Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC

Purpose: Expediting the diagnosis of pancreatic ductal adenocarcinoma (PDAC) would benefit care management, especially for the start of treatments requiring histological evidence. This study evaluated the combined diagnostic performance of circulating biomarkers obtained by peripheral and portal blood liquid biopsy in patients with resectable PDAC. Experimental design: Liquid biopsies were performed in a prospective translational clinical trial (PANC-CTC #NCT03032913) including 22 patients with resectable PDAC and 28 noncancer controls from February to November 2017. Circulating tumor cells (CTCs) were detected using the CellSearch® method or after RosetteSep® enrichment combined with CRISPR/Cas9-improved KRAS mutant alleles quantification by droplet digital PCR. CD63 bead-coupled Glypican-1 (GPC1)-positive exosomes were quantified by flow cytometry. Results: Liquid biopsies were positive in 7/22 (32%), 13/22 (59%), and 14/22 (64%) patients with CellSearch® or RosetteSep®-based CTC detection or GPC1-positive exosomes, respectively, in peripheral and/or portal blood. Liquid biopsy performance was improved in portal blood only with CellSearch®, reaching 45% of PDAC identification (5/11) versus 10% (2/22) in peripheral blood. Importantly, combining CTC and GPC1-positive-exosome detection displayed 100% of sensitivity and 80% of specificity, with a negative predictive value of 100%. High levels of GPC1+-exosomes and/or CTC presence were significantly correlated with progression-free survival and with overall survival when CTC clusters were found. Conclusion: This study is the first to evaluate combined CTC and exosome detection to diagnose resectable pancreatic cancers. Liquid biopsy combining several biomarkers could provide a rapid, reliable, noninvasive decision-making tool in early, potentially curable pancreatic cancer. Moreover, the prognostic value could select patients eligible for neoadjuvant treatment before surgery. This exploratory study deserves further validation.

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Mo1344 DEVELOPMENT OF A NOVEL CIRCULAR RNA-BASED, NONINVASIVE LIQUID BIOPSY ASSAY FOR THE EARLY DETECTION OF PANCREATIC DUCTAL ADENOCARCINOMA

Gastroenterology ◽

10.1016/s0016-5085(20)32821-3 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-857

Author(s):

SOUVIK GHATAK ◽

Satoshi Nishiwada ◽

Eunsung Jun ◽

Fuminori Sonohara ◽

Yasuhiro Kodera ◽

...

Keyword(s):

Early Detection ◽

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Circular Rna ◽

Ductal Adenocarcinoma

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MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions

Clinical Chemistry ◽

10.1373/clinchem.2009.137364 ◽

2010 ◽

Vol 56 (4) ◽

pp. 603-612 ◽

Cited By ~ 142

Author(s):

Maël Chalret du Rieu ◽

Jérôme Torrisani ◽

Janick Selves ◽

Talal Al Saati ◽

Anny Souque ◽

...

Keyword(s):

Early Detection ◽

Mouse Model ◽

Pancreatic Ductal Adenocarcinoma ◽

Early Stage ◽

Survival Rates ◽

Ductal Adenocarcinoma ◽

Early Event ◽

Precursor Lesions ◽

Tissue Samples ◽

Ductal Cells

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. Methods: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. Results: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. Conclusions: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.

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Sa1361 – Utility of Liquid Biopsy Using Urine in Patients with Pancreatic Ductal Adenocarcinoma

Gastroenterology ◽

10.1016/s0016-5085(19)37648-6 ◽

2019 ◽

Vol 156 (6) ◽

pp. S-326-S-327

Author(s):

Hiroyuki Terasawa ◽

Hideaki Kinugasa ◽

Kazuhiro Nouso ◽

Soichiro Ako ◽

Mami Hirai ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma

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Utility of liquid biopsy using urine in patients with pancreatic ductal adenocarcinoma

Cancer Biology & Therapy ◽

10.1080/15384047.2019.1638685 ◽

2019 ◽

Vol 20 (10) ◽

pp. 1348-1353 ◽

Cited By ~ 1

Author(s):

Hiroyuki Terasawa ◽

Hideaki Kinugasa ◽

Soichiro Ako ◽

Mami Hirai ◽

Hiroshi Matsushita ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma

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P-212 The genetic and epigenetic abnormalities of plasma cfDNA as liquid biopsy biomarkers for diagnosis and prognosis stratification of pancreatic ductal adenocarcinoma

Annals of Oncology ◽

10.1016/j.annonc.2021.05.266 ◽

2021 ◽

Vol 32 ◽

pp. S171

Author(s):

Y. Wang ◽

R. Jiang ◽

S. Xiao ◽

Y. Shi ◽

J. Zheng ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma ◽

Diagnosis And Prognosis

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187 A LIQUID BIOPSY EXOSOMAL MICRORNA PANEL FOR PREDICTING RECURRENCE FOLLOWING SURGERY IN PATIENTS WITH PANCREATIC DUCTAL ADENOCARCINOMA

