Identification of Serum miRNA Signature and Establishment of a Nomogram for Risk Stratification in Patients With Pancreatic Ductal Adenocarcinoma

Authors

Raju Kandimalla
Tadanobu Shimura
Saurav Mallik
Fuminori Sonohara
Susan Tsai
Douglas B Evans
Song Cheol Kim
Hideo Baba
Yasuhiro Kodera
Daniel Von Hoff
Xi Chen
Ajay Goel

Publication Date

1-1-2022

Journal

Annals of Surgery

DOI

10.1097/SLA.0000000000003945

PMID

32398486

PMCID

PMC7648727

PubMedCentral® Posted Date

1-1-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Carcinoma, Pancreatic Ductal, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, MicroRNAs, Middle Aged, Neoplasm Staging, Pancreatic Neoplasms, Retrospective Studies, Risk Assessment, Pancreatic ductal adenocarcinoma, overall survival, molecular subtypes, miRNA, prognosis, risk-stratification

Abstract

OBJECTIVE: The aim of the study was to perform mRNA-miRNA regulatory network analyses to identify a miRNA panel for molecular subtype identification and stratification of high-risk patients with pancreatic ductal adenocarcinoma (PDAC).

BACKGROUND: Recent transcriptional profiling effort in PDAC has led to the identification of molecular subtypes that associate with poor survival; however, their clinical significance for risk stratification in patients with PDAC has been challenging.

METHODS: By performing a systematic analysis in The Cancer Genome Atlas and International Cancer Genome Consortium cohorts, we discovered a panel of miRNAs that associated with squamous and other poor molecular subtypes in PDAC. Subsequently, we used logistic regression analysis to develop models for risk stratification and Cox proportional hazard analysis to determine survival prediction probability of this signature in multiple cohorts of 433 patients with PDAC, including a tissue cohort (n = 199) and a preoperative serum cohort (n = 51).

RESULTS: We identified a panel of 9 miRNAs that were significantly upregulated (miR-205-5p and -934) or downregulated (miR-192-5p, 194-5p, 194-3p, 215-5p, 375-3p, 552-3p, and 1251-5p) in PDAC molecular subtypes with poor survival [squamous, area under the receiver operating characteristic curve (AUC) = 0.90; basal, AUC = 0.89; and quasimesenchymal, AUC = 0.83]. The validation of this miRNA panel in a tissue clinical cohort was a significant predictor of overall survival (hazard ratio = 2.48, P < 0.0001), and this predictive accuracy improved further in a risk nomogram which included key clinicopathological factors. Finally, we were able to successfully translate this miRNA predictive signature into a liquid biopsy-based assay in preoperative serum specimens from PDAC patients (hazard ratio: 2.85, P = 0.02).

CONCLUSION: We report a novel miRNA risk-stratification signature that can be used as a noninvasive assay for the identification of high-risk patients and potential disease monitoring in patients with PDAC.

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