title: Global 5-Hydroxymethylcytosine Levels Are Profoundly Reduced in Multiple Genitourinary Malignancies.
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.
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Enrico
authors.initials: E
authors.lastname: Munari
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Department of Scientific Research, Norte University; Centro para el Desarrollo de la Investigación Científica (CEDIC) Asunción, Asunción, Paraguay.
authors.forename: Alcides
authors.initials: A
authors.lastname: Chaux
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Ajay M
authors.initials: AM
authors.lastname: Vaghasia
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Department of Pathology, Isfahan University of Medical Sciences, Isfahan Kidney Diseases Research Center, Isfahan, Iran.
authors.forename: Diana
authors.initials: D
authors.lastname: Taheri
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Karram
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Stephania M
authors.initials: SM
authors.lastname: Bezerra
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Nilda
authors.initials: N
authors.lastname: Gonzalez Roibon
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: William G
authors.initials: WG
authors.lastname: Nelson
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Yegnasubramanian
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, 21231, United States of America.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Haffner
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D014565:Urogenital Neoplasms / Q000235:genetics*
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine