An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study

Kota Nakamura; Zhongxu Zhu; Souvick Roy; Eunsung Jun; Haiyong Han; Ruben M. Munoz; Satoshi Nishiwada; Geeta Sharma; Derek Cridebring; Frederic Zenhausern; Seungchan Kim; Denise J. Roe; Sourat Darabi; In-Woong Han; Douglas B. Evans; Suguru Yamada; Michael J. Demeure; Carlos Becerra; Scott A. Celinski; Erkut Borazanci; Susan Tsai; Yasuhiro Kodera; Joon Oh Park; John S. Bolton; Xin Wang; Song Cheol Kim; Daniel Von Hoff; Ajay Goel

doi:10.1053/j.gastro.2022.06.090

An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study

Kota Nakamura (Co-first Author), Zhongxu Zhu (Co-first Author), Souvick Roy (Co-first Author), Eunsung Jun (Co-first Author), Haiyong Han, Ruben M. Munoz, Satoshi Nishiwada, Geeta Sharma, Derek Cridebring, Frederic Zenhausern, Seungchan Kim, Denise J. Roe, Sourat Darabi, In-Woong Han, Douglas B. Evans, Suguru Yamada, Michael J. Demeure, Carlos Becerra, Scott A. Celinski, Erkut BorazanciSusan Tsai, Yasuhiro Kodera, Joon Oh Park, John S. Bolton, Xin Wang^*, Song Cheol Kim^*, Daniel Von Hoff^*, Ajay Goel^*

^*Corresponding author for this work

Department of Biomedical Sciences

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

128 Citations (Scopus)

Abstract

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and majority of patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lack adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly miRNAs, offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.

Methods: Small RNA-sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 non-disease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs was prioritized that discriminated PDAC patients from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n=191) using quantitative real time PCR (qRT-PCR) assays.

Results: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (AUC=0.98 training cohort; AUC=0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages 1&II; AUC=0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/ml; AUC=0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC=0.99 vs. AUC=0.86 for CA19-9 alone).

Conclusions: In this study, an exosome-based liquid-biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

Original language	English
Pages (from-to)	1252-1266.e2
Journal	Gastroenterology
Volume	163
Issue number	5
Online published	16 Jul 2022
DOIs	https://doi.org/10.1053/j.gastro.2022.06.090
Publication status	Published - Nov 2022

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

Diagnostic Biomarker
Exosome
Liquid Biopsy
miRNA Signature
Pancreatic Cancer

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10.1053/j.gastro.2022.06.090

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Nakamura, K., Zhu, Z., Roy, S., Jun, E., Han, H., Munoz, R. M., Nishiwada, S., Sharma, G., Cridebring, D., Zenhausern, F., Kim, S., Roe, D. J., Darabi, S., Han, I.-W., Evans, D. B., Yamada, S., Demeure, M. J., Becerra, C., Celinski, S. A., ... Goel, A. (2022). An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study. Gastroenterology, 163(5), 1252-1266.e2. https://doi.org/10.1053/j.gastro.2022.06.090

@article{ae5b0224a1a147c796b08af6f442e49d,

title = "An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study",

abstract = "Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and majority of patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lack adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly miRNAs, offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.Methods: Small RNA-sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 non-disease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs was prioritized that discriminated PDAC patients from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n=191) using quantitative real time PCR (qRT-PCR) assays.Results: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (AUC=0.98 training cohort; AUC=0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages 1&II; AUC=0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/ml; AUC=0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC=0.99 vs. AUC=0.86 for CA19-9 alone).Conclusions: In this study, an exosome-based liquid-biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.",

keywords = "Diagnostic Biomarker, Exosome, Liquid Biopsy, miRNA Signature, Pancreatic Cancer",

author = "Kota Nakamura and Zhongxu Zhu and Souvick Roy and Eunsung Jun and Haiyong Han and Munoz, {Ruben M.} and Satoshi Nishiwada and Geeta Sharma and Derek Cridebring and Frederic Zenhausern and Seungchan Kim and Roe, {Denise J.} and Sourat Darabi and In-Woong Han and Evans, {Douglas B.} and Suguru Yamada and Demeure, {Michael J.} and Carlos Becerra and Celinski, {Scott A.} and Erkut Borazanci and Susan Tsai and Yasuhiro Kodera and Park, {Joon Oh} and Bolton, {John S.} and Xin Wang and Kim, {Song Cheol} and {Von Hoff}, Daniel and Ajay Goel",

year = "2022",

month = nov,

doi = "10.1053/j.gastro.2022.06.090",

language = "English",

volume = "163",

pages = "1252--1266.e2",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders",