Gastroenterology ◽

10.1016/s0016-5085(21)00858-1 ◽

2021 ◽

Vol 160 (6) ◽

pp. S-46

Author(s):

Satoshi Nishiwada ◽

Ya Cui ◽

Masayuki Sho ◽

Eunsung Jun ◽

Takahiro Akahori ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma ◽

Exosomal Microrna

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Fluorescence Liquid Biopsy for Cancer Detection Is Improved by Using Cationic Dendronized Hyperbranched Polymer

International Journal of Molecular Sciences ◽

10.3390/ijms22126501 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6501

Author(s):

Violeta Morcuende-Ventura ◽

Sonia Hermoso-Durán ◽

Natalia Abian-Franco ◽

Roberto Pazo-Cid ◽

Jorge L. Ojeda ◽

...

Keyword(s):

Ovarian Cancer ◽

Pancreatic Ductal Adenocarcinoma ◽

Cancer Patients ◽

Liquid Biopsy ◽

Classification Performance ◽

Ductal Adenocarcinoma ◽

Diagnostic Tools ◽

Diagnostic Model ◽

Healthy Individuals ◽

Serum Samples

(1) Background: Biophysical techniques applied to serum samples characterization could promote the development of new diagnostic tools. Fluorescence spectroscopy has been previously applied to biological samples from cancer patients and differences from healthy individuals were observed. Dendronized hyperbranched polymers (DHP) based on bis(hydroxymethyl)propionic acid (bis-MPA) were developed in our group and their potential biomedical applications explored. (2) Methods: A total of 94 serum samples from diagnosed cancer patients and healthy individuals were studied (20 pancreatic ductal adenocarcinoma, 25 blood donor, 24 ovarian cancer, and 25 benign ovarian cyst samples). (3) Results: Fluorescence spectra of serum samples (fluorescence liquid biopsy, FLB) in the presence and the absence of DHP-bMPA were recorded and two parameters from the signal curves obtained. A secondary parameter, the fluorescence spectrum score (FSscore), was calculated, and the diagnostic model assessed. For pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer, the classification performance was improved when including DHP-bMPA, achieving high values of statistical sensitivity and specificity (over 85% for both pathologies). (4) Conclusions: We have applied FLB as a quick, simple, and minimally invasive promising technique in cancer diagnosis. The classification performance of the diagnostic method was further improved by using DHP-bMPA, which interacted differentially with serum samples from healthy and diseased subjects. These preliminary results set the basis for a larger study and move FLB closer to its clinical application, providing useful information for the oncologist during patient diagnosis.

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Understanding the Genetics of Pancreatic Adenocarcinoma

10.2310/7800.16077 ◽

2017 ◽

Author(s):

Apoorve Nayyar ◽

Jen Jen Yeh

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

High Throughput Sequencing ◽

Cellular Proliferation ◽

Molecular Subtypes ◽

Expression Patterns ◽

Ductal Adenocarcinoma ◽

Early Event ◽

Familial Pancreatic Cancer ◽

Structural Variations ◽

Cancer Heterogeneity

The underlying molecular basis of pancreatic ductal adenocarcinoma (PDAC) is complex, with multiple genetic, epigenetic, and transcriptomic changes. Five to 10% of PDAC cases have a hereditary basis, with multiple risk-conferring genetic mutations running in the family. All PDAC tumors develop from noninvasive precursor lesions that reflect the temporal accumulation of mutations. Recent advances in high-throughput sequencing technologies have facilitated a better understanding of the diverse mutational landscape of PDAC, reaffirming the role of genes previously known to be mutated (K-ras, CDKN2A, TP53, SMAD4, SLIT/ROBO, SWI/SNF) and revealing novel insights into the differential gene expression patterns and structural variations involved. K-ras mutation, an early event in disease pathogenesis, plays a pivotal role in the initiation, progression, and maintenance of PDAC, with the mutation type impacting disease pathophysiology and prognosis. The subsequent loss of tumor suppressors (CDKN2A, TP53, SMAD4) promotes genetic instability and uncontrolled cellular proliferation. Molecular subtypes with potential prognostic and therapeutic relevance have been identified. The challenge now is to translate this wealth of knowledge to the clinic. This review contains 3 figures, 3 tables and 50 references Key words: familial pancreatic cancer, heterogeneity, molecular subtypes, pancreatic ductal adenocarcinoma, whole genome/exome sequencing

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Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma

Frontiers in Medicine ◽

10.3389/fmed.2021.788869 ◽

2022 ◽

Vol 8 ◽

Author(s):

Daniel C. Osei-Bordom ◽

Gagandeep Sachdeva ◽

Niki Christou

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Liquid Biopsy ◽

Ductal Adenocarcinoma ◽

Advanced Stage ◽

Resistance To Treatment

Pancreatic ductal adenocarcinomas (PDAC) represent one of the deadliest cancers worldwide. Survival is still low due to diagnosis at an advanced stage and resistance to treatment. Herein, we review the main types of liquid biopsy able to help in both prognosis and adaptation of treatments.

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