ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Kidney cancer is characterized by aberrant methylation of tissue-specific enhancers that are prognostic for overall survival.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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47 citing papers in PubMed, 71 citations in OpenAlex.
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- Super-enhancer DNA methylation in cancer: the mechanism of action and therapeutic directions.Frontiers in oncology · 2025Review
- Temperature-Wise Calibration Increases the Accuracy of DNA Methylation Levels Determined by High-Resolution Melting (HRM).International journal of molecular sciences · 2024Article
- Multimodal analysis of genome-wide methylation, copy number aberrations, and end motif signatures enhances detection of early-stage breast cancer.Frontiers in oncology · 2023Article
- JUND Promotes Tumorigenesis via Specifically Binding on Enhancers of Multiple Oncogenes in Cervical Cancer.OncoTargets and therapy · 2023Article
- Renal Cell Cancer and Obesity.International journal of molecular sciences · 2022Review
- Clinical significance of novel DNA methylation biomarkers for renal clear cell carcinoma.Journal of cancer research and clinical oncology · 2022Article
- Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- PBRM1 loss in kidney cancer unbalances the proximal tubule master transcription factor hub to repress proximal tubule differentiation.Cell reports · 2021Article
- The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.Annual review of cancer biology · 2021Article
- Association of variably methylated tumour DNA regions with overall survival for invasive lobular breast cancer.Clinical epigenetics · 2021Article
- Identification of DNA methylation signatures associated with poor outcome in lower-risk Stage, Size, Grade and Necrosis (SSIGN) score clear cell renal cell cancer.Clinical epigenetics · 2021Article
- NCI 6896: a phase I trial of vorinostat (SAHA) and isotretinoin (13-cis retinoic acid) in the treatment of patients with advanced renal cell carcinoma.Investigational new drugs · 2020Article
- Oncometabolites in renal cancer.Nature reviews. Nephrology · 2020Review
- Restoring the epigenetically silenced PCK2 suppresses renal cell carcinoma progression and increases sensitivity to sunitinib by promoting endoplasmic reticulum stress.Theranostics · 2020Article
- Perturbing Enhancer Activity in Cancer Therapy.Cancers · 2019Review
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Authors and funding
19 authors at 2 institutions in 1 country.
Funding
Abstract
purposeEven though recent studies have shown that genetic changes at enhancers can influence carcinogenesis, most methylomic studies have focused on changes at promoters. We used renal cell carcinoma (RCC), an incurable malignancy associated with mutations in epigenetic regulators, as a model to study genome-wide patterns of DNA methylation at a high resolution. EXPERIMENTAL
designAnalysis of cytosine methylation status of 1.3 million CpGs was determined by the HELP assay in RCC and healthy microdissected renal tubular controls.
resultsWe observed that the RCC samples were characterized by widespread hypermethylation that preferentially affected gene bodies. Aberrant methylation was particularly enriched in kidney-specific enhancer regions associated with H3K4Me1 marks. Various important underexpressed genes, such as SMAD6, were associated with aberrantly methylated, intronic enhancers, and these changes were validated in an independent cohort. MOTIF analysis of aberrantly hypermethylated regions revealed enrichment for binding sites of AP2a, AHR, HAIRY, ARNT, and HIF1 transcription factors, reflecting contributions of dysregulated hypoxia signaling pathways in RCC. The functional importance of this aberrant hypermethylation was demonstrated by selective sensitivity of RCC cells to low levels of decitabine. Most importantly, methylation of enhancers was predictive of adverse prognosis in 405 cases of RCC in multivariate analysis. In addition, parallel copy-number analysis from MspI representations demonstrated novel copy-number variations that were validated in an independent cohort of patients.
conclusionsOur study is the first high-resolution methylome analysis of RCC, demonstrates that many kidney-specific enhancers are targeted by aberrant hypermethylation, and reveals the prognostic importance of these epigenetic changes in an independent cohort.
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