Discovery of myopodin methylation in bladder cancer.
Myopodin is an actin-binding protein that shuttles between the nucleus and the cytoplasm. After identifying an enriched CpG island encompassing the transcription site of myopodin, we aimed at evaluating the potential relevance of myopodin methylation in bladder cancer. The epigenetic silencing of myopodin by hypermethylation was tested in bladder cancer cells (n=12) before and after azacytidine treatment. Myopodin hypermethylation was associated with gene expression, being increased in vitro by this demethylating agent. The methylation status of myopodin promoter was then evaluated by methylation-specific polymerase chain reaction (MS-PCR) analyses. Myopodin was revealed to be frequently methylated in a large series of 466 bladder tumours (68.7%). Myopodin methylation was significantly associated with tumour stage (p<0.0005) and tumour grade (p=0.037). Myopodin expression patterns were analysed by immunohistochemistry on tissue arrays containing bladder tumours for which myopodin methylation was assessed (n=177). The presence of low nuclear myopodin expression alone (p = 0.031) or combined with myopodin methylation (p=0.008) was associated with poor survival. Moreover, myopodin methylation in 164 urinary specimens distinguished patients with bladder cancer from controls with a sensitivity of 65.0%, a specificity of 79.8%, and a global accuracy of 75.3%. Thus, myopodin was identified to be epigenetically modified in bladder cancer. The association of myopodin methylation and nuclear expression patterns with cancer progression and clinical outcome, together with its ability to detect bladder cancer patients using urinary specimens, suggests the utility of incorporating myopodin methylation assessment in the clinical management of patients affected by uroepithelial neoplasias.
Cebrian
V
V
Tumor Markers Group, Molecular Pathology Program, Spanish National Cancer Center, Madrid, Spain.
Alvarez
M
M
Aleman
A
A
Palou
J
J
Bellmunt
J
J
Gonzalez-Peramato
P
P
Cordón-Cardo
C
C
García
J
J
Piulats
J M
JM
Sánchez-Carbayo
M
M
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008745:Methylation; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D046888:Tissue Array Analysis / Q000379:methods; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; D008840:Microfilament Proteins; C503979:SYNPO2 protein, human