Aberrant Promoter Methylation of PCDH17 (Protocadherin 17) in Serum and its Clinical Significance in Renal Cell Carcinoma

Abstract

BackgroundCurrent studies indicated that PCDH17 functions as a tumor suppressor, which is frequently inactivated by aberrant promoter methylation in urologic tumors. The main purpose of this study was to investigate the methylation status of PCDH17 in serum and its clinical significance in renal cell carcinoma (RCC).Material/MethodsThe methylation status of PCDH17 in serum samples of 142 RCC patients and 34 controls was evaluated by methylation-specific PCR (MSP). Then we correlated PCDH17 methylation status with the clinicopathologic features of RCC patients and patient outcomes.ResultsWe found that PCDH17 was more frequently methylated in RCC patients than in controls. Moreover, PCDH17 methylation in serum was significantly correlated with advanced stage (p=0.044), higher grade (p=0.019), lymph node metastasis (p=0.008) and tumor progression (p<0.001). In addition, patients with methylated PCDH17 had shorter progression-free survival (p<0.001) and overall survival (p=0.017) than patients without, and PCDH17 methylation in serum was an independent prognostic factor for worse progression-free survival (HR: 4.215, 95% CI: 1.376–9.032, p<0.001) and overall survival (HR: 5.092, 95% CI: 1.149–12.357, p=0.046) of patients with RCC.ConclusionsThe present study indicates that PCDH17 methylation in serum is a frequent event in RCC and associated with risk factors of poor outcomes. Moreover, PCDH17 methylation in serum is a potential prognostic biomarker for patients with RCC after surgery.

Recurrent transcriptional loss of the PCDH17 tumor suppressor in laryngeal squamous cell carcinoma is partially mediated by aberrant promoter DNA methylation

“…Similar findings were published at that time for esophageal squamous cell carcinoma . Since then, numerous other studies contributed to the understanding of the tumor suppressor functionality of PCDH17 , such as the inhibition of EMT and of tumor cell migration …”

“…Concluding, our findings showing recurrent DNA hypermethylation of PCDH17 is an argument to consider its DNA methylation status as a diagnostic and prognostic biomarker in LSCC. This suggestion is further supported by recent reports where PCDH17 DNA methylation was detected in blood serum of prostate and renal cancer patients and urine sediments of bladder cancer patients . Therefore, in near future, testing for PCDH17 promoter DNA methylation along with other biomarkers in cfDNA isolated from peripheral blood could allow minimally invasive diagnostics of head and neck cancer.…”

“…19 Since then, numerous other studies contributed to the understanding of the tumor suppressor functionality of PCDH17, such as the inhibition of EMT and of tumor cell migration. [20][21][22][23] Here we further corroborate the role of PCDH17 as a tumor suppressor gene in LSCC and focus mainly on explaining the molecular mechanism responsible for the gene silencing. In line with the above cited publications on other tumor types, in our study we found recurrent DNA hypermethylation of the promoter region in 15% of LSCC primary tumors (DNA methylation level > 50 %) beside homozygous deletions of PCDH17 to be the main cause of the gene transcriptional silencing.…”

Frequent promoter methylation of HOXD10 in endometrial carcinoma and its pathological significance

“…Hypermethylation of promoters of a number of TSGs, such as EGF-containing fibulin extracellular matrix protein 1, glutathione S-transferase P1, suppressor of cytokine signaling 3, 3OST2, basic helix-loop-helix family member E22/cysteine deoxygenase 1/CUGBP Elva-like family member 4, SHP1 and transmembrane protein with EGF-like and two follistatin-like domains 2, have been studied in certain EC tissues and cell lines (such as Ishikawa and KLE) and the methylation frequency is high (26)(27)(28)(29)(30)(31). The present study investigated five TSGs (HOXD10, SHH, ZNF545, PCDH17 and MEIS1) whose promoters are reported to be hypermethylated in other malignancies but have not been evaluated for methylation in EC (32)(33)(34)(35)(36)(37)(38)(39)(40). For example, HOXD10 is hypermethylated and lowly expressed in colon adenocarcinoma cells, which downregulates the RHOC/AKT/MAPK pathway to enhance apoptosis and restrict the proliferation, migration and invasion of colon adenocarcinoma (32,33).…”

“…ZNF545 functions as a tumor suppressor in colorectal cancer and is frequently inactivated by promoter methylation (36,37). Hypermethylation of PCDH17 is correlated to poor prognosis in acute lymphoblastic leukemia (38,39). MEIS1 genes are frequently hypermethylated in different types of leukemia (40).…”