Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez, Danielle J.; Simon, M. Celeste

doi:10.1016/j.bbcan.2018.06.003

Cited by 115 publications

(103 citation statements)

References 110 publications

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“…The first steps in understanding RCC genetics were VHL disease studies . VHL disease is an autosomal‐dominant syndrome that predisposes disease‐bearing individuals to a variety of benign and malignant neoplasms.…”

Section: Molecular Mechanisms Underlying Rcc Carcinogenesismentioning

confidence: 99%

“…Namely, overexpressed vascular endothelial growth factor (VEGF) binds to its tyrosine kinase receptors present on both endothelial and RCC cells. These receptors activate either RAS/MEK/ERK or PI3K/AKT/mTOR pathway accentuating tumor progression by further HIF1α production . However, it has been shown that VHL inactivation alone is not sufficient for RCC progression .…”

Section: Molecular Mechanisms Underlying Rcc Carcinogenesismentioning

confidence: 99%

“…1,[8][9][10] 2 | MOLECULAR MECHANISMS UNDERLYING RCC CARCINOGENESIS The first steps in understanding RCC genetics were VHL disease studies. 11 VHL disease is an autosomal-dominant syndrome that predisposes disease-bearing individuals to a variety of benign and malignant neoplasms. Those patients inherit a germline mutation of the VHL tumor suppressor gene and tumor development depends on the somatic inactivation or loss of the second wild-type allele.…”

Section: Introductionmentioning

confidence: 99%

“…These receptors activate either RAS/MEK/ERK or PI3K/AKT/mTOR pathway accentuating tumor progression by further HIF1α production. 11 However, it has been shown that VHL inactivation alone is not sufficient for RCC progression. [15][16][17] Indeed, apart from mutations in PBRM1, SETD2 and BAP1 chromatin-modifier genes, [15][16][17] F I G U R E 1 Summary of major signaling pathways in RCC.…”

Section: Introductionmentioning

confidence: 99%

“…19 Still, although pVHL inactivation occurs in 90% of all RCC patients, it seems that VHL loss alone is not sufficient to induce RCC. 1,11 Long latent period of more than 30 years in individuals who harbor VHL germline mutations to develop RCC and the finding that loss of VHL is unable to induce RCC in mice indicate that additional genetic and/or epigenetic events are probably necessary for development of RCC. 16,17 All mentioned mechanisms indicate the complex nature of RCC at the molecular level ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

et al. 2019

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Renal cell carcinoma (RCC) represents a group of histologically similar neoplasms with significant intratumor and intertumor genetic heterogeneity. Recognized risk factors for RCC development include smoking, hypertension, obesity, as well as von Hippel–Lindau (VHL) disease. Inactivation of VHL, deregulated nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) pathway, and altered redox homeostasis, together with changes in glutathione transferase (GST) profile, are considered as important contributing factors in RCC development and progression. Although the available results of both gene–gene and gene–environment analysis are quite heterogeneous, they clearly indicate that certain GST genotypes may play a role as risk modifiers, either individually or in combination with other Phase I or Phase II gene polymorphisms, as well as in subjects exposed to relevant substrates. Seemingly, GST genotyping could identify individuals with impaired detoxification in renal parenchyma that are at higher risk of developing RCC. In addition to well established roles of GSTs in conjugation and biotransformation of xenobiotics, GSTs have emerged as significant regulators of pathways determining cell proliferation and survival. Indeed, there are evidence in favor of GST significance, not only in terms of risk for RCC development, but also with respect to progression and prognosis. So far, GSTM1‐active genotype was confirmed to be an independent predictor of higher risk of overall mortality. Therefore, it is reasonable to assume that certain GST variants may assist in individual RCC risk assessment, as well as postoperative prognosis. Even more, GST profiling might contribute to development of personalized targeted therapy in RCC patients.

