PD-L1 was evaluated with emphasis on diagnostic and prognostic implications. (2) Methods: we analyzed PD-1 and PD-L1 IHC expression in tumor tissues and soluble forms (sPD-1 and sPD-L1) in plasma from 89 patients with CCRCC, of which 23 were metastatic and 16 received systemic therapy. The primary endpoint was evaluation of overall survival using Kaplan-Meier analysis and the Cox regression model. Plasma samples from healthy volunteers were also evaluated. (3) Results: Interestingly, sPD-1 and sPD-L1 levels were lower in cancer patients than in controls. sPD-1 and sPD-L1 levels and their counterpart tissue expression both at the tumor center and infiltrating front were not associated. Higher expression of both PD-1 and PD-L1 were associated with tumor grade, necrosis and tumor size. PD-1 was associated to tumor stage (pT) and PD-L1 to metastases. sPD-1 and sPD-L1 were not associated with clinico-pathological parameters, although both were higher in patients with synchronous metastases compared to metachronous ones and sPD-L1 was also higher for metastatic patients compared to non-metastatic patients. sPD-1 was also associated with the International Metastatic Renal Cell Cancer Database Consortium (IMDC) prognostic groups in metastatic CCRCC and also to the Morphology, Attenuation, Size and Structure (MASS) response criteria in metastatic patients treated with systemic therapy, mainly tyrosine-kinase inhibitors. Regarding prognosis, PD-L1 immunostaining at the tumor center with and without the tumor front was associated with worse survival, and so was sPD-L1 at a cut-off >793 ng/mL. Combination of positivity at both the tissue and plasma level increased the level of significance to predict prognosis. (4) Conclusions: Our findings corroborate the role of PD-L1 IHC to evaluate prognosis in CCRCC and present novel data on the usefulness of plasma sPD-L1 as a promising biomarker of survival in this neoplasia. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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Review

Jump to: Editorial, Research, Other

17 pages, 823 KiB

Open AccessReview

Radiogenomics in Clear Cell Renal Cell Carcinoma: A Review of the Current Status and Future Directions

by Sari Khaleel, Andrew Katims, Shivaram Cumarasamy, Shoshana Rosenzweig, Kyrollis Attalla, A Ari Hakimi and Reza Mehrazin

Cancers 2022, 14(9), 2085; https://doi.org/10.3390/cancers14092085 - 22 Apr 2022

Cited by 11 | Viewed by 3041

Abstract

Radiogenomics is a field of translational radiology that aims to associate a disease’s radiologic phenotype with its underlying genotype, thus offering a novel class of non-invasive biomarkers with diagnostic, prognostic, and therapeutic potential. We herein review current radiogenomics literature in clear cell renal [...] Read more.

Radiogenomics is a field of translational radiology that aims to associate a disease’s radiologic phenotype with its underlying genotype, thus offering a novel class of non-invasive biomarkers with diagnostic, prognostic, and therapeutic potential. We herein review current radiogenomics literature in clear cell renal cell carcinoma (ccRCC), the most common renal malignancy. A literature review was performed by querying PubMed, Medline, Cochrane Library, Google Scholar, and Web of Science databases, identifying all relevant articles using the following search terms: “radiogenomics”, “renal cell carcinoma”, and “clear cell renal cell carcinoma”. Articles included were limited to the English language and published between 2009–2021. Of 141 retrieved articles, 16 fit our inclusion criteria. Most studies used computed tomography (CT) images from open-source and institutional databases to extract radiomic features that were then modeled against common genomic mutations in ccRCC using a variety of machine learning algorithms. In more recent studies, we noted a shift towards the prediction of transcriptomic and/or epigenetic disease profiles, as well as downstream clinical outcomes. Radiogenomics offers a platform for the development of non-invasive biomarkers for ccRCC, with promising results in small-scale retrospective studies. However, more research is needed to identify and validate robust radiogenomic biomarkers before integration into clinical practice. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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19 pages, 1133 KiB

Open AccessReview

The Next Paradigm Shift in the Management of Clear Cell Renal Cancer: Radiogenomics—Definition, Current Advances, and Future Directions

by Nikhil Gopal, Pouria Yazdian Anari, Evrim Turkbey, Elizabeth C. Jones and Ashkan A. Malayeri

Cancers 2022, 14(3), 793; https://doi.org/10.3390/cancers14030793 - 4 Feb 2022

Cited by 14 | Viewed by 3523

Abstract

With improved molecular characterization of clear cell renal cancer and advances in texture analysis as well as machine learning, diagnostic radiology is primed to enter personalized medicine with radiogenomics: the identification of relationships between tumor image features and underlying genomic expression. By developing [...] Read more.

