A Combined four-mRNA Signature Associated with Lymphatic Metastasis for Prognosis of Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Lymph node metastasis (LNM) is a common mode of metastasis of CRC. However, the combined mRNA biomarkers associated with LNM of CRC that can effectively predict CRC prognosis have not been reported yet. Methods: To identify biomarkers that are associated with LNM, we collected data from the The Cancer Genome Atlas (TCGA) database. The edgeR package was searched to seek LNM-related genes by comparisons between cancer samples and normal colorectal tissues and between LNM and non-LNM (NLNM) of CRC. Univariate and multivariate regression analysis of genes in the intersection to build gene signature associated with independent prognosis of CRC, and then verified by Kaplan-Meier curve and log-rank test, receiver operating characteristic (ROC) curve was used to determine the efficiency of survival prediction of our four-mRNA signature. Finally, the potential molecular mechanisms and properties of these gene signature were also explored with functional and pathway enrichment analysis. Results: 329 mRNAs were up-regulated in CRC tissues with LNM, and 8461 mRNAs were up-regulated in CRC tissues, the intersection is 100 mRNAs. After univariate and multivariate Cox regression analysis of 100 mRNAs, a novel four LNM related mRNAs (EPHA8, KRT85, GABRA3, and CLPSL1) were screened as independent prognostic indicators of CRC. Surprisingly, the four-mRNA signature can predict the prognosis of CRC patients independently of clinical factors andthe area under the curve (AUC) of the ROC is 0.730. The novel four-mRNA signature was used to identify high and low-risk groups. Stratified analysis indicated the risk score based on four-mRNA signature was an independent prognostic indicator for female, T3+T4, N1+N2 ,stage III+IV and patients with no new tumor event. Functional annotation of this risk model in high-risk patients revealed that pathways associated with neuroactive ligand-receptor interaction, estrogen signaling pathway, and steroid hormone biosynthesis. Conclusions: By conducting TCGA data mining, our study demonstrated that a four-mRNA signature associated with LNM can be used as a combined biomarker for independent prognosis of CRC.

Identification of a 5-Gene-Based Scoring System by WGCNA and LASSO to Predict Prognosis for Rectal Cancer Patients

“…As a result, the AUC was, respectively, 0.653 and 0.74 for COAD and READ, which were both lower than that of our signature panel. Moreover, in line with other signature panels identified for CRC or CC patients [ 6 – 9 , 24 ], our risk score was demonstrated to be an independent factor for the prognosis prediction and stratify the survival of patients with the same TNM stage. Also, the AUC and the C-index of the risk score were higher than those of age (AUC = 0.5; C-index = 0.569), pathologic M (AUC = 0.503; C-index = 0.555), pathologic N (AUC = 0.672; C-index = 0.658), and pathologic stage (AUC = 0.549; C-index = 0.610) and the model with all clinical factors (AUC = 0.843; C-index = 0.817).…”

“…Although all of the 5 signature genes were not included in the previous signature panels for CRC [ 6 – 9 , 24 ], some of them were found to be associated with the progression and prognosis of CRC (including ASB2, GPR15, TCL1A, and PRPH) [ 28 – 31 ]. High ASB2 expression was shown to predict a short relapse-free survival for patients with CRC [ 28 ].…”

“…This four-mRNA signature panel can effectively predict the prognosis of CRC patients, with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.730. The stratified analysis indicated that the patients belonging to the same T stage (T3+T4), N stage (N1+N2), or TNM stage (III+IV) can also be stratified into the high-risk and low-risk groups using this 4-gene signature panel [ 6 ]. The study of Zuo et al revealed that a six-mRNA signature panel had a significant prognostic value to discriminate the high-risk patients from the low-risk patients, with an AUC of 0.711 and 0.683 for 3-year and 5-year survival, respectively.…”

A 15-Gene Signature and Prognostic Nomogram for Predicting Overall Survival in Non-Distant Metastatic Oral Tongue Squamous Cell Carcinoma

“…In recent years, more and more multiple-biomarker signatures and prognostic nomograms have been established and utilized for clinical decision-making and prognostic evaluation for different type of cancers (5,(10)(11)(12). However, few biomarker-based signatures and prognostic nomograms have been studied in relationship to OTSCC (13)(14)(15).…”

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

“…Proliferation, migration, and invasion of gastric cancer cells are associated with EPHA8 kinase-mediated signaling involving the ADAM10 protein and downstream serine/threonine kinase AKT pathways [ 180 ]. Increased EPHA8 expression also associates with increased clinicopathological features or poor prognoses in oral tongue squamous cell carcinoma [ 181 ], colorectal cancer [ 182 ], and ovarian cancer [ 183 ]. Studies of EPHA8 phosphorylation sites revealed physical associations between EPHA8 and FYN proto-oncogene kinase (FYN) and implicate FYN kinase as a major downstream target for EPHA8 signaling [ 184 ].…”