Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer

Abstract

Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed hypermethylated in kidney cancer. Myopodin methylation status identified which patients showed a more aggressive clinical behavior and predicted antiangiogenic response. These observations support the clinical utility of an unmethylated myopodin as a prognostic and predictive biomarker in kidney cancer.

Synaptopodin‐2 suppresses metastasis of triple‐negative breast cancer via inhibition of YAP/TAZ activity

“…Synaptopodin-2 (SYNPO2), also known as myopodin, is actin-bundling protein, and is characterized as a putative tumour suppressor in aggressive cancers [34][35][36][37][38]. Frequent loss of expression and genetic alteration of SYNPO2 have been found, in various advanced cancers, to be correlated with high rates of clinical relapse and metastasis [35,[37][38][39][40][41]. Further studies revealed that suppression of SYNPO2 expression promoted tumour growth, migration, and invasion, thus promoting tumour metastasis [42,43].…”

MiR-376b-3p Is Associated With Long-term Response to Sunitinib in Metastatic Renal Cell Carcinoma Patients

“…Several studies have focused, so far, on non-coding RNAs as predictive biomarkers of TKIs. Excluding non-coding RNA biomarkers, differential levels of cytokines, some genetic variants, several blood-based molecules, circulating cancer cells and epigenetic patterns have been associated with response to various TKIs (9)(10)(11)(12)(13)(14)(15). It has been shown that the response to sunitinib in mRCC is associated with standard blood serum markers such as C-reactive protein (16) and proangiogenic and proinflammatory cytokine C-X-C motif chemokine ligand containing glutamic acid, leucine arginine motif (17,18).…”

Molecular mechanisms of resistance to tyrosine kinase inhibitor in clear cell renal cell carcinoma

“…128 Some studies have shown the prognostic role of DNA methylation in TKI treatment. 130,131 Tumor microenvironment factors…”

“…Overexpression of QPCT promoted sunitinib resistance through Ras/Raf/ERK signaling pathway 128 . Some studies have shown the prognostic role of DNA methylation in TKI treatment 130,131 …”