With improved molecular characterization of clear cell renal cancer and advances in texture analysis as well as machine learning, diagnostic radiology is primed to enter personalized medicine with radiogenomics: the identification of relationships between tumor image features and underlying genomic expression. By developing surrogate image biomarkers, clinicians can augment their ability to non-invasively characterize a tumor and predict clinically relevant outcomes (i.e., overall survival; metastasis-free survival; or complete/partial response to treatment). It is thus important for clinicians to have a basic understanding of this nascent field, which can be difficult due to the technical complexity of many of the studies. We conducted a review of the existing literature for radiogenomics in clear cell kidney cancer, including original full-text articles until September 2021. We provide a basic description of radiogenomics in diagnostic radiology; summarize existing literature on relationships between image features and gene expression patterns, either computationally or by radiologists; and propose future directions to facilitate integration of this field into the clinical setting. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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14 pages, 307 KiB

Open AccessReview

Prognostic Factors for Localized Clear Cell Renal Cell Carcinoma and Their Application in Adjuvant Therapy

by Kalle E. Mattila, Paula Vainio and Panu M. Jaakkola

Cancers 2022, 14(1), 239; https://doi.org/10.3390/cancers14010239 - 4 Jan 2022

Cited by 21 | Viewed by 3728

Abstract

Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized [...] Read more.

Approximately 20% of patients with renal cell carcinoma (RCC) present with primarily metastatic disease and over 30% of patients with localized RCC will develop distant metastases later, after complete resection of the primary tumor. Accurate postoperative prognostic models are essential for designing personalized surveillance programs, as well as for designing adjuvant therapy and trials. Several clinical and histopathological prognostic factors have been identified and adopted into prognostic algorithms to assess the individual risk for disease recurrence after radical or partial nephrectomy. However, the prediction accuracy of current prognostic models has been studied in retrospective patient cohorts and the optimal set of prognostic features remains unclear. In addition to traditional histopathological prognostic factors, novel biomarkers, such as gene expression profiles and circulating tumor DNA, are extensively studied to supplement existing prognostic algorithms to improve their prediction accuracy. Here, we aim to give an overview of existing prognostic features and prediction models for localized postoperative clear cell RCC and discuss their role in the adjuvant therapy trials. The results of ongoing placebo-controlled adjuvant therapy trials may elucidate prognostic factors and biomarkers that help to define patients at high risk for disease recurrence. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

24 pages, 1432 KiB

Open AccessReview

Molecular Mechanisms of Resistance to Immunotherapy and Antiangiogenic Treatments in Clear Cell Renal Cell Carcinoma

by Pablo Álvarez Ballesteros, Jesús Chamorro, María San Román-Gil, Javier Pozas, Victoria Gómez Dos Santos, Álvaro Ruiz Granados, Enrique Grande, Teresa Alonso-Gordoa and Javier Molina-Cerrillo

Cancers 2021, 13(23), 5981; https://doi.org/10.3390/cancers13235981 - 28 Nov 2021

Cited by 37 | Viewed by 4743

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is the most common histological subtype arising from renal cell carcinomas. This tumor is characterized by a predominant angiogenic and immunogenic microenvironment that interplay with stromal, immune cells, and tumoral cells. Despite the obscure prognosis traditionally related to this entity, strategies including angiogenesis inhibition with tyrosine kinase inhibitors (TKIs), as well as the enhancement of the immune system with the inhibition of immune checkpoint proteins, such as PD-1/PDL-1 and CTLA-4, have revolutionized the treatment landscape. This approach has achieved a substantial improvement in life expectancy and quality of life from patients with advanced ccRCC. Unfortunately, not all patients benefit from this success as most patients will finally progress to these therapies and, even worse, approximately 5 to 30% of patients will primarily progress. In the last few years, preclinical and clinical research have been conducted to decode the biological basis underlying the resistance mechanisms regarding angiogenic and immune-based therapy. In this review, we summarize the insights of these molecular alterations to understand the resistance pathways related to the treatment with TKI and immune checkpoint inhibitors (ICIs). Moreover, we include additional information on novel approaches that are currently under research to overcome these resistance alterations in preclinical studies and early phase clinical trials. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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13 pages, 293 KiB

