A bile-based microRNA signature for differentiating malignant from benign pancreaticobiliary disease

Mireia Mato Prado; Jisce R Puik; Leandro Castellano; Elena López-Jiménez; Daniel S K Liu; Laura L Meijer; Tessa Y S Le Large; Eleanor Rees; Niccola Funel; Shivan Sivakumar; Stephen P Pereira; Geert Kazemier; Babs M Zonderhuis; Joris I Erdmann; Rutger-Jan Swijnenburg; Andrea Frilling; Long R Jiao; Justin Stebbing; Elisa Giovannetti; Jonathan Krell; Adam E Frampton

doi:10.1186/s40164-023-00458-3

A bile-based microRNA signature for differentiating malignant from benign pancreaticobiliary disease

Exp Hematol Oncol. 2023 Dec 1;12(1):101. doi: 10.1186/s40164-023-00458-3.

Authors

Mireia Mato Prado^#^{1

2}, Jisce R Puik^#^{3

4}, Leandro Castellano^{1

5}, Elena López-Jiménez¹, Daniel S K Liu¹, Laura L Meijer^{3

4}, Tessa Y S Le Large^{3

4}, Eleanor Rees¹, Niccola Funel⁶, Shivan Sivakumar⁷, Stephen P Pereira⁸, Geert Kazemier^{3

4}, Babs M Zonderhuis^{3

4}, Joris I Erdmann^{3

4}, Rutger-Jan Swijnenburg^{3

4}, Andrea Frilling⁹, Long R Jiao⁹, Justin Stebbing^{1

10}, Elisa Giovannetti^{11

12}, Jonathan Krell^#¹³, Adam E Frampton^#^{14

15

16

17}

Affiliations

¹ Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, UK.
² UK Dementia Research Institute, Institute of Neurology, University College London, London, UK.
³ Department of Surgery, Amsterdam UMC Location Vrije Universiteit Amsterdam, De Boelelaan 1117, Amsterdam, The Netherlands.
⁴ Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
⁵ School of Life Sciences, University of Sussex, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK.
⁶ Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
⁷ Oncology Department and Institute of Immunology and Immunotherapy, Birmingham Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
⁸ Institute for Liver & Digestive Health, Royal Free Hospital Campus, University College London, London, UK.
⁹ HPB Surgical Unit, Department of Surgery & Cancer, Imperial College London, London, UK.
¹⁰ Department of Biomedical Sciences, Anglia Ruskin University, Cambridge, UK.
¹¹ Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands. elisa.giovannetti@gmail.com.
¹² Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, Pisa, Italy. elisa.giovannetti@gmail.com.
¹³ Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, UK. j.krell@imperial.ac.uk.
¹⁴ Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, UK. adam.frampton@surrey.ac.uk.
¹⁵ HPB Surgical Unit, Department of Surgery & Cancer, Imperial College London, London, UK. adam.frampton@surrey.ac.uk.
¹⁶ HPB Surgical Unit, Royal Surrey NHS Foundation Trust, Guildford, Surrey, UK. adam.frampton@surrey.ac.uk.
¹⁷ Section of Oncology, Dept. of Clinical & Experimental Medicine, FHMS, University of Surrey, Guildford, UK. adam.frampton@surrey.ac.uk.

^# Contributed equally.

Abstract

Differentiating between pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) is crucial for the appropriate course of treatment, especially with advancements in the role of neoadjuvant chemotherapies for PDAC, compared to CCA. Furthermore, benign pancreaticobiliary diseases can mimic malignant disease, and indeterminate lesions may require repeated investigations to achieve a diagnosis. As bile flows in close proximity to these lesions, we aimed to establish a bile-based microRNA (miRNA) signature to discriminate between malignant and benign pancreaticobiliary diseases. We performed miRNA discovery by global profiling of 800 miRNAs using the NanoString nCounter platform in prospectively collected bile samples from malignant (n = 43) and benign (n = 14) pancreaticobiliary disease. Differentially expressed miRNAs were validated by RT-qPCR and further assessed in an independent validation cohort of bile from malignant (n = 37) and benign (n = 38) pancreaticobiliary disease. MiR-148a-3p was identified as a discriminatory marker that effectively distinguished malignant from benign pancreaticobiliary disease in the discovery cohort (AUC = 0.797 [95% CI 0.68-0.92]), the validation cohort (AUC = 0.772 [95% CI 0.66-0.88]), and in the combined cohorts (AUC = 0.752 [95% CI 0.67-0.84]). We also established a two-miRNA signature (miR-125b-5p and miR-194-5p) that distinguished PDAC from CCA (validation: AUC = 0.815 [95% CI 0.67-0.96]; and combined cohorts: AUC = 0.814 [95% CI 0.70-0.93]). Our research stands as the largest, multicentric, global profiling study of miRNAs in the bile from patients with pancreaticobiliary disease. We demonstrated their potential as clinically useful diagnostic tools for the detection and differentiation of malignant pancreaticobiliary disease. These bile miRNA biomarkers could be developed to complement current approaches for diagnosing pancreaticobiliary cancers.

Keywords: Bile; Biliary stricture; Biomarker; Cholangiocarcinoma; Pancreatic ductal adenocarcinoma; microRNA.

Publication types

Letter

Abstract

Publication types

Grants and funding