Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer

Gut. 2024 Mar 7;73(4):639-648. doi: 10.1136/gutjnl-2023-331074.

Abstract

Objective: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed.

Design: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites.

Results: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92).

Conclusion: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Keywords: METHYLATION; PANCREATIC CANCER; TUMOUR MARKERS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma* / diagnosis
  • Adenocarcinoma* / genetics
  • Adenocarcinoma* / pathology
  • Biomarkers, Tumor
  • CA-19-9 Antigen
  • Carcinoma, Pancreatic Ductal* / diagnosis
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / pathology
  • Cell-Free Nucleic Acids* / metabolism
  • DNA Methylation
  • Humans
  • Pancreas / pathology
  • Pancreatic Neoplasms* / diagnosis
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism

Substances

  • CA-19-9 Antigen
  • Biomarkers, Tumor
  • Cell-Free Nucleic Acids