Extracellular Vesicle Analysis Allows for Identification of Invasive IPMN

Gastroenterology. 2021 Mar;160(4):1345-1358.e11. doi: 10.1053/j.gastro.2020.11.046. Epub 2020 Dec 7.

Abstract

Background and aims: Advances in cross-sectional imaging have resulted in increased detection of intraductal papillary mucinous neoplasms (IPMNs), and their management remains controversial. At present, there is no reliable noninvasive method to distinguish between indolent and high risk IPMNs. We performed extracellular vesicle (EV) analysis to identify markers of malignancy in an attempt to better stratify these lesions.

Methods: Using a novel ultrasensitive digital extracellular vesicle screening technique (DEST), we measured putative biomarkers of malignancy (MUC1, MUC2, MUC4, MUC5AC, MUC6, Das-1, STMN1, TSP1, TSP2, EGFR, EpCAM, GPC1, WNT-2, EphA2, S100A4, PSCA, MUC13, ZEB1, PLEC1, HOOK1, PTPN6, and FBN1) in EV from patient-derived cell lines and then on circulating EV obtained from peripheral blood drawn from patients with IPMNs. We enrolled a total of 133 patients in two separate cohorts: a clinical discovery cohort (n = 86) and a validation cohort (n = 47).

Results: From 16 validated EV proteins in plasma samples collected from the discovery cohort, only MUC5AC showed significantly higher levels in high-grade lesions. Of the 11 patients with invasive IPMN (inv/HG), 9 had high MUC5AC expression in plasma EV of the 11 patients with high-grade dysplasia alone, only 1 had high MUC5AC expression (sensitivity of 82%, specificity of 100%). These findings were corroborated in a separate validation cohort. The addition of MUC5AC as a biomarker to imaging and high-riskstigmata allowed detection of all cases requiring surgery, whereas imaging and high-risk stigmata alone would have missed 5 of 14 cases (36%).

Conclusions: MUC5AC in circulating EV can predict the presence of invasive carcinoma within IPMN. This approach has the potential to improve the management and follow-up of patients with IPMN including avoiding unnecessary surgery.

Keywords: Early detection; Exosome; IPMN; Pancreatic cancer; Precancer.

Publication types

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

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Biomarkers, Tumor / blood*
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Pancreatic Ductal / blood
  • Carcinoma, Pancreatic Ductal / diagnosis*
  • Carcinoma, Pancreatic Ductal / pathology
  • Diagnosis, Differential
  • Extracellular Vesicles / metabolism*
  • Female
  • Healthy Volunteers
  • Humans
  • Liquid Biopsy / methods
  • Male
  • Mice
  • Middle Aged
  • Mucin 5AC / blood
  • Mucin 5AC / metabolism
  • Neoplasm Invasiveness / pathology
  • Pancreatic Ducts / diagnostic imaging
  • Pancreatic Ducts / pathology
  • Pancreatic Intraductal Neoplasms / blood
  • Pancreatic Intraductal Neoplasms / diagnosis*
  • Pancreatic Intraductal Neoplasms / pathology
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / diagnosis*
  • Pancreatic Neoplasms / pathology
  • Proof of Concept Study
  • Xenograft Model Antitumor Assays

Substances

  • Biomarkers, Tumor
  • MUC5AC protein, human
  • Mucin 5AC