Abstract
Solid tumors are characterized by a plethora of epigenetic changes. In particular, patterns methylation of cytosines at the 5-position (5mC) in the context of CpGs are frequently altered in tumors. Recent evidence suggests that 5mC can get converted to 5-hydroxylmethylcytosine (5hmC) in an enzymatic process involving ten eleven translocation (TET) protein family members, and this process appears to be important in facilitating plasticity of cytosine methylation. Here we evaluated the global levels of 5hmC using a validated immunohistochemical staining method in a large series of clear cell renal cell carcinoma (n = 111), urothelial cell carcinoma (n = 55) and testicular germ cell tumors (n = 84) and matched adjacent benign tissues. Whereas tumor-adjacent benign tissues were mostly characterized by high levels of 5hmC, renal cell carcinoma and urothelial cell carcinoma showed dramatically reduced staining for 5hmC. 5hmC levels were low in both primary tumors and metastases of clear cell renal cell carcinoma and showed no association with disease outcomes. In normal testis, robust 5hmC staining was only observed in stroma and Sertoli cells. Seminoma showed greatly reduced 5hmC immunolabeling, whereas differentiated teratoma, embryonal and yolk sack tumors exhibited high 5hmC levels. The substantial tumor specific loss of 5hmC, particularly in clear cell renal cell carcinoma and urothelial cell carcinoma, suggests that alterations in pathways involved in establishing and maintaining 5hmC levels might be very common in cancer and could potentially be exploited for diagnosis and treatment.
Highlights
Epigenetic alterations are amongst the most common changes in human malignancies. [1,2,3,4] In particular changes in the pattern of cytosine methylation have been extensively studied in numerous cancer types and show favorable properties as disease biomarkers. [1,4,5]PLOS ONE | DOI:10.1371/journal.pone.0146302 January 19, 20165-Hydroxymethylcytosine in Genitourinary Malignancies pending, “5-HYDROXYMETHYLCYTOSINE IN HUMAN CANCER”, United States Patent Application number: 13/956,879)
In many solid tumors, the global levels of 5mC show a decrease whereas methylation marks are gained in particular sites of the genome establishing stable and heritable alterations that can contribute to cancer progression. [2,3] Despite the stability of these marks, there is evidence for ongoing epigenetic plasticity and clonal selection in solid tumors. [6,7,8] A intriguing potential mechanism for dynamic alterations in the 5mC genomic content is the oxidation of 5mC to 5-hydroxymethylcytosine (5hmC). 5hmC was first characterized in bacteriophages and was later detected in mammalian genomes
[9] More recently, the observation that 5mC can become oxidized in a highly directed manner to 5hmC by the ten eleven translocation protein family (TET1-3) has spurred increased interest in 5hmC biology. [10,11,12,13] Importantly, it was shown that 5hmC can be further metabolized by TET enzymes to 5-formylcytosine and 5-carboxycytosine, which can subsequently be removed from the genome by base excision repair or decarboxylation. [14,15] on one hand the oxidation of 5mC to 5hmC represents an intriguing pathway for epigenetic plasticity
Summary
5-Hydroxymethylcytosine in Genitourinary Malignancies pending, “5-HYDROXYMETHYLCYTOSINE IN HUMAN CANCER”, United States Patent Application number: 13/956,879). This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. In many solid tumors, the global levels of 5mC show a decrease whereas methylation marks are gained in particular sites of the genome establishing stable and heritable alterations that can contribute to cancer progression. The potential signal transduction mechanisms of 5hmC have not been fully elucidated; distribution pattern of 5hmC in mammalian genomes suggest a role of 5hmC for transcriptional regulation, since 5hmC marks have been shown to be most prevalent at upstream regulatory gene regions. The potential signal transduction mechanisms of 5hmC have not been fully elucidated; distribution pattern of 5hmC in mammalian genomes suggest a role of 5hmC for transcriptional regulation, since 5hmC marks have been shown to be most prevalent at upstream regulatory gene regions. [12,16,17]
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