Integrated genomic analysis of recurrence-associated small non-coding RNAs in oesophageal cancer

Abstract

Objective Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict. A better understanding of the biology of ESCC recurrence is needed to improve patient care. Our goal was to identify small non-coding RNAs (sncRNAs) that could predict the likelihood of recurrence after surgical resection and to uncover potential molecular mechanisms that dictate clinical heterogeneity. Design We developed a robust prediction model for recurrence based on the analysis of the expression profile data of sncRNAs from 108 fresh frozen ESCC specimens as a discovery set and assessment of the associations between sncRNAs and recurrence-free survival (RFS). We also evaluated the mechanistic and therapeutic implications of sncRNA obtained through integrated analysis from multiple data sets. Results We developed a risk assessment score for recurrence (RAS) with three sncRNAs (miR-223, miR-1269a, and nc886) whose expression was significantly associated with RFS in the discovery cohort (N=108). RAS was validated in an independent cohort of 512 patients. In multivariable analysis, RAS was an independent predictor of recurrence (hazard ratio, 2.27; 95% confidence interval, 1.26 to 4.09; P=0.007). This signature implies the expression of ΔNp63 and multiple alterations of driver genes like PIK3CA. We suggested therapeutic potentials of immune checkpoint inhibitors in low-risk patients, and Polo-like kinase, mTOR, and HDAC inhibitors in high-risk patients. Conclusion We developed an easy-to-use prognostic model with three sncRNAs as robust prognostic markers for postoperative recurrence of ESCC. We anticipate that such a stratified and systematic, tumor-specific biologic approach will potentially contribute to significant improvement in ESCC treatment.

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma

“…MiRNAs are another important class of regulatory noncoding RNAs involved in liver diseases. (36) The most up-regulated miRNA in this study was miR-1269a (73-fold), which has been linked with relapse and metastasis of colorectal cancer, (37) relapse of squamous cell esophageal carcinoma, (38) and proliferation of HCC by down-regulation of forkhead box O1 (FOXO1). (39) One interesting down-regulated miRNA in our study was miR-4485-3p, which was found deregulated in a gastric cancer cell line (40) and shown to block angiogenesis in Kaposi's sarcoma.…”

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

“…Finally, the 381 genes differentially expressed in TET subgroups between CIN and others (P<10 −7 , FDR <10 −7 , and fold change >2) were defined as CIN gene set (Supplementary Table S1). To determine mRNA signatures identifying the molecular subtypes of validation cohort 2 and melanoma cohort (19), we adopted a previously developed model (20). Briefly, gene-expression data in the training set were combined to form a series of classifiers according to the compound covariate predictor (CCP) algorithm and the robustness of the classifier was estimated by the misclassification rate determined during leave-one-out cross-validation (LOOCV) of the training set.…”

Novel insights into the molecular heterogeneity of hepatocellular carcinoma

“…miRNAs are another important class of regulatory non-coding RNAs involved in liver diseases [24,25,58]. The most dramatically deregulated miRNA in our samples was miR-1269a (73-fold upregulated), which has been reported associated with colorectal carcinoma relapse and metastasis [59], relapse of esophageal squamous cell carcinoma [60], and proliferation of HCC via downregulation of FOXO1 [61]. However, we only detected an slight downregulation of FOXO1 (2.9-fold), which suggests that other targets of miR-1269a may also be involved in the HCC pathology.…”