Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling

Siri Vreim Ørbeck; Theresa Jakobsen; Juan Luis García-Rodríguez; Mark Burton; Lukas Gammelgaard Rasmussen; Jesper Dupont Ewald; Claus Wilki Fristrup; Per Pfeiffer; Michael Bau Mortensen; Lasse Sommer Kristensen; Sönke Detlefsen

doi:10.1016/j.pan.2024.04.004

Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling

Siri Vreim Ørbeck, Theresa Jakobsen, Juan Luis García-Rodríguez, Mark Burton, Lukas Gammelgaard Rasmussen, Jesper Dupont Ewald, Claus Wilki Fristrup, Per Pfeiffer, Michael Bau Mortensen, Lasse Sommer Kristensen, Sönke Detlefsen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

3 Citations (Scopus)

Abstract

Background/Objectives: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. Methods: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. Results: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from −3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. Conclusions: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.

Original language	English
Journal	Pancreatology
Volume	24
Issue	5
Pages (from-to)	706-718
Number of pages	13
ISSN	1424-3903
DOIs	https://doi.org/10.1016/j.pan.2024.04.004
Publication status	Published - Aug 2024

Keywords

circRNA
Pancreatic ductal adenocarcinoma
Prognosis
RNA sequencing
Survival

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Ørbeck, S. V., Jakobsen, T., García-Rodríguez, J. L., Burton, M., Rasmussen, L. G., Ewald, J. D., Fristrup, C. W., Pfeiffer, P., Mortensen, M. B., Kristensen, L. S., & Detlefsen, S. (2024). Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling. Pancreatology, 24(5), 706-718. https://doi.org/10.1016/j.pan.2024.04.004

@article{a84bebcc9b174c67972ab2c99b50a4a8,

title = "Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling",

abstract = "Background/Objectives: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. Methods: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. Results: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from −3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. Conclusions: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.",

keywords = "circRNA, Pancreatic ductal adenocarcinoma, Prognosis, RNA sequencing, Survival",

author = "{\O}rbeck, {Siri Vreim} and Theresa Jakobsen and Garc{\'i}a-Rodr{\'i}guez, {Juan Luis} and Mark Burton and Rasmussen, {Lukas Gammelgaard} and Ewald, {Jesper Dupont} and Fristrup, {Claus Wilki} and Per Pfeiffer and Mortensen, {Michael Bau} and Kristensen, {Lasse Sommer} and S{\"o}nke Detlefsen",

year = "2024",

month = aug,

doi = "10.1016/j.pan.2024.04.004",

language = "English",

volume = "24",

pages = "706--718",

journal = "Pancreatology",

issn = "1424-3903",

publisher = "Elsevier B.V.",

number = "5",

}

Ørbeck, SV, Jakobsen, T , García-Rodríguez, JL, Burton, M, Rasmussen, LG, Ewald, JD, Fristrup, CW, Pfeiffer, P, Mortensen, MB, Kristensen, LS & Detlefsen, S 2024, 'Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling', Pancreatology, vol. 24, no. 5, pp. 706-718. https://doi.org/10.1016/j.pan.2024.04.004

Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling. / Ørbeck, Siri Vreim; Jakobsen, Theresa ; García-Rodríguez, Juan Luis et al.
In: Pancreatology, Vol. 24, No. 5, 08.2024, p. 706-718.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling

AU - Ørbeck, Siri Vreim

AU - Jakobsen, Theresa

AU - García-Rodríguez, Juan Luis

AU - Burton, Mark

AU - Rasmussen, Lukas Gammelgaard

AU - Ewald, Jesper Dupont

AU - Fristrup, Claus Wilki

AU - Pfeiffer, Per

AU - Mortensen, Michael Bau

AU - Kristensen, Lasse Sommer

AU - Detlefsen, Sönke

PY - 2024/8

Y1 - 2024/8

N2 - Background/Objectives: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. Methods: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. Results: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from −3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. Conclusions: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.

AB - Background/Objectives: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. Methods: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. Results: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from −3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. Conclusions: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.

KW - circRNA

KW - Pancreatic ductal adenocarcinoma

KW - Prognosis

KW - RNA sequencing

KW - Survival

UR - http://www.scopus.com/inward/record.url?scp=85192704543&partnerID=8YFLogxK

U2 - 10.1016/j.pan.2024.04.004

DO - 10.1016/j.pan.2024.04.004

M3 - Journal article

C2 - 38724419

AN - SCOPUS:85192704543

SN - 1424-3903

VL - 24

SP - 706

EP - 718

JO - Pancreatology

JF - Pancreatology

IS - 5

ER -

Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling

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