Abstract
Gene expression profiling has been vastly used to extract the genes that can predict the clinical outcome in patients with diverse cancers, including diffuse large B-cell lymphoma (DLBCL). With the aid of bioinformatics and computational analysis on gene expression data, various prognostic gene signatures for DLBCL have been recently developed. The major drawback of the previous signatures is their inability to correctly predict survival in external data sets. In other words, they are not reproducible in other datasets. Hence, in this study, we sought to determine the gene(s) that can reproducibly and robustly predict survival in patients with DLBCL. Gene expression data were extracted from 7 datasets containing 1636 patients (GSE10846 [n = 420], GSE31312 [n = 470], GSE11318 [n = 203], GSE32918 [n = 172], GSE4475 [n = 123], GSE69051 [n = 157], and GSE34171 [n = 91]). Genes significantly associated with overall survival were detected using the univariate Cox proportional hazards analysis with a P value < 0.001 and a false discovery rate (FDR) < 5%. Thereafter, significant genes common between all the datasets were extracted. Additionally, chromosomal aberrations in the corresponding region of the final common gene(s) were evaluated as copy number alterations using the single nucleotide polymorphism (SNP) data of 570 patients with DLBCL (GSE58718 [n = 242], GSE57277 [n = 148], and GSE34171 [n = 180]). Our results indicated that reticulon family gene 1 (RTN1) was the only gene that met our rigorous pipeline criteria and associated with a favorable clinical outcome in all the datasets (P < 0.001, FDR < 5%). In the multivariate Cox proportional hazards analysis, this gene remained independent of the routine international prognostic index components (i.e., age, stage, lactate dehydrogenase level, Eastern Cooperative Oncology Group [ECOG] performance status, and number of extranodal sites) (P < 0.0001). Furthermore, no significant chromosomal aberration was found in the RTN1 genomic region (14q23.1: Start 59,595,976/End 59,870,966).
Highlights
Reticulon family gene 1 (RTN1) is a reticulonencoding gene that is associated with the endoplasmic reticulum
The analysis revealed that 3 genes—namely APOC1, reticulon family gene 1 (RTN1), and PLAU—fulfilled the criteria and were significantly associated with the clinical outcome at an false discovery rate (FDR) < 10% and a P value < 0.001 (Supplementary Table 1)
When the FDR cutoff value was set at 5%, only RTN1 met our rigorous pipeline criteria and was significantly associated with survival at a P value < 0.001 in the 1636 patients encompassing all the 7 data sets (Fig. 1 and Supplementary Figures)
Summary
Reticulon family gene 1 (RTN1) (formerly termed “neuroendocrine-specific protein” [NSP]) is a reticulonencoding gene that is associated with the endoplasmic reticulum. It has been shown that RTN1 reduces the anti-apoptotic activity of a protein encoded by BCL2like 1 (BCL2L1) (ie, B-cell lymphoma-extra large [Bcl-xL]). Because of the major shortages of previous prognostic gene signatures developed based on gene expression profiling[8,9,10,11,12,13], we sought to find the gene(s) that can reproducibly predict the clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). Computational approaches, we obtained a surprising result: The RTN1 gene was robustly and reliably associated with a favorable outcome in 1636 patients with DLBCL (including 7 gene expression data sets). The RTN1 gene remained as one of the most powerful independent prognostic factors in comparison with the international prognostic index (IPI) components
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