Clear cell renal cell carcinoma with wild‐type <i>von Hippel‐Lindau</i> gene: a non‐existent or new tumour entity?

Batavia, Aashil A.; Schraml, Peter; Moch, Holger

doi:10.1111/his.13749

Cited by 36 publications

(24 citation statements)

References 54 publications

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“…In addition, clear cell tumors with VHL wild type and mutations in TCEB1 have been recently described to increase HIF stabilization via the same mechanism as VHL inactivation. Unfortunately, TCEB1 was not included in our panel [21].…”

Section: Discussionmentioning

confidence: 99%

Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

et al. 2020

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Background: Clear cell tubulo-papillary renal cell carcinoma (cctpRCC) is characterized by clear cell morphology, but differs from conventional clear cell carcinoma (ccRCC) for its indolent clinical behavior and genetic background. The differential diagnosis between the two is based on histology and immunohistochemistry (IHC). Methods: We performed a comparative case-control histological, IHC, and genetic analysis by next generation sequencing (NGS), to point out the differences in 10 cases of cctpRCC, and six controls of ccRCC with low stage and grade. Results: All 16 cases showed the IHC profile with cytokeratin 7, racemase, and carbonic anhydrase IX expected for the histological features of each tumor type. By contrast, the NGS mutation analysis that covered 207 amplicons of 50 oncogenes or tumor suppressor genes provided conflicting results. Among the 10 cctpRCC cases, eight (80%) were wild type for all of the genes in the panel, while two (20%) harbored VHL mutations typical of ccRCC. Three of the six (50%) ccRCC control cases showed expected VHL mutations; two (33%) harbored pathogenic mutations in the p53 or the CKIT genes; and one (16%) was wild type. Conclusion: We can assume that histology and ICH are not sufficient for a definitive diagnosis of cctpRCC or ccRCC. Although with a panel covering 50 genes, we found that 80% of cctpRCC were genetically silent; thus, suggesting an indolent biology of these tumors. The differential diagnosis between ccptRCC and ccRCC for the choice of the best therapeutic strategy likely requires the comprehensive evaluation of histology, IHC, and at least VHL mutations.

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Section: Discussionmentioning

confidence: 99%

Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

et al. 2020

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“…Clear cell renal cell carcinoma (ccRCC) represents 70–80% of all cancers of the kidneys 2 . Biallelic inactivation of the von Hippel–Lindau ( VHL ) tumour suppressor gene is a truncal genetic event that arises in the majority of cases of ccRCC 3 – 6 , demonstrating that loss of one or more of the various tumour suppressor functions of the pVHL protein isoforms 2 , 7 is central to the earliest steps in the initiation of tumour formation. Subsequent mutations or chromosomal copy number alterations in epigenetic regulatory genes (including PBRM1 , BAP1 , SETD2 , and KDM5C ), cell-cycle regulatory genes (including TP53 , CDKN2A , and MYC ) or PI3K pathway genes (including PIK3CA , PTEN , MTOR , and TSC1 ) arise recurrently in ccRCC and are believed to cooperate with VHL inactivation to promote the development and evolution of ccRCC tumours 8 , 9 .…”

Section: Introductionmentioning

confidence: 99%

HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

et al. 2020

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Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth. Both HIF-1α and HIF-2α are required for the clear cell phenotype. Transcriptomic and proteomic analyses reveal that HIF-1α regulates glycolysis while HIF-2α regulates genes associated with lipoprotein metabolism, ribosome biogenesis and E2F and MYC transcriptional activities. HIF-2α-deficient tumours are characterised by increased antigen presentation, interferon signalling and CD8 + T cell infiltration and activation. Single copy loss of HIF1A or high levels of HIF2A mRNA expression correlate with altered immune microenvironments in human ccRCC. These studies reveal an oncogenic role of HIF-1α in ccRCC initiation and suggest that alterations in the balance of HIF-1α and HIF-2α activities can affect different aspects of ccRCC biology and disease aggressiveness.

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“…CDC20 is important in the regulation of cell cycle, and its expression is upregulated in a variety of malignant tumors 33,34 . Hypoxia-inducible factor-1α (HIF-1α) was found to directly bind to the ES-FLI-1 promoter and could be closely related to the invasiveness of Ewing sarcoma, while TCEB1 could increase HIF stabilization 35,36 . Thus, TCEB1 targeted drug might be helpful for ES treatment.…”

Section: Discussionmentioning

confidence: 99%

Identification of aberrantly methylated-differentially expressed genes and potential agents for Ewing’s sarcoma

Gao

et al. 2020

Preprint

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Background DNA methylation is a common epigenetic regulatory way, and it plays a critical role in various human diseases. However, the potential role of how DNA methylation impacts Ewing’s sarcoma (ES) is not clear. This study aimed to explore the regulatory role of DNA methylation in ES. Methods The microarray data of gene expression and methylation were downloaded from Gene Expression Omnibus (GEO) database, and analyzed via GEO2R. Venn analysis was then applied to identify aberrantly methylated differentially expressed genes (DEGs). Subsequently, Function and pathway enrichment analysis was conducted. Protein-protein interaction (PPI) network was constructed. Hub genes were determined. Besides, a connectivity map (CMap) analysis was performed to screen bioactive compounds for ES treatment. Results A total of 135 hypomethylated high expression genes and 523 hypermethylated low expression genes were identified. The hypomethylated high expression genes were enriched in signal transduction and the apoptosis process. Meanwhile, hypermethylated low expression genes were related to DNA replication and transcription regulation. We next determined 10 hub genes through PPI analysis, among them, C3, TF, and TCEB1 might serve as diagnostic and therapeutic targets. Furthermore, CMap analysis revealed 6 chemicals as potential options for ES treatment. Conclusions For the first time, we jointly analyzed gene profiling and methylation data about ES. The introduction of DNA methylation characteristics over DEGs is helpful to understand the pathogenesis of ES. The identified hub aberrantly methylated DEGs and chemicals might provide some novel insights on ES treatment.

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Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

Cited by 36 publications

References 54 publications

Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice

Identification of aberrantly methylated-differentially expressed genes and potential agents for Ewing’s sarcoma

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