High methylation levels of PCDH10 predict poor prognosis in patients with pancreatic ductal adenocarcinoma

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is not a clinically homogeneous disease, but subsets of patients with distinct prognosis and response to therapy can be identified by genome-wide analyses. Mutations in major PDAC driver genes were associated with poor survival. By bioinformatics analysis, we identified protocadherins among the most frequently mutated genes in PDAC suggesting an important role of these genes in the biology of this tumor. Promoter methylation of protocadherins has been suggested as a prognostic marker in different tumors, but in PDAC this epigenetic modification has not been extensively studied. Thus, we evaluated whether promoter methylation of three frequently mutated protocadherins, PCDHAC2, PCDHGC5 and PCDH10 could be used as survival predictors in PDAC patients. Methods DNA extracted from 23 PDACs and adjacent non-neoplastic pancreatic tissues were bisulfite treated. Combined Bisulfite Restriction Analysis (COBRA) coupled to denaturing high-performance liquid chromatography (dHPLC) detection and bisulfite genomic sequencing (BGS) were used to determine the presence of methylated CpG dinucleotides in the promoter amplicons analyzed. Results In an exploratory analysis, two protocadherins showed the same pattern of CpG methylation in PDAC and adjacent non-neoplastic pancreatic tissues: lack of methylation for PCDHAC2 , complete methylation for PCDHGC5 . Conversely, the third protocadherin analyzed, PCDH10 , showed a variable degree of CpG methylation in PDAC and absence of methylation in adjacent non-neoplastic pancreatic tissues. At Kaplan–Meier analysis, high levels of PCDH10 methylation defined according to the receiver operating characteristic (ROC) curve analysis were significantly associated with worse progression-free survival (PFS) rates ( P = 0.008), but not with overall survival (OS). High levels of PCDH10 methylation were a prognostic factor influencing PFS (HR = 4.0: 95% CI, 1.3–12.3; P = 0.016), but not the OS. Conclusions In this study, we show for the first time that the methylation status of PCDH10 can predict prognosis in PDAC patients with a significant impact on the outcome in terms of progression-free survival. High levels of PCDH10 promoter methylation could be useful to identify patients at high risk of disease progression, contributing to a more accurate stratification of PDAC patients for personalized clinical management.

Calcium Signaling Alterations Caused by Epigenetic Mechanisms in Pancreatic Cancer: From Early Markers to Prognostic Impact

“…Later, this tumor suppressor gene was investigated in other PDAC cell lines and, as expected, the PCDH10 promoter methylation again correlated with reduced protein expression. This study also showed high methylation levels in clinical samples ( n = 23), and the presence of this methylation pattern was associated with reduced progression-free survival [ 44 ]. Using the TCGA data, Mishra et al analyzed a genome-wide DNA methylation profile, and although the genes of the Ca 2+ signaling pathway occupied the fourth position in the functional enrichment of differentially methylated probes, this finding was not further explored [ 11 ].…”

A novel sensitive detection method for DNA methylation in circulating free DNA of pancreatic cancer

“…Dysregulation of HOX genes is associated with cancer and are often methylated in many cancer types, as well as in pancreatic cancer [37]. PCDH10, a member of the protocadherin family, is frequently mutated in pancreatic cancer [38]; it is known as a tumor suppressor and is often silenced by DNA methylation in many types of cancer [39] [40]. Semaphorin signaling seems to play an important role in the development of pancreatic cancer, with a high frequency of mutations in SEMA3A and SEMA3B [41].…”

A novel methylation signature predicts inferior outcome of patients with PDAC

“…Experimental evidence shows that the methylation status of PCDH10 can predict the prognosis of patients with PDAC and has a significant effect on progression-free survival. High levels of PCDH10 promoter methylation may help to identify patients at high risk of disease progression and more accurately stratify patients with PDAC for personalized clinical management [ 22 ]. Patients with hypomethylated MUC1 and MUC4 have lower OS and thus these are potential prognostic biomarkers of PDAC [ 23 ].…”