Clinicopathological and prognostic impact of somatic mutations in Chinese patients with clear cell renal cell carcinoma

Bi, Hai; Yin, J W; Zhou, Lang; Wu, Yaqian; Ge, Liyuan; Lu, Min; Liu, Lei; Zhang, Hongxian; Zhao, Yue; Liu, Cheng; Ma, Lulin

doi:10.21037/tau-20-1410

Cited by 8 publications

(12 citation statements)

References 35 publications

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“…1c ). Interestingly, mutation frequencies of these genes exhibited ethnic and geographic variations among the East Asian 2 , 24 , 29 , TCGA 3 , and European 25 cohorts. Specifically, VHL (45.2–64.3% in East Asian vs. 46.2% in TCGA vs. 73.4% in European) and SETD2 (8.0–12.2% in East Asian vs. 13.9% in TCGA vs. 19.1% in European) had the highest mutation frequency in the European cohort.…”

Section: Resultsmentioning

confidence: 99%

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population

Feng

et al. 2022

Nat Commun

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Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1–3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.

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Section: Resultsmentioning

confidence: 99%

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population

Feng

et al. 2022

Nat Commun

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“…Although ccRCC is known for abnormal lipid accumulation of cholesterol, cholesterol esters, and neutral lipids (triglycerides) [3], the underlying molecular mechanisms remain unclear. Furthermore, most patients with ccRCCs harbor chromosomal 3p loss and genomic mutations in the Von Hippel-Lindau Tumor Suppressor (VHL) allele, followed by the secondary loss of multiple tumor suppressor genes including PBRM1, SETD2, PTEN, and/or TP53 [4][5][6][7]. ccRCCs are also known to be highly resistant to conventional cytotoxic, radiation, and hormone therapies, and nephrectomy is the only therapeutic option used to cure early and local ccRCCs.…”

Section: Introductionmentioning

confidence: 99%

“…The current treatment options offered to metastatic patients include inhibitors of (i) tyrosine kinases, (ii) mTORC signaling, and (iii) immune control checkpoints. Despite the initial response, most metastatic ccRCC patients will develop resistance to these targeted therapies [4][5][6][7]. Therefore, deciphering the molecular mechanisms underlying renal tumor progression is urgently needed to develop new therapeutic strategies to cure ccRCC.…”

Section: Introductionmentioning

confidence: 99%

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Goujon

Woszczyk

Gaudelot

et al. 2022

Cancers

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Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

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“…For example, The Cancer Genome Atlas (TCGA) has conducted comprehensive molecular characterizations in ccRCC, including alterations in genes controlling cellular oxygen sensing (for example, VHL ) and the maintenance of chromatin states (for example, PBRM1 ) ( 9 ). However, most of the researches were conducted on patients from Western countries or focused on the prognostic value of gene alteration ( 10 , 11 ). The genomic landscape in Chinese ccRCC still needs to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

et al. 2021

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Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). The genomic landscape in Chinese ccRCC needs to be elucidated. Herein, we investigated the molecular features of Chinese ccRCC patients. Genomic profiling of DNA was performed through next-generation sequencing (NGS) in Chinese patients with ccRCC between January 2017 and March 2020. Clinical information including age, gender, and tumor histology was collected. Immunohistochemistry (IHC) staining for PD-L1 expression was performed using PD-L1 IHC 22C3 pharmDx assay or Ventana PD-L1 SP263 assay. Data analyses were performed using R 3.6.1. A total of 880 Chinese ccRCC patients who have undergone NGS were included in this study. The most common somatic alterations were detected in VHL (59.7%), PBRM1 (18.0%), SETD2 (12.2%), BAP1 (10.2%), and TP53 (9.4%). Compared with The Cancer Genome Atlas (TCGA) database, a higher mutation frequency of VHL (59.7% vs. 50.0%, p < 0.001) and TP53 (9.4% vs. 3.5%, p < 0.001) and a lower mutation frequency of PBRM1 (18.0% vs. 31.0%, p < 0.001) were found in the Chinese cohort. Of the 460 patients who were evaluated for PD-L1 expression, 139 (30.2%) had positive PD-L1 expression. The median tumor mutational burden (TMB) value was 4.5 muts/Mb (range, 0–46.0). Five (0.7%) patients were identified as microsatellite instability-high (MSI-H). Furthermore, 52 (5.9%) patients were identified to carry pathogenic or likely pathogenic germline mutations in 22 cancer predisposition genes. This is the first large-scale comprehensive genomic analysis for Chinese ccRCC patients, and these results might provide a better understanding of molecular features in Chinese ccRCC patients, which can lead to an improvement in the personalized treatment for these patients.

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Clinicopathological and prognostic impact of somatic mutations in Chinese patients with clear cell renal cell carcinoma

Cited by 8 publications

References 35 publications

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population

A proteogenomic analysis of clear cell renal cell carcinoma in a Chinese population

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Comprehensive Genomic Landscape in Chinese Clear Cell Renal Cell Carcinoma Patients

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