Loss of CDKN1A mRNA and Protein Expression Are Independent Predictors of Poor Outcome in Chromophobe Renal Cell Carcinoma Patients

Ohashi, Riuko; Angori, Silvia; Batavia, Aashil A.; Rupp, Niels J.; Ajioka, Yoichi; Schraml, Peter; Moch, Holger

doi:10.3390/cancers12020465

Cited by 25 publications

(16 citation statements)

References 59 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…So, it is worthy of additional studies on SNCAIP function and potentially drug development in ccRCC. We also identified CDKN1A alterations in the metastatic groups, and loss of CDKN1A had been proved to be an unfavorable predictor of prognosis in chromophobe renal cell carcinoma patients [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

Meng

Jiang

Cui

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

Clear cell renal cell carcinoma (ccRCC) accounts for more than 75% of renal cell carcinoma. Nearly 25% of ccRCC patients were diagnosed with metastasis. Though the genomic profile of ccRCC has been widely studied, the difference between localized and metastatic ccRCC was not clarified. Primary tumor samples and matched whole blood were collected from 106 sporadic patients diagnosed with renal clear cell carcinoma at Qilu Hospital of Shandong University from January 2017 to November 2019, and 17 of them were diagnosed with metastasis. A hybridization capture-based next-generation sequencing of 618 cancer-related genes was performed to investigate the somatic and germline variants, tumor mutation burden (TMB), and microsatellite instability (MSI). Five genes with significantly different prevalence were identified in the metastatic group, especially TOP1 (17.65% vs. 0%) and SNCAIP (17.65% vs. 0%). The altered frequency of PBRM1 (0% vs. 27%) and BAP1 (24% vs. 10%) differed between the metastatic and nonmetastatic groups, which may relate to the prognosis. Of these 106 patients, 42 patients (39.62%) had at least one alteration in DNA damage repair (DDR) genes, including 58.82% of metastatic ccRCC patients and 35.96% of ccRCC patients without metastasis. Ten pathogenic or likely pathogenic (P/LP) variants were identified in 11 sporadic clear cell renal cell carcinoma patients (10.38%), including rarely reported ATM (n=1), MUTYH (n=1), NBN (n=1), RAD51D (n=1), and BRCA2 (n=1). No significant difference in the ratio of P/LP variant carriers or TMB was identified between the metastatic and nonmetastatic groups. We found a unique genomic feature of Chinese metastatic ccRCC patients with a higher prevalence of alterations in DDR, TOP1, and SNCAIP. Further investigated studies and drug development are needed in the future.

show abstract

Section: Discussionmentioning

confidence: 99%

Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

Meng

Jiang

Cui

et al. 2020

BioMed Research International

View full text Add to dashboard Cite

show abstract

“…P21, also known as CDKN1A which resided in 6p21.2 20,21 , has been investigated involvement in cell cycle regulation, differentiation, cell migration, cytoskeletal dynamic, apoptosis, transcription, DNA repair, induction of totipotent stem cells, autophagy and senescence 22,23 . Commonly accepted is that P21 as a member of cyclin-dependent kinase inhibitors (CDKI) interacts with various cell cycle proteins to mediate G1/S growth phase arrest in response to different stimuli 24,25 .…”

Section: Discussionmentioning

confidence: 99%

KRT23 Acts as an Oncogene in Hepatocellular Carcinoma by Regulating P21 via PI3K/AKT/GSK3β Pathway

