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An Exosome-based Transcriptomic Signature for Noninvasive, Early Detection of Patients With Pancreatic Ductal Adenocarcinoma: A Multicenter Cohort Study
- Authors
- Nakamura, K.[Nakamura, K.]; Zhu, Z.[Zhu, Z.]; Roy, S.[Roy, S.]; Jun, E.[Jun, E.]; Han, H.[Han, H.]; Munoz, R.M.[Munoz, R.M.]; Nishiwada, S.[Nishiwada, S.]; Sharma, G.[Sharma, G.]; Cridebring, D.[Cridebring, D.]; Zenhausern, F.[Zenhausern, F.]; Kim, S.[Kim, S.]; Roe, D.J.[Roe, D.J.]; Darabi, S.[Darabi, S.]; Han, I.-W.[Han, I.-W.]; Evans, D.B.[Evans, D.B.]; Yamada, S.[Yamada, S.]; Demeure, M.J.[Demeure, M.J.]; Becerra, C.[Becerra, C.]; Celinski, S.A.[Celinski, S.A.]; Borazanci, E.[Borazanci, E.]; Tsai, S.[Tsai, S.]; Kodera, Y.[Kodera, Y.]; Park, J.O.[Park, J.O.]; Bolton, J.S.[Bolton, J.S.]; Wang, X.[Wang, X.]; Kim, S.C.[Kim, S.C.]; Von, Hoff D.[Von, Hoff D.]; Goel, A.[Goel, A.]
- Issue Date
- Nov-2022
- Publisher
- W.B. Saunders
- Keywords
- Diagnostic Biomarker; Exosome; Liquid Biopsy; miRNA Signature; Pancreatic Cancer
- Citation
- Gastroenterology, v.163, no.5, pp.1252 - 1266.e2
- Indexed
- SCIE
SCOPUS
- Journal Title
- Gastroenterology
- Volume
- 163
- Number
- 5
- Start Page
- 1252
- End Page
- 1266.e2
- ISSN
- 0016-5085
- Abstract
- Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising worldwide, and most patients present with an unresectable disease at initial diagnosis. Measurement of carbohydrate antigen 19-9 (CA19-9) levels lacks 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 micro RNAs (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 nondisease controls. Using machine-learning algorithms, a panel of cell-free (cf) and exosomal (exo) miRNAs were prioritized that discriminated patients with PDAC from control subjects. Subsequently, the performance of the biomarkers was trained and validated in independent cohorts (n = 191) using quantitative reverse transcription polymerase chain reaction (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 (area under the curve [AUC] = 0.98 training cohort; AUC = 0.93 validation cohort); but more importantly, was equally robust for the identification of early-stage PDAC (stages I and 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. © 2022 AGA Institute
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