Abstract
BackgroundMajority of gastric cancers (GC) are diagnosed at advanced stages which contributes towards their poor prognosis. In view of this clinical challenge, identification of non-invasive biomarker for early diagnosis is imperative. Herein, we aimed to develop a non-invasive, liquid-biopsy based assay by using circular RNAs (circRNAs) as molecular biomarkers for early detection of GC.MethodsWe performed systematic biomarker discovery and validation of the candidate circRNAs in matched tissue specimens of GC and adjacent normal mucosa. Next, we translated the discovered circRNA based biomarker panel into serum samples in a training and validation cohort of GC patients (n = 194) and non-disease controls (n = 94) and evaluated their diagnostic performance. In addition, we measured the expression of circRNAs in serum samples of pre- and post-surgical GC patients and evaluated the specificity of circRNAs biomarker panel with respect to other gastro-intestinal (GI) malignancies.ResultsWe identified 10-circRNAs in the discovery phase with subsequent validation in a pilot cohort of GC tissue specimens. Using a training cohort of patients, we developed an 8-circRNA based risk-prediction model for the diagnosis of GC. We observed that our biomarker panel robustly discriminated GC patients from non-disease controls with an AUC of 0.87 in the training, and AUC of 0.83 in the validation cohort. Notably, the biomarker panel could robustly identify even early-stage GC patients, regardless of their tumor histology (diffuse vs. intestinal). The decreased expression of circRNAs in post-surgery serum specimens indicated their tumor-specificity and their potential source of origin in the systemic circulation.ConclusionsWe identified a panel of 8-circRNAs as non-invasive, liquid-biopsy biomarkers which might serve as potential diagnostic biomarkers for the early detection of GC.
Highlights
Gastric cancer (GC) is the fifth most-commonly diagnosed cancer, and as per GLOBOCAN 2020 reports, this malignancy ranks as the fourth leading cause of cancerrelated deaths worldwide [1]
We selected Circular RNA (circRNA) that were more robustly expressed in the gastric cancers (GC) vs. adjacent normal mucosa (ANM) tissues and exhibited a log2FC > 2, which led to the identification of 10 candidate circRNAs (Fig. 1C)
We performed receiver operating characteristic (ROC) analysis to evaluate the performance of these circRNA biomarkers as a combination panel for its ability to discriminate GC tissues from ANM
Summary
Gastric cancer (GC) is the fifth most-commonly diagnosed cancer, and as per GLOBOCAN 2020 reports, this malignancy ranks as the fourth leading cause of cancerrelated deaths worldwide [1]. In a few East Asian countries, endoscopy is available at an affordable cost and has allowed establishment of nationwide endoscopic surveillance programs. These GC screening programs have been clinically significant, as they have facilitated early detection of GC, and have allowed timely treatment interventions which has resulted in an overall improved prognosis for this malignancy [5, 6]. Majority of gastric cancers (GC) are diagnosed at advanced stages which contributes towards their poor prognosis. In view of this clinical challenge, identification of non-invasive biomarker for early diagnosis is imperative. We aimed to develop a non-invasive, liquid-biopsy based assay by using circular RNAs (circRNAs) as molecular biomarkers for early detection of GC
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