CLO19-060: Blood Exosomal Long RNA Profiling Identifies Diagnostic and Prognostic Markers in Pancreatic Ductal Adenocarcinoma

Background: Long RNAs have been recently identified in human blood exosomes, posing clinical implications. Whether exosomal long RNAs (exoLRs) could constitute key future biomarkers for noninvasive diagnosis, therapeutic evaluation, and prognosis in cancer remains unknown. The study aimed to explore the exoLR landscape of human blood exosomes and evaluate the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of pancreatic ductal adenocarcinoma (PDAC) based on exoLR profiling. Methods: A case-control study of 267 cases including 137 patients with PDAC and 39 with chronic pancreatitis (CP) plus 91 blood donors as healthy participants was conducted. The exoLR profile of pretreated blood samples was analyzed by exoLR-sequencing (exoLR-seq). Results: An average of 15,000 exoLRs were reliably detected for each sample through exoLR-seq, and 1,053 exoLRs were differentially expressed in PDAC. Based on these data, we constructed a diagnostic signature (d-signature) that showed high accuracy with an area under the curve (AUC) of 0.977 (95% CI: 0.958–0.996), a sensitivity of 92.42% (95% CI: 83.2%–97.49%), and a specificity of 95% (95% CI: 87.69%–98.62%) in a training cohort (n=146), which was further confirmed in a validation cohort (n=93). Notably, the combination of d-signature and CA19-9 yielded an AUC of 0.963 (95% CI: 0.909–1.017), with a sensitivity of 98.13% (95% CI: 93.41%–99.77%) and specificity of 94.59% (95% CI: 81.81%–99.34%). Additionally, we constructed a prognostic prediction model (exoLR p-signature) that effectively predicted prognosis and survival in patients with PDAC (P=9.838e-08). Conclusions: This study clearly demonstrated the value of exoLR profiling in cancer marker discovery and the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of PDAC.

Background: Long RNAs have been recently identified in human blood exosomes, posing clinical implications. Whether exosomal long RNAs (exoLRs) could constitute key future biomarkers for noninvasive diagnosis, therapeutic evaluation, and prognosis in cancer remains unknown. The study aimed to explore the exoLR landscape of human blood exosomes and evaluate the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of pancreatic ductal adenocarcinoma (PDAC) based on exoLR profiling. Methods: A case-control study of 267 cases including 137 patients with PDAC and 39 with chronic pancreatitis (CP) plus 91 blood donors as healthy participants was conducted. The exoLR profile of pretreated blood samples was analyzed by exoLR-sequencing (exoLR-seq). Results: An average of 15,000 exoLRs were reliably detected for each sample through exoLR-seq, and 1,053 exoLRs were differentially expressed in PDAC. Based on these data, we constructed a diagnostic signature (d-signature) that showed high accuracy with an area under the curve (AUC) of 0.977 (95% CI: 0.958–0.996), a sensitivity of 92.42% (95% CI: 83.2%–97.49%), and a specificity of 95% (95% CI: 87.69%–98.62%) in a training cohort (n=146), which was further confirmed in a validation cohort (n=93). Notably, the combination of d-signature and CA19-9 yielded an AUC of 0.963 (95% CI: 0.909–1.017), with a sensitivity of 98.13% (95% CI: 93.41%–99.77%) and specificity of 94.59% (95% CI: 81.81%–99.34%). Additionally, we constructed a prognostic prediction model (exoLR p-signature) that effectively predicted prognosis and survival in patients with PDAC (P=9.838e-08). Conclusions: This study clearly demonstrated the value of exoLR profiling in cancer marker discovery and the feasibility of developing a diagnostic or prognostic signature for early detection and prognostic prediction of PDAC.

Figure 1
Figure 1

ExoLR profiling in the diagnosis of PDAC. (A–B) ROC for performance of exoLR d-signature in the training (A) and validation cohorts (B). (C–D) Unsupervised hierarchical clustering of 8 exoLRs selected for use in the d-signature in the training (C) and validation cohorts (D). (E) ExoLR d-signature in healthy, chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) subjects. (F) ExoLR d-signature in PDAC patients in stage I–IV. (G) ROC for performance of exoLR d-signature compared with that of CA19-9 in the differential diagnosis of PDAC and CP. (H) DCA to compare the net benefit of combined exoLR d-signature and CA19-9 (red line) with that of CA19-9 alone (blue line) for PDAC vs CP. AUC, area under the curve. CI, confidence interval.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 3.5; 10.6004/jnccn.2018.7141

Figure 2
Figure 2

ExoLRs in the prognostic prediction of PDAC. (A–B) Kaplan–Meier curves of overall survival for PDAC patients with low or high risk, according to the prognostic signature (P-signature) in the training (A) and validation cohorts (B). (C) ROC for the p-signature, tumor stage, and p-signature combined with tumor stage in the whole PDAC cohort. (D) Kaplan–Meier survival curves of PDAC patients with combinations of exoLR p-signature and tumor stage in the whole PDAC cohort. AUC, area under the curve. CI, confidence interval.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 17, 3.5; 10.6004/jnccn.2018.7141

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Corresponding Author: Zhen Chen, PhD
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    ExoLR profiling in the diagnosis of PDAC. (A–B) ROC for performance of exoLR d-signature in the training (A) and validation cohorts (B). (C–D) Unsupervised hierarchical clustering of 8 exoLRs selected for use in the d-signature in the training (C) and validation cohorts (D). (E) ExoLR d-signature in healthy, chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) subjects. (F) ExoLR d-signature in PDAC patients in stage I–IV. (G) ROC for performance of exoLR d-signature compared with that of CA19-9 in the differential diagnosis of PDAC and CP. (H) DCA to compare the net benefit of combined exoLR d-signature and CA19-9 (red line) with that of CA19-9 alone (blue line) for PDAC vs CP. AUC, area under the curve. CI, confidence interval.

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    ExoLRs in the prognostic prediction of PDAC. (A–B) Kaplan–Meier curves of overall survival for PDAC patients with low or high risk, according to the prognostic signature (P-signature) in the training (A) and validation cohorts (B). (C) ROC for the p-signature, tumor stage, and p-signature combined with tumor stage in the whole PDAC cohort. (D) Kaplan–Meier survival curves of PDAC patients with combinations of exoLR p-signature and tumor stage in the whole PDAC cohort. AUC, area under the curve. CI, confidence interval.

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