Guo¹,

Ma²,

Wang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background:Hepatocellular carcinoma (HCC) is a leading cancer worldwide for which diagnosis, treatment and progression are largely unknown. Keratin23 is a potential biomarker forHCC development; however, regulatory mechanisms underlying its expression remain unclear. Inthis research we explored the expression and effect of KRT23 underlying HCC development. Materials and methods:GEPIA was applied to analyze the expression of KRT23 in HCC samples and Kaplan-Merier survival analysis for patients’ prognosis. Next, IHC was further conducted for confirming its expression in HCC tissues. Meanwhile qRT-PCR and western blot analysis were applied to examine the expression of KRT23 on both mRNA and protein level in HCC cell lines compared with immortal hepatocyte LO2. Cell experiments including MTT assay, apoptosis analysis, cell cycle assay and clone formation assay were conducted for cell proliferation while transwell assay and scratch test for metastasis in vitro. Moreover, xenograft tumors in nude mice were further conducted for verification in vivo. As for mechanism in depth, immunofluorescence and western blot were operated to explore the effect of KRT23 on EMT and PI3K/AKT/GSK3βsignaling pathway. Furthermore, Co-immunoprecipitation was applied for interaction between KRT23 and P21. Functional rescue experiments were conducted to further testify their mutual effect.Results:For this research, we discovered the high expression of KRT23 in HCC samples and cell lines. Functionally, KRT23 knockdown reduced cell proliferation and metastasis in vitro and vivo. Furthermore, KRT23 participated in EMT progression and interacted with P21 to mediate PI3K/AKT/GSK3βpathway in HCC development.Conclusion:To summarize, KRT23 accelerated HCC proliferation and metastasis by regulating P21 via PI3K/AKT/GSK3βpathway.

show abstract

“…CDKN1A, which resides in 6p21.2, is affected by frequent loss of one chromosome 6 allele in chromophobe RCC. 53 Analysis of TCGA data of chromophobe RCC demonstrated that loss of one CDKN1A allele was closely linked to lower CDKN1A mRNA expression levels. It has been recently shown that decreased CDKN1A expression at mRNA and protein levels were associated with short overall survival and were independent predictors of prognosis in chromophobe RCC.…”

Section: Molecular Studies and The 'Cell Of Origin' Theorymentioning

confidence: 99%

Chromophobe renal cell carcinoma: current and controversial issues

Moch

Ohashi

2021

Pathology

Self Cite

View full text Add to dashboard Cite

It has been 35 years since Professor Thoenes and his colleagues discovered chromophobe renal cell carcinoma (RCC). Since then, our knowledge about this tumour entity has changed and novel tumour entities have been discovered. The aim of this review is to discuss recent molecular findings and open questions in diagnosing chromophobe-like/oncocytic neoplasms. The broader differential diagnosis of chromophobe-like and oncocytomalike neoplasms includes SDH-deficient renal cell carcinoma, fumarate hydratase (FH) deficient RCC, epitheloid angiomyolipoma ('oncocytoma like'), MiT family translocation RCC and the emerging entity of eosinophilic solid and cystic renal cell carcinoma. After separation of these tumours from chromophobe RCC, it becomes evident that chromophobe RCC are low malignant tumours with a 5-6% risk of metastasis. Recent next generation sequencing (NGS) and DNA methylation profiling studies have confirmed Thoenes' theory of a distal tubule derived origin of chromophobe RCC and renal oncocytomas. Comprehensive genomic analyses of chromophobe RCC have demonstrated a low somatic mutation rate and identified TP53 and PTEN as the most frequently mutated genes, whereas 'unclassified' RCC with oncocytic or chromophobe-like features can show somatic inactivating mutations of TSC2 or activating mutations of MTOR as the primary molecular alterations. For the future, it would be desirable to create a category of 'oncocytic/chromophobe RCC, NOS' with the potential of further molecular studies for identification of TSC1/2 mutations in these rare tumours.

show abstract

Loss of CDKN1A mRNA and Protein Expression Are Independent Predictors of Poor Outcome in Chromophobe Renal Cell Carcinoma Patients

Cited by 25 publications

References 59 publications

Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

Genomic Analysis Reveals Novel Specific Metastatic Mutations in Chinese Clear Cell Renal Cell Carcinoma

KRT23 Acts as an Oncogene in Hepatocellular Carcinoma by Regulating P21 via PI3K/AKT/GSK3β Pathway

Chromophobe renal cell carcinoma: current and controversial issues

Contact Info

Product

Resources

About