Methylation of PCDH17 and NEFH as prognostic biomarker for nonmetastatic RCC: A cohort study

Abstract

DNA methylation makes up a main part of the molecular mechanism of cancer evolution and has shown promising results in the prognosis of renal cell cancer (RCC). In this study, we investigated the possible association of promoter methylation of PCDH17, NEFH, RASSF1A, and FHIT, genes with the prognosis of nonmetastatic RCC patients. Cancerous and normal adjacent tissues from surgical specimens of 41 patients with long follow-up were treated for DNA isolation and bisulfite conversion. The gene promoter methylation was determined with quantitative methylation-specific PCR (qMSP). Wilcoxon signed-rank test was used for paired methylation comparisons, while univariate linear regression and Mann-Whitney test were applied for associating methylation status with clinical and disease characteristics. Cox regression proportional hazards models and Kaplan-Meier plots were used for survival analyses in reference to methylation status. Paired comparisons showed tissue-specific hypermethylation for PCDH17 (P < .001), NEFH (P < .001), RASSF1A (P = .032), while a positive association of methylation in normal tissues with age was demonstrated for PCDH17 (P < .001), RASSF1A (P < .001), FHIT (P < .001). PCDH17 was more methylated in cases with clear cell RCC (P = .015) and high-grade tumor (P = .013), while NEFH methylation was higher in locally advanced cases (P = .032). PCDH17 hypermethylation in cancerous and normal tissues was linked to shorter disease-specific survival (DSS, P = .026, P = .004), disease-free survival (DFS, P = .004, P = .019) while NEFH hypermethylation in cancerous tissues was related to shorter DSS (P = .032). Increased methylation difference of NEFH was also associated with shorter DSS (P = .041) and DFS (P = .020), while the corresponding parameter for PCDH17 was associated with poor DFS (P = .014). Kaplan-Meier curves for hypermethylation in cancer tissues demonstrated different clinical courses for PCDH17 (P = .017), NEFH (P = .023) regarding DSS, and PCDH17 (P = .001) regarding DFS. Our study not only highlights the prognostic value of promoter methylation of PCDH17 and NEFH in cancer tissues but also is the first report of the prognostic value of methylation alterations in normal tissues. Our findings are the first report of the prognostic value of methylation alterations in normal tissues, which can contribute to improved assessment of recurrence risk.

Ubiquitin ligase NEDD4 promotes the proliferation of hepatocellular carcinoma cells through targeting PCDH17 protein for ubiquitination and degradation

“…Although some studies have been performed to investigate the regulation of PCDH17, the mechanisms by which PCDH17 acts as a tumor suppressor in certain types of human cancers have not been fully elucidated. It has been reported that many factors can contribute to low PCDH17 expression, such as noncoding RNA, acetylation modification, and methylation modification ( 22 , 23 , 24 ). However, whether there are other regulatory mechanisms for the abnormal expression of PCDH17 still needs to be further revealed.…”

“…Multiple studies have shown that PCDH17 is downregulated and loss of PCDH17 can promote the proliferation and metastasis of tumor cells, such as gastric cancer, colorectal cancer, breast cancer, and HCC ( 19 , 20 , 21 ), thus it could be served as a biomarker in several human cancers. In addition, it has been reported that many factors can contribute to low PCDH17 expression, such as noncoding RNA ( 22 ), acetylation modification ( 23 ), and methylation modification ( 24 ); however, the regulatory mechanism of its posttranslational, such as ubiquitination, is still unclear.…”

PBRM1 mutation and WDR72 expression as potential combinatorial biomarker for predicting the response to Nivolumab in patients with ccRCC: a tumor marker prognostic study

“…Shenoy et al reviewed that the methylation degree in the promoter region of various tumor suppressor genes in ccRCC tumor tissues is higher than that in normal tissues [45]. It was also reported that hypermethylation in promoter region of several tumor suppression genes, such as PCDH17, NEFH, GREM1, GATA5, LAD1, NEFH, NEURL and SFRP1, was associated with poor survival of ccRCC patients [46][47][48]. In the present study, we found that the patients with hypomethylation of two sites in WDR72 promoter region had remarkably improved survival, which provides a potential target for the treatment of ccRCC.…”

Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications

“…Koudonas et al [7] demonstrated that hypermethylation of the TSGs PCDH17, NEFH, and RASSF1A in resected renal cell carcinoma compared to normal tissue was associated with worse survival outcomes. A 2020 study of paired tumor tissue samples and matched healthy control tissue from patients with prostate cancer identified 7500 differentially methylated regions (DMRs).…”