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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.

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