Discovery and validation of immune-associated long non-coding RNA biomarkers associated with clinically molecular subtype and prognosis in diffuse large B cell lymphoma

Abstract

BackgroundDiffuse large B-cell lymphoma (DLBCL) is an aggressive and complex disease characterized by wide clinical, phenotypic and molecular heterogeneities. The expression pattern and clinical implication of long non-coding RNAs (lncRNAs) between germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes in DLBCL remain unclear. This study aims to determine whether lncRNA can serve as predictive biomarkers for subtype classification and prognosis in DLBCL.MethodsGenome-wide comparative analysis of lncRNA expression profiles were performed in a large number of DLBCL patients from Gene Expression Omnibus (GEO), including GSE31312 cohort (N = 426), GSE10846 (N = 350) cohort and GSE4475 cohort (N = 129). Novel lncRNA biomarkers associated with clinically molecular subtype and prognosis were identified in the discovery cohort using differential expression analyses and weighted voting algorithm. The predictive value of the lncRNA signature was then assessed in two independent cohorts. The functional implication of lncRNA signature was also analyzed by integrative analysis of lncRNA and mRNA.ResultsSeventeen of the 156 differentially expressed lncRNAs between GCB and ABC subtypes were identified as candidate biomarkers and integrated into form a lncRNA-based signature (termed SubSigLnc-17) which was able to discriminate between GCB and ABC subtypes with AUC of 0.974, specificity of 89.6% and sensitivity of 92.5%. Furthermore, subgroups of patients characterized by the SubSigLnc-17 demonstrated significantly different clinical outcome. The reproducible predictive power of SubSigLnc-17 in subtype classification and prognosis was successfully validated in the internal validation cohort and another two independent patient cohorts. Integrative analysis of lncRNA-mRNA suggested that these candidate lncRNA biomarkers were mainly related to immune-associated processes, such as T cell activation, leukocyte activation, lymphocyte activation and Chemokine signaling pathway.ConclusionsOur study uncovered differentiated lncRNA expression pattern between GCB and ABC DLBCL and identified a 17-lncRNA signature for subtype classification and prognosis prediction. With further prospective validation, our study will improve the understanding of underlying molecular heterogeneities in DLBCL and provide candidate lncRNA biomarkers in DLBCL classification and prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0580-4) contains supplementary material, which is available to authorized users.

Differential expression of long non‐coding RNAs are related to proliferation and histological diversity in follicular lymphomas

“…LncRNAs are emerging as important actors in the regulation of genes involved in relevant processes for oncogenesis (Huang et al , ). Accordingly, expression deregulation of lncRNA is being increasingly described in relation to the pathogenesis and progression of many neoplasms (Bhan et al , ), including lymphoid tumours (Doose et al , ; Li et al , ; Zhao et al , ; Zhou et al , ). Nevertheless the lncRNA expression profiles in FL remain widely unexplored (Pan et al , ).…”

“…Interestingly, altered expression of several lncRNA has been increasingly found in different neoplasms and their modulated target genes include those known to be involved in oncogenesis (Huang et al , ; Bhan et al , ). The differential expression of lncRNA in lymphoid neoplasms has been less studied, but some lncRNAs have been identified with significant relationship with prognosis or treatment response, such as MINCR in Burkitt Lymphoma or MALAT1 and others in DLBCL (Doose et al , ; Li et al , ; Zhao et al , ; Zhou et al , ).…”

Long non-coding RNA NEAT1 regulates E2F3 expression by competitively binding to miR-377 in non-small cell lung cancer

“…Moreover, lncRNAs also have the potential function as diagnostic or prognostic markers of cancer (4)(5)(6)(7)(8)(9)(10). Nuclear enriched abundant transcript 1 (NEAT1) is a nuclear-restricted lncRNA that has two isoforms: NEAT1-1 and NEAT1-2 (11).…”

Long Non-Coding RNAs: Rising Regulators of Plant Reproductive Development

“…Initially regarded as "noise" within the genome, lncRNAs have attracted increasing research interest, and several lncRNAs have been functionally characterized at transcriptional and post-transcriptional levels [8][9][10]. LncRNAs can be regarded as gene regulatory factors, especially in the diagnosis and prognosis of human diseases [11][12][13][14][15][16]. In plants, the identification of lncRNAs typically receives more attention than research on functions and mechanisms, although continuously emerging studies report specific developmental expression patterns which suggest potentially important biological functions [17][18][19].…”