A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer

Kota Nakamura, Goretti Hernández, Geeta G Sharma, Yuma Wada, Jasjit K Banwait, Natalia González, Jose Perea, Francesc Balaguer, Hiroyuki Takamaru, Yutaka Saito, Yuji Toiyama, Yasuhiro Kodera, C Richard Boland, Luis Bujanda, Enrique Quintero, Ajay Goel, Kota Nakamura, Goretti Hernández, Geeta G Sharma, Yuma Wada, Jasjit K Banwait, Natalia González, Jose Perea, Francesc Balaguer, Hiroyuki Takamaru, Yutaka Saito, Yuji Toiyama, Yasuhiro Kodera, C Richard Boland, Luis Bujanda, Enrique Quintero, Ajay Goel

Abstract

Background & aims: Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC.

Methods: A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays.

Results: In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity.

Conclusions: Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.

Keywords: Diagnostic Biomarker; Early-Onset Colorectal Cancer; Liquid Biopsy; miRNA Panel.

Conflict of interest statement

Conflict of Interest: None of the authors has any potential conflicts to disclose.

Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.
Figure 1.
Differentially expressed miRNAs in patients with early stage EOCRC vs. normal mucosa specimens. (A) The overall workflow for this study. (B) A volcano plot illustrating miRNAs significantly upregulated in EOCRC (stage I-II) vs. normal mucosa specimens. (C) Receiver operating characteristics (ROC) curve analysis with the selected 7 candidate miRNAs for discriminating stage I/II EOCRC tumors. *P<0.05
Figure 2.
Figure 2.
Diagnostic performance of the miRNA panel in EOCRC vs. non-disease controls. (A) The ROC curves analysis for a 4-miRNA panel in the training cohort. (B) Risk score distribution plot in the training cohort. (C) ROC curves analysis for a 4-miRNA panel in the validation cohort. (D) Risk score distribution plot in the validation cohort.
Figure 3.
Figure 3.
Diagnostic potential evaluation of the miRNA biomarker panel to identify different stages of EOCRC patients. (A) ROC curve analysis to identify early stage (I and II) and late stage (III and IV) patients with EOCRC from non-disease controls in the validation cohort and (B) Risk score analysis based on risk prediction formulae in early vs. late stage EOCRC patients and non-disease control in the validation cohort. (C) Decision curve analysis to evaluate the performance of the miRNA panel.
Figure 4.
Figure 4.
Evaluation of the miRNA panel in pre vs. post-operative blood specimens. (A) Expression of candidate miRNAs in pre- and post-operative plasma specimens from EOCRC patients. (B) Assessment of risk probability based on risk prediction formula between pre-and postoperative EOCRC specimens.

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