Plasma extracellular vesicle long RNA profiling identifies a diagnostic signature for the detection of pancreatic ductal adenocarcinoma

Gut. 2020 Mar;69(3):540-550. doi: 10.1136/gutjnl-2019-318860. Epub 2019 Sep 27.


Objective: Pancreatic ductal adenocarcinoma (PDAC) is difficult to diagnose at resectable stage. Recent studies have suggested that extracellular vesicles (EVs) contain long RNAs. The aim of this study was to develop a diagnostic (d-)signature for the detection of PDAC based on EV long RNA (exLR) profiling.

Design: We conducted a case-control study with 501 participants, including 284 patients with PDAC, 100 patients with chronic pancreatitis (CP) and 117 healthy subjects. The exLR profile of plasma samples was analysed by exLR sequencing. The d-signature was identified using a support vector machine algorithm and a training cohort (n=188) and was validated using an internal validation cohort (n=135) and an external validation cohort (n=178).

Results: We developed a d-signature that comprised eight exLRs, including FGA, KRT19, HIST1H2BK, ITIH2, MARCH2, CLDN1, MAL2 and TIMP1, for PDAC detection. The d-signature showed high accuracy, with an area under the receiver operating characteristic curve (AUC) of 0.960, 0.950 and 0.936 in the training, internal validation and external validation cohort, respectively. The d-signature was able to identify resectable stage I/II cancer with an AUC of 0.949 in the combined three cohorts. In addition, the d-signature showed superior performance to carbohydrate antigen 19-9 in distinguishing PDAC from CP (AUC 0.931 vs 0.873, p=0.028).

Conclusion: This study is the first to characterise the plasma exLR profile in PDAC and to report an exLR signature for the detection of pancreatic cancer. This signature may improve the prognosis of patients who would have otherwise missed the curative treatment window.

Keywords: diagnosis; extracellular vesicle; long RNA; pancreatic ductal adenocarcinoma.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Alpha-Globulins / genetics
  • Area Under Curve
  • CA-19-9 Antigen / blood
  • Carcinoma, Pancreatic Ductal / blood*
  • Carcinoma, Pancreatic Ductal / diagnosis*
  • Carcinoma, Pancreatic Ductal / genetics
  • Case-Control Studies
  • Child
  • Claudin-1 / genetics
  • Extracellular Vesicles / metabolism*
  • Female
  • Fibrinogen / genetics
  • Humans
  • Keratin-19 / genetics
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Myelin and Lymphocyte-Associated Proteolipid Proteins / genetics
  • Pancreatic Neoplasms / blood*
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / genetics
  • Pancreatitis, Chronic / blood
  • RNA / blood*
  • RNA, Circular / blood
  • RNA, Long Noncoding / blood
  • RNA, Messenger / blood
  • ROC Curve
  • Sequence Analysis, RNA
  • Support Vector Machine
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Ubiquitin-Protein Ligases / genetics
  • Young Adult


  • Alpha-Globulins
  • CA-19-9 Antigen
  • CLDN1 protein, human
  • Claudin-1
  • FGA protein, human
  • KRT19 protein, human
  • Keratin-19
  • MAL2 protein, human
  • Membrane Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • RNA, Circular
  • RNA, Long Noncoding
  • RNA, Messenger
  • TIMP1 protein, human
  • Tissue Inhibitor of Metalloproteinase-1
  • inter-alpha-inhibitor
  • RNA
  • Fibrinogen
  • MARCHF2 protein, human
  • Ubiquitin-Protein Ligases