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J Clin Med. 2018 Sep 20;7(10). pii: E295. doi: 10.3390/jcm7100295.

The Combination of MiRNA-196b, LCN2, and TIMP1 is a Potential Set of Circulating Biomarkers for Screening Individuals at Risk for Familial Pancreatic Cancer.

Author information

1
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. bartsch@med.uni-marburg.de.
2
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. gercken@staff.uni-marburg.de.
3
Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Faculty of Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377 Munich, Germany. strauch@helmholtz-muenchen.de.
4
Institute of Genetic Epidemiology, Helmholtz Zentrum München⁻German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. strauch@helmholtz-muenchen.de.
5
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. RonjaWieboldt@web.de.
6
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Elvira.Matthaei@med.uni-marburg.de.
7
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. vinona.wagner@dkfz.de.
8
Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Faculty of Medicine, Ludwig-Maximilians-Universität, Marchioninistr. 15, D-81377 Munich, Germany. susanne.rospleszcz@helmholtz-muenchen.de.
9
Institute of Genetic Epidemiology, Helmholtz Zentrum München⁻German Research Center for Environmental Health, Ingolstädter Landstr. 1, D-85764 Neuherberg, Germany. susanne.rospleszcz@helmholtz-muenchen.de.
10
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Agnes.95@web.de.
11
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Frederike.Franke@uksh.de.
12
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Ioannis.Mintziras@uk-gm.de.
13
Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. christian.bauer@med.uni-marburg.de.
14
Department of Gastroenterology, Endocrinology and Metabolism, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. tobias.grote@med.uni-marburg.de.
15
Department of Diagnostic and Interventional Radiology, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. figiel@med.uni-marburg.de.
16
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. difazio@med.uni-marburg.de.
17
Department of Hematology, Oncology and Immunology, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. Andreas.Burchert@med.uni-marburg.de.
18
Center for Tumor and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, D-35043 Marburg, Germany. silke.reinartz@staff.uni-marburg.de.
19
Center for Tumor and Immune Biology, Philipps University Marburg, Hans-Meerwein-Str. 3, D-35043 Marburg, Germany. poggevon@staff.uni-marburg.de.
20
Department of Pathology, Technical University Munich, Trogerstr. 18, D-81675 Munich, Germany. guenter.kloeppel@tum.de.
21
Department of Visceral, Thoracic and Vascular Surgery, Philipps University Marburg, Baldingerstrasse, D-35043 Marburg, Germany. slater@med.uni-marburg.de.

Abstract

Individuals at risk (IAR) of familial pancreatic cancer (FPC) are good candidates for screening. Unfortunately, neither reliable imaging modalities nor biomarkers are available to detect high-grade precursor lesions or early cancer. Circulating levels of candidate biomarkers LCN2, TIMP1, Glypican-1, RNU2-1f, and miRNA-196b were analyzed in 218 individuals with sporadic pancreatic ductal adenocarcinoma (PDAC, n = 50), FPC (n = 20), chronic pancreatitis (n = 10), IAR with relevant precursor lesions (n = 11) or non-relevant lesions (n = 5), 20 controls, and IAR with (n = 51) or without (n = 51) lesions on pancreatic imaging. In addition, corresponding duodenal juice samples were analyzed for Glypican-1 (n = 144) enrichment and KRAS mutations (n = 123). The panel miR-196b/LCN2/TIMP1 could distinguish high-grade lesions and stage I PDAC from controls with absolute specificity and sensitivity. In contrast, Glypican-1 enrichment in serum exosomes and duodenal juice was not diagnostic. KRAS mutations in duodenal juice were detected in 9 of 12 patients with PDAC and only 4 of 9 IAR with relevant precursor lesions. IAR with lesions on imaging had elevated miR-196b/LCN2/TIMP1 levels (p = 0.0007) and KRAS mutations in duodenal juice (p = 0.0004) significantly more often than IAR without imaging lesions. The combination miR-196b/LCN2/TIMP1 might be a promising biomarker set for the detection of high-grade PDAC precursor lesions in IAR of FPC families.

KEYWORDS:

Glypican-1; KRAS mutation; LCN2/NGAL; TIMP1; miRNA-196b; pancreatic ductal adenocarcinoma

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