Open AccessReview

Mutation Profile Variability in the Primary Tumor and Multiple Pulmonary Metastases of Clear Cell Renal Cell Carcinoma. A Review of the Literature and Analysis of Four Metastatic Cases

by Kristyna Prochazkova, Nikola Ptakova, Reza Alaghehbandan, Sean R. Williamson, Tomáš Vaněček, Josef Vodicka, Vladislav Treska, Joanna Rogala, Kristyna Pivovarcikova, Kvetoslava Michalova, Maryna Slisarenko, Milan Hora, Michal Michal and Ondrej Hes

Cancers 2021, 13(23), 5906; https://doi.org/10.3390/cancers13235906 - 24 Nov 2021

Cited by 4 | Viewed by 2136

Abstract

(1) Background: There are limited data concerning inter-tumoral and inter-metastatic heterogeneity in clear cell renal cell carcinoma (CCRCC). The aim of our study was to review published data and to examine mutation profile variability in primary and multiple pulmonary metastases (PMs) in our [...] Read more.

(1) Background: There are limited data concerning inter-tumoral and inter-metastatic heterogeneity in clear cell renal cell carcinoma (CCRCC). The aim of our study was to review published data and to examine mutation profile variability in primary and multiple pulmonary metastases (PMs) in our cohort of four patients with metastatic CCRCC. (2) Methods: Four patients were enrolled in this study. The clinical characteristics, types of surgeries, histopathologic results, immunohistochemical and genetic evaluations of corresponding primary tumor and PMs, and follow-up data were recorded. (3) Results: In our series, the most commonly mutated genes were those in the canonically dysregulated VHL pathway, which were detected in both primary tumors and corresponding metastasis. There were genetic profile differences between primary and metastatic tumors, as well as among particular metastases in one patient. (4) Conclusions: CCRCC shows heterogeneity between the primary tumor and its metastasis. Such mutational changes may be responsible for suboptimal treatment outcomes in targeted therapy settings. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

26 pages, 1568 KiB

Open AccessReview

Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma

by Myung-Chul Kim, Zeng Jin, Ryan Kolb, Nicholas Borcherding, Jonathan Alexander Chatzkel, Sara Moscovita Falzarano and Weizhou Zhang

Cancers 2021, 13(22), 5856; https://doi.org/10.3390/cancers13225856 - 22 Nov 2021

Cited by 50 | Viewed by 5084

Abstract

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8⁺ T cell infiltration being the predictor for poor prognosis–normally [...] Read more.

Several clinicopathological features of clear cell renal cell carcinomas (ccRCC) contribute to make an “atypical” cancer, including resistance to chemotherapy, sensitivity to anti-angiogenesis therapy and ICIs despite a low mutational burden, and CD8⁺ T cell infiltration being the predictor for poor prognosis–normally CD8⁺ T cell infiltration is a good prognostic factor in cancer patients. These “atypical” features have brought researchers to investigate the molecular and immunological mechanisms that lead to the increased T cell infiltrates despite relatively low molecular burdens, as well as to decipher the immune landscape that leads to better response to ICIs. In the present study, we summarize the past and ongoing pivotal clinical trials of immunotherapies for ccRCC, emphasizing the potential molecular and cellular mechanisms that lead to the success or failure of ICI therapy. Single-cell analysis of ccRCC has provided a more thorough and detailed understanding of the tumor immune microenvironment and has facilitated the discovery of molecular biomarkers from the tumor-infiltrating immune cells. We herein will focus on the discussion of some major immune cells, including T cells and tumor-associated macrophages (TAM) in ccRCC. We will further provide some perspectives of using molecular and cellular biomarkers derived from these immune cell types to potentially improve the response rate to ICIs in ccRCC patients. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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13 pages, 432 KiB

Open AccessReview

First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma: What Are the Most Appropriate Combination Therapies?

by Yann-Alexandre Vano, Sylvain Ladoire, Réza Elaidi, Slimane Dermeche, Jean-Christophe Eymard, Sabrina Falkowski, Marine Gross-Goupil, Gabriel Malouf, Bérangère Narciso, Christophe Sajous, Sophie Tartas, Eric Voog and Alain Ravaud

Cancers 2021, 13(21), 5548; https://doi.org/10.3390/cancers13215548 - 5 Nov 2021

Cited by 12 | Viewed by 3932

Abstract

The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) [...] Read more.

