Oxidative stress and DNA hypermethylation status in renal cell carcinoma arising in patients on dialysis

Mitochondria not only are the main source of ATP synthesis but also regulate cellular redox balance and calcium homeostasis. Its dysfunction can lead to a variety of diseases and promote cancer and metastasis. In this study, we aimed to explore the molecular characteristics and prognostic significance of mitochondrial genes (MTGs) related to oxidative stress in clear cell renal cell carcinoma (ccRCC). A total of 75 differentially expressed MTGs were analyzed from The Cancer Genome Atlas (TCGA) database, including 46 upregulated and 29 downregulated MTGs. Further analysis screened 6 prognostic-related MTGs (ACAD11, ACADSB, BID, PYCR1, SLC25A27, and STAR) and was used to develop a signature. Kaplan-Meier survival and receiver operating characteristic (ROC) curve analyses showed that the signature could accurately distinguish patients with poor prognosis and had good individual risk stratification and prognostic potential. Stratified analysis based on different clinical variables indicated that the signature could be used to evaluate tumor progression in ccRCC. Moreover, we found that there were significant differences in immune cell infiltration between the low- and high-risk groups based on the signature and that ccRCC patients in the low-risk group responded better to immunotherapy than those in the high-risk group (46.59% vs 35.34%, P = 0.008 ). We also found that the expression levels of these prognostic MTGs were significantly associated with drug sensitivity in multiple ccRCC cell lines. Our study for the first time elucidates the biological function and prognostic significance of mitochondrial molecules associated with oxidative stress and provides a new protocol for evaluating treatment strategies targeting mitochondria in ccRCC patients.

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A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (Guadecitabine), in children and adults with SDH-deficient GIST, pheochromocytoma, and paraganglioma, and HLRCC-associated kidney cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.11540 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 11540-11540

Author(s):

Mary Frances Wedekind ◽

Jaydira Del Rivero ◽

Fernanda Irene Arnaldez ◽

Ramaprasad Srinivasan ◽

Melissa Spencer ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Renal Cell ◽

Phase Ii Study ◽

Krebs Cycle ◽

Dna Hypermethylation ◽

Open Label ◽

Open Label Phase ◽

Grade 3

11540 Background: Loss of activity of the Krebs cycle component succinate dehydrogenase (SDH) complex is a mechanism of tumorigenesis in SDH-deficient cancers. Accumulation of the metabolite succinate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation. Guadecitabine is a small molecule DNA methyltransferase inhibitor. We conducted a Phase II study to test the hypothesis that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Study Objectives: Our primary objective was to assess the clinical activity of guadecitabine in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Secondarily, we desired to evaluate the toxicities of patients on treatment with guadecitabine. Methods: We conducted a single site, open label, phase II study using a small optimal two-stage design to evaluate response in SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Patients >12 years of age received guadecitabine subcutaneously at 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity via imaging response was assessed utilizing RECISTv1.1. Toxicities were graded using version 4.0 of the NCI Common Toxicity Criteria. All patients were included in analysis. Results: We enrolled nine patients (6F:3M) with an age range of 18-57 years. Seven patients had SDH-deficient GIST (78%), one patient with paraganglioma (11%), and one with HLRCC-associated renal cell carcinoma (11%). No patients had a complete or partial response. Five patients came off study due to progression (56%) with one death due to disease progression in the patient with HLRCC-associated renal cell carcinoma (11%). Three patients (33%) withdrew due to lack of response with stable disease. One patient was withdrawn due to investigator’s discretion (11%). Toxicities possibly, probably, or definitely related to drug included grade 3 leukopenia (11%) febrile neutropenia (11%), grade 3-4 neutropenia (22%) requiring dose reductions, grade 3 hypertension (11%), grade 2 lung infection requiring hospitalization (11%). Conclusions: In this single site, open label, phase II study in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell cancer guadecitabine was tolerated by the majority of patients. No complete or partial responses were observed. Clinical trial information: NCT03165721 .

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Renal cell carcinoma and oxidative stress: The lack of peroxisomes

Acta Histochemica ◽

10.1016/j.acthis.2009.03.003 ◽

2010 ◽

Vol 112 (4) ◽

pp. 364-371 ◽

Cited By ~ 34

Author(s):

Wilma M. Frederiks ◽

Klazina S. Bosch ◽

Kees A. Hoeben ◽

Jan van Marle ◽

Sigrun Langbein

Keyword(s):

Oxidative Stress ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

And Oxidative Stress

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CLDN10 associated with immune infiltration is a novel prognostic biomarker for clear cell renal cell carcinoma

Epigenomics ◽

10.2217/epi-2020-0256 ◽

2020 ◽

Author(s):

Wuping Yang ◽

Lei Li ◽

Kenan Zhang ◽

Kaifang Ma ◽

Yanqing Gong ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Biomarker ◽

Clinicopathological Characteristics ◽

Dna Hypermethylation ◽

Cell Renal Cell Carcinoma ◽

Using Data ◽

Cox Analysis

Aims: To identify the clinical roles of CLDN10 in clear cell renal cell carcinoma (ccRCC). Materials & methods: Using data from TCGA-KIRC, GEO DataSets and laboratory experiments to determine the prognostic and clinicopathological characteristics of CLDN10. Results: CLDN10 expression was remarkably reduced in ccRCC. Downregulated CLDN10 was related to metastasis and poor prognosis. Multivariate Cox analysis determined that elevated CLDN10 expression was independently correlated with longer OS and DFS. Moreover, CLDN10 expression was negatively associated with the methylation levels of cg10305311 and cg16275739. CLDN10 expression was also associated with naive CD4 and memory T-cell and dendritic cell infiltration. Conclusions: Immune-related CLDN10 is an independent prognostic biomarker of ccRCC. DNA hypermethylation plays an important role in decreased CLDN10 expression.

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