Abstract
BackgroundNoninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored. Inflammation is known to play an important role in the tumor microenvironment of CRC. Therefore, the aim of this study was to elucidate novel inflammatory biomarkers related to early diagnosis and prognosis of CRC.MethodsBased on the results from a multiplex assay and a pan-cancer screening of TCGA data with 18 cancer types, we identified several targeted biomarkers. We further confirmed these results using a trial cohort of 112 CRC patients and 151 controls (59 healthy donors, 52 colitis and 40 colorectal adenoma patients) by Elisa and immunohistochemistry (IHC). The biomarkers expression levels in CRC patients of different clinical stages were compared. The targeted biomarkers panel was developed using logistic regression model and was then validated using an independent cohort including 75 CRC patients and 90 controls (35 healthy donors, 20 colitis and 35 colorectal adenoma patients). Diagnostic accuracy was evaluated using area under the receiver-operating characteristic (ROC) curve and overall survival analysis was used for prognosis. Gene ontology (GO) analyses and Gene set enrichment analyses (GSEA) were performed to predict the function of the candidate biomarkers.ResultsCCL20 and IL-17A were identified as candidate biomarkers using multiplex assay and pan-cancer screening of TCGA data. Elisa and IHC demonstrated that both CCL20 and IL-17A levels were highly expressed in CRC patients, more especially in patients with advanced stage disease. A signature expression of the two biomarkers showed high diagnostic accuracy of CRC. Importantly, the diagnostic sensitivity and specificity were still satisfactory in the early stage and low carcinoembryonic antigen (CEA) level groups. Bioinformatics analysis revealed that CCL20 and IL-17A may be involved in CRC progression. In addition, the diagnostic performance of CCL20 and IL-17A in combination was superior to that of either marker alone.ConclusionsSerum CCL20 and IL-17A levels were identified as independent prognostic markers for CRC. The CCL20-IL-17A panel exhibited a good performance in the diagnosis of early stage CRC.
Highlights
Noninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored
Identification of candidate biomarkers for CRCTo identify potential CRC biomarkers, we examined the levels of serum inflammatory cytokines and chemokines in CRC patients and healthy donors (HD) using a multiplex assay
The serum levels of CC ligand 20 (CCL20), CXCL10, CCL2, IL-9, IL-21, and IL-17A were significantly higher in CRC patients than in HD (Fig. 2a)
Summary
Noninvasive and effective methods of early diagnosis of colorectal cancer (CRC) are underexplored. The aim of this study was to elucidate novel inflammatory biomarkers related to early diagnosis and prognosis of CRC. Colorectal cancer (CRC) is one of the most common cancers, and the second leading cause of cancer related mortality globally [1]. Despite the development of screening strategies such as colonoscopy, fecal occult-blood testing, and stool DNA test, early diagnosis of CRC remains unrealized. The frequently used serum tumor biomarkers carcinoembryonic antigens (CEA) and carbohydrate antigens 19-9 (CA19-9), present with limited sensitivity and specificity to early stage CRC diagnosis and yield controversial prognostic values [4, 5]. The identification of some novel and noninvasive biomarkers for early diagnosis of CRC are extremely high in demand
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