The development of antiangiogenic treatments, followed by immune checkpoint inhibitors (ICI), has significantly changed the management of metastatic clear cell renal cell cancer. Several phase III trials show the superiority of combination therapy, dual immunotherapy (ICI-ICI) or ICI plus tyrosine kinase inhibitors (TKI) of the vascular endothelium growth factor (VEGF) over sunitinib monotherapy. The question is therefore what is the best combination for a given patient? A strategy based on the International Metastatic Database Consortium (IMDC) classification is currently recommended with pembrolizumab + axitinib, cabozantinib + nivolumab, and lenvatinib + pembrolizumab (for all patients) or nivolumab + ipilimumab (for patients with intermediate or poor risk), which are the first-line treatment standards of care. However, several issues remain unresolved and require further investigation, such as the PD-L1 status, the relevance of possible options based on the patient’s profile, and consideration of second-line and subsequent treatments. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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30 pages, 813 KiB

Open AccessReview

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

by Javier C. Angulo, Claudia Manini, Jose I. López, Angel Pueyo, Begoña Colás and Santiago Ropero

Cancers 2021, 13(9), 2071; https://doi.org/10.3390/cancers13092071 - 25 Apr 2021

Cited by 26 | Viewed by 4280

Abstract

Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and [...] Read more.

Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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7 pages, 1189 KiB

Open AccessPerspective

Towards Personalized Sampling in Clear Cell Renal Cell Carcinomas

by Claudia Manini, Estíbaliz López-Fernández and José I. López

Cancers 2022, 14(14), 3381; https://doi.org/10.3390/cancers14143381 - 12 Jul 2022

Cited by 7 | Viewed by 1444

Abstract

Intratumor heterogeneity (ITH) is a constant evolutionary event in all malignant tumors, and clear cell renal cell carcinoma (CCRCC) is a paradigmatic example. ITH is responsible for most therapeutic failures in the era of precision oncology, so its precise detection remains a must [...] Read more.

Intratumor heterogeneity (ITH) is a constant evolutionary event in all malignant tumors, and clear cell renal cell carcinoma (CCRCC) is a paradigmatic example. ITH is responsible for most therapeutic failures in the era of precision oncology, so its precise detection remains a must in modern medicine. Unfortunately, classic sampling protocols do not resolve the problem as expected and several strategies have been being implemented in recent years to improve such detection. Basically, multisite tumor sampling (MSTS) and the homogenization of the residual tumor tissue are on display. A next step of the MSTS strategy considering the recently discovered patterns of ITH regionalization is presented here, the so-called personalized MSTS (pMSTS). This modification consists of paying more attention to sample the tumor periphery since it is this area with maximum levels of ITH. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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11 pages, 5473 KiB

Open AccessCommentary

A Comprehensive Commentary on the Multilocular Cystic Renal Neoplasm of Low Malignant Potential: A Urologist’s Perspective

by Tomas Pitra, Kristyna Pivovarcikova, Reza Alaghehbandan, Adriena Bartos Vesela, Radek Tupy, Milan Hora and Ondrej Hes

Cancers 2022, 14(3), 831; https://doi.org/10.3390/cancers14030831 - 6 Feb 2022

Cited by 8 | Viewed by 3809

Abstract

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) is a cystic renal tumor with indolent clinical behavior. In most of cases, it is an incidental finding during the examination of other health issues. The true incidence rate is estimated to be between [...] Read more.

Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) is a cystic renal tumor with indolent clinical behavior. In most of cases, it is an incidental finding during the examination of other health issues. The true incidence rate is estimated to be between 1.5% and 4% of all RCCs. These lesions are classified according to the Bosniak classification as Bosniak category III. There is a wide spectrum of diagnostic tools that can be utilized in the identification of this tumor, such as computed tomography (CT), magnetic resonance (MRI) or contrast-enhanced ultrasonography (CEUS). Management choices of these lesions range from conservative approaches, such as clinical follow-up, to surgery. Minimally invasive techniques (i.e., robotic surgery and laparoscopy) are preferred, with an emphasis on nephron sparing surgery, if clinically feasible. Full article

(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma 2021–2022)

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