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Section: Molecular Mechanisms Underlying Rcc Carcinogenesismentioning

confidence: 99%

Section: Molecular Mechanisms Underlying Rcc Carcinogenesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

et al. 2019

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N6‐methyladenosine‐modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis‐regulated Hippo pathway

Miao

Wang

Shi

et al. 2023

Cancer Communications

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Background The mechanism of metabolism reprogramming is an unsolved problem in clear cell renal cell carcinoma (ccRCC). Recently, it was discovered that the Hippo pathway altered tumor metabolism and promoted tumor progression. Thus, this study aimed at identifying key regulators of metabolism reprogramming and the Hippo pathway in ccRCC and pinpointing potential therapeutic targets for ccRCC patients. Methods Hippo‐related gene sets and metabolic gene sets were used to screen potential regulators of the Hippo pathway in ccRCC. Public databases and samples from patients were applied to investigate the association of dihydrolipoamide branched chain transacylase E2 ( DBT ) with ccRCC and Hippo signaling. The role of DBT was confirmed by gain or loss of function assays in vitro and in vivo. Mechanistic results were yielded by luciferase reporter assay, immunoprecipitation, mass spectroscopy, and mutational studies. Results DBT was confirmed as a Hippo‐related marker with significant prognostic predictive value, and its downregulation was caused by methyltransferase‐like‐3 (METTL3)‐mediated N6‐methyladenosine (m 6 A) modification in ccRCC. Functional studies specified DBT as a tumor suppressor for inhibiting tumor progression and correcting the lipid metabolism disorder in ccRCC. Mechanistic findings revealed that annexin A2 (ANXA2) interacted with the lipoyl‐binding domain of DBT to activate Hippo signaling which led to decreased nuclear localization of yes1‐associated transcriptional regulator (YAP) and transcriptional repression of lipogenic genes. Conclusions This study demonstrated a tumor‐suppressive role for the DBT/ANXA2/YAP axis‐regulated Hippo signaling and suggested DBT as a potential target for pharmaceutical intervention in ccRCC.

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Exosome‐related lncRNA score: A value‐based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma

Yang,

Zhang,

Zhan

et al. 2024

Cancer Medicine

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BackgroundExosomes play a crucial role in intercellular communication in clear cell renal cell carcinoma (ccRCC), while the long non‐coding RNAs (lncRNAs) are implicated in tumorigenesis and progression.AimsThe purpose of this study is to construction a exosomes‐related lncRNA score and a ceRNA network to predict the response to immunotherapy and potential targeted drug in ccRCC.MethodsData of ccRCC patients were obtained from the TCGA database. Pearson correlation analysis was used to identify eExosomes‐related lncRNAs (ERLRs) from Top10 exosomes‐related genes that have been screened. The entire cohort was randomly divided into a training cohort and a validation cohort in equal scale. LASSO regression and multivariate cox regression was used to construct the ERLRs‐based score. Differences in clinicopathological characteristics, immune microenvironment, immune checkpoints, and drug susceptibility between the high‐ and low‐risk groups were also investigated. Finally, the relevant ceRNA network was constructed by machine learning to analyze their potential targets in immunotherapy and drug use of ccRCC patients.ResultsA score consisting of 4ERLRs was identified, and patients with higher ERLRs‐based score tended to have a worse prognosis than those with lower ERLRs‐based score. ROC curves and multivariate Cox regression analysis demonstrated that the score could be considered as a risk factor for prognosis in both training and validation cohorts. Moreover, patients with high scores are predisposed to experience poor overall survival, a larger prevalence of advanced stage (III‐IV), a greater tumor mutational burden, a higher infiltration of immunosuppressive cells, and a greater likelihood of responding favorably to immunotherapy. The importance of EMX2OS was determined by mechanical learning, and the ceRNA network was constructed, and EMX2OS may be a potential therapeutic target, possibly exerting its function through the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis.ConclusionsBased on machine learning, a novel ERLRs‐based score was constructed for predicting the survival of ccRCC patients. The ERLRs‐based score is a promising potential independent prognostic factor that is closely correlated with the immune microenvironment and clinicopathological characteristics. Meanwhile, we screened out key lncRNAEMX2OS and identified the EMX2OS/hsa‐miR‐31‐5p/TLN2 axis, which may provide new clues for the targeted therapy of ccRCC.

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Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Cited by 115 publications

References 110 publications

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

Glutathione transferase genotypes may serve as determinants of risk and prognosis in renal cell carcinoma

N6‐methyladenosine‐modified DBT alleviates lipid accumulation and inhibits tumor progression in clear cell renal cell carcinoma through the ANXA2/YAP axis‐regulated Hippo pathway

Exosome‐related lncRNA score: A value‐based individual treatment strategy for predicting the response to immunotherapy in clear cell renal cell carcinoma

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