Tissue methylated DNA markers for sporadic pancreatic cancer are strongly associated with familial and genetically predisposed pancreatic cancer

Abstract

High-risk individuals (HRIs) with familial and genetic predisposition to pancreatic ductal adenocarcinoma (PDAC) are eligible for screening. There is no accurate biomarker for detecting early-stage PDAC. We previously demonstrated that a panel of methylated DNA markers (MDMs) accurately detect sporadic PDAC. In this study we compared the distribution of MDMs in DNA extracted from tissue of PDAC cases who carry germline mutations and non-carriers with family history, with control tissue and demonstrate high discrimination like that seen in sporadic PDAC. These results provide scientific rationale for examining plasma MDMs in HRIs with the goal of developing a minimally-invasive early detection test.

Keywords: Biomarker; DNA methylation; Pancreatic cancer.

Fig. 1.

Left: Case and control tissue distribution in the study groups (Sporadic, Family History and Mutation) with overlapping area indicating paired case and control tissue availability with adequate DNA recovery. Right: Composite principal components analysis (PCA) score comparing sporadic, familial, and mutation-positive pancreatic ductal adenocarcinoma (PDAC) case groups to distant normal pancreatic tissue.

Fig. 2.

Comparative AUCs for discrimination of pancreatic ductal adenocarcinoma (PDAC) from control tissue using the PCA score derived from the methylated DNA marker panel assayed on tissue-extracted DNA from cases and controls from three PDAC groups-sporadic, familial (FamHx) and in those harboring a pathogenic germline mutation (Mutation).