number = "5",

}

Nakamura, K, Zhu, Z, Roy, S, Jun, E, Han, H, Munoz, RM, Nishiwada, S, Sharma, G, Cridebring, D, Zenhausern, F, Kim, S, Roe, DJ, Darabi, S, Han, I-W, Evans, DB, Yamada, S, Demeure, MJ, Becerra, C, Celinski, SA, Borazanci, E, Tsai, S, Kodera, Y, Park, JO, Bolton, JS, Wang, X, Kim, SC, Von Hoff, D & Goel, A 2022, 'An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study', Gastroenterology, vol. 163, no. 5, pp. 1252-1266.e2. https://doi.org/10.1053/j.gastro.2022.06.090

An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study. / Nakamura, Kota (Co-first Author); Zhu, Zhongxu (Co-first Author); Roy, Souvick (Co-first Author) et al.
In: Gastroenterology, Vol. 163, No. 5, 11.2022, p. 1252-1266.e2.

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

TY - JOUR

T1 - An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma

T2 - A multicenter cohort study

AU - Nakamura, Kota

AU - Zhu, Zhongxu

AU - Roy, Souvick

AU - Jun, Eunsung

AU - Han, Haiyong

AU - Munoz, Ruben M.

AU - Nishiwada, Satoshi

AU - Sharma, Geeta

AU - Cridebring, Derek

AU - Zenhausern, Frederic

AU - Kim, Seungchan

AU - Roe, Denise J.

AU - Darabi, Sourat

AU - Han, In-Woong

AU - Evans, Douglas B.

AU - Yamada, Suguru

AU - Demeure, Michael J.

AU - Becerra, Carlos

AU - Celinski, Scott A.

AU - Borazanci, Erkut

AU - Tsai, Susan

AU - Kodera, Yasuhiro

AU - Park, Joon Oh

AU - Bolton, John S.

AU - Wang, Xin

AU - Kim, Song Cheol

AU - Von Hoff, Daniel

AU - Goel, Ajay

PY - 2022/11

Y1 - 2022/11

N2 - Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and majority of patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lack adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly miRNAs, offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.Methods: Small RNA-sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 non-disease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs was prioritized that discriminated PDAC patients from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n=191) using quantitative real time PCR (qRT-PCR) assays.Results: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (AUC=0.98 training cohort; AUC=0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages 1&II; AUC=0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/ml; AUC=0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC=0.99 vs. AUC=0.86 for CA19-9 alone).Conclusions: In this study, an exosome-based liquid-biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

AB - Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and majority of patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lack adequate sensitivity and specificity for early detection; hence, there is an unmet need to develop alternate molecular diagnostic biomarkers for PDAC. Emerging evidence suggests that tumor-derived exosomal cargo, particularly miRNAs, offer an attractive platform for the development of cancer-specific biomarkers. Herein, genomewide profiling in blood specimens was performed to develop an exosome-based transcriptomic signature for noninvasive and early detection of PDAC.Methods: Small RNA-sequencing was undertaken in a cohort of 44 patients with an early-stage PDAC and 57 non-disease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs was prioritized that discriminated PDAC patients from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n=191) using quantitative real time PCR (qRT-PCR) assays.Results: The sequencing analysis initially identified a panel of 30 overexpressed miRNAs in PDAC. Subsequently using qRT-PCR assays, the panel was reduced to 13 markers (5 cf- and 8 exo-miRNAs), which successfully identified patients with all stages of PDAC (AUC=0.98 training cohort; AUC=0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages 1&II; AUC=0.93). Furthermore, this transcriptomic signature successfully identified CA19-9 negative cases (<37 U/ml; AUC=0.96), when analyzed in combination with CA19-9 levels, significantly improved the overall diagnostic accuracy (AUC=0.99 vs. AUC=0.86 for CA19-9 alone).Conclusions: In this study, an exosome-based liquid-biopsy signature for the noninvasive and robust detection of patients with PDAC was developed.

KW - Diagnostic Biomarker

KW - Exosome

KW - Liquid Biopsy

KW - miRNA Signature

KW - Pancreatic Cancer

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UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85138796559&origin=recordpage

U2 - 10.1053/j.gastro.2022.06.090

DO - 10.1053/j.gastro.2022.06.090

M3 - RGC 21 - Publication in refereed journal

C2 - 35850192

SN - 0016-5085

VL - 163

SP - 1252-1266.e2

JO - Gastroenterology

JF - Gastroenterology

IS - 5

ER -

An exosome-based transcriptomic signature for noninvasive, early detection of patients with pancreatic ductal adenocarcinoma: A multicenter cohort study

Abstract

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