Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognostication.
Renal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC). We found that the expression levels of 3 genes--SMYD2, SETD3, and NO66--was significantly altered in a set of RCTs, which was further validated in a large independent cohort. Higher expression levels were found in RCTs compared to normal renal tissues (RNTs) and in chRCCs comparatively to oncocytomas. SMYD2 and SETD3 mRNA levels correlated with protein expression assessed by immunohistochemistry. SMYD2 transcript levels discriminated RCTs from RNT, with 82.1% sensitivity and 100% specificity [area under curve (AUC) = 0.959], and distinguished chRCCs from oncocytomas, with 71.0% sensitivity and 73.3% specificity (AUC = 0.784). Low expression levels of SMYD2, SETD3, and NO66 were significantly associated with shorter disease-specific and disease-free survival, especially in patients with non-organ confined tumors. We conclude that expression of selected HMTs and HDMs might constitute novel biomarkers to assist in RCT diagnosis and assessment of tumor aggressiveness.
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.|b Department of Pathology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Ana Sílvia
AS
Pires-Luís
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.|b Department of Pathology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Márcia
M
Vieira-Coimbra
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.|c School of Allied Health Sciences (ESTSP); Polytechnic of Porto ; Porto , Portugal.
Filipa Quintela
FQ
Vieira
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Pedro
P
Costa-Pinheiro
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Rui
R
Silva-Santos
b Department of Pathology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Paula C
PC
Dias
d Department of Epidemiology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Luís
L
Antunes
e Department of Urology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Francisco
F
Lobo
e Department of Urology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.
Jorge
J
Oliveira
f Life and Health Sciences Research Institute (ICVS); School of Health Sciences; University of Minho ; Braga , Portugal.|g ICVS/3B's - PT Government Associate Laboratory; University of Minho; Braga/Guimarães ; Portugal.
Céline S
CS
Gonçalves
f Life and Health Sciences Research Institute (ICVS); School of Health Sciences; University of Minho ; Braga , Portugal.|g ICVS/3B's - PT Government Associate Laboratory; University of Minho; Braga/Guimarães ; Portugal.
Bruno M
BM
Costa
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.|b Department of Pathology ; Portuguese Oncology Institute - Porto ; Porto , Portugal.|h Department of Pathology and Molecular Immunology ; Institute of Biomedical Sciences Abel Salazar (ICBAS) - University of Porto ; Porto , Portugal.
Rui
R
Henrique
a Cancer Biology and Epigenetics Group - Research Center; Portuguese Oncology Institute - Porto ; Porto , Portugal.|h Department of Pathology and Molecular Immunology ; Institute of Biomedical Sciences Abel Salazar (ICBAS) - University of Porto ; Porto , Portugal.
Carmen
C
Jerónimo
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D003937:Diagnosis, Differential; D049308:Dioxygenases; D055088:Early Detection of Cancer; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics* / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D049308:Dioxygenases; D056466:Histone Demethylases; C492859:RIOX1 protein, human; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C584641:SETD3 protein, human; C512569:SMYD2 protein, human
NO66; Renal cell tumors; SETD3; SMYD2; epigenetic biomarkers; histone covalent modifications; histone methyltransferases