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pmid:28103885
Discovery and validation of immune-associated long non-coding RNA biomarkers associated with clinically molecular subtype and prognosis in diffuse large B cell lymphoma.
Meng Zhou · Hengqiang Zhao · Wanying Xu · Siqi Bao · Liang Cheng · Jie Sun
Molecular cancer · 2017 doi:10.1186/s12943-017-0580-4
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Complete file
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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.\nMETHODS: Genome-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.\nRESULTS: Seventeen 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.\nCONCLUSIONS: Our 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.", "claims": [{"id": "claim-method", "statement": "To construct a lncRNA-based molecular signature for subtype classification and prognosis prediction, we developed a supervised subgroup predictive classifier using the weighted voting algorithm as previously described [34] based on the weighted votes of a set of informative lncRNAs.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:28103885", "locator": "sections[7] \"Formulation of lncRNA-based molecular signature\" paragraph 2", "quote": "To construct a lncRNA-based molecular signature for subtype classification and prognosis prediction, we developed a supervised subgroup predictive classifier using the weighted voting algorithm as previously described [34] based on the weighted votes of a set of informative lncRNAs."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The gene expression data and clinical data in this study can be found online at the Gene Expression Omnibus under accession numbers GSE31312 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31312), GSE10846 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10846) and GSE4475 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4475).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:28103885", "locator": "sections[21] \"ack\" paragraph 1", "quote": "The gene expression data and clinical data in this study can be found online at the Gene Expression Omnibus under accession numbers GSE31312 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE31312), GSE10846 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE10846) and GSE4475 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE4475)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:28103885"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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biomarkers associated with clinically molecular subtype", "row_count": 18, "column_count": 6}, "table": {"label": "Table 2", "caption": "Candidate lncRNAs biomarkers associated with clinically molecular subtype and prognosis of DLBCL", "rows": [["Ensembl id", "Gene symbol", "Chromosomal position", "p-value", "FDR", "signal-to-noise ratio"], ["ENSG00000226688.5", "ENTPD1-AS1", "Chr 10: 95,753,206-96,090,238 (−)", "5.34E-10", "1.78E-07", "0.453"], ["ENSG00000229558.2", "SACS-AS1", "Chr 13: 23,418,971-23,428,869 (+)", "2.2E-07", "3.94E-05", "0.404"], ["ENSG00000224660.1", "SH3BP5-AS1", "Chr 3: 15,254,184-15,264,493 (+)", "4.93E-12", "3.83E-09", "0.502"], ["ENSG00000231090.1", "RP11-101C11.1", "Chr 1: 55,217,861-55,234,177 (+)", "3.88E-09", "1.13E-06", "0.421"], ["ENSG00000224730.1", "AC009892.10", "Chr 19: 54,635,722-54,638,892 (−)", "1.03E-07", "2.36E-05", "0.38"], ["ENSG00000255443.1", "RP1-68D18.4", "Chr 11: 35,210,343-35,214,985 (−)", "3.48E-07", "5.8E-05", "0.361"], ["ENSG00000236901.4", "MIR600HG", "Chr 9: 123,109,494-123,115,477 (−)", "9.02E-07", "1.4E-04", "0.359"], ["ENSG00000279130.1", "RP11-278 J6.4", "Chr 5: 143,406,959-143,407,420 (+)", "2.57E-06", "3.737E-04", "0.341"], ["ENSG00000260303.1", "RP11-203B7.2", "Chr 4: 146,052,604-146,056,762 (−)", "1.33E-07", "2.57E-05", "0.395"], ["ENSG00000231163.4", "CSMD2-AS1", "Chr 1: 33,868,953-33,885,458 (+)", "2.76E-10", "1.29E-07", "0.493"], ["ENSG00000245864.2", "CTC-467 M3.1", "Chr 5: 88,676,218-88,722,831 (+)", "1.12E-07", "2.36E-05", "0.379"], ["ENSG00000223479.3", "RP4-788P17.1", "Chr 1: 73,635,216-73,715,214 (+)", "2.91E-12", "3.39E-09", "0.514"], ["ENSG00000259976.1", "RP11-553 L6.5", "Chr 3: 114,314,501-114,316,179 (−)", "6.09E-08", "1.58E-05", "0.386"], ["ENSG00000245694.7", "CRNDE", "Chr 16: 54,918,863-54,929,189 (−)", "3.49E-06", "4.71E-04", "0.328"], ["ENSG00000259354.4", "RP11-519G16.3", "Chr 15: 45,448,427-45,513,767 (+)", "3.7E-10", "1.44E-07", "0.494"], ["ENSG00000254418.1", "RP11-21 L19.1", "Chr 11: 14,262,846-14,273,691 (−)", "2.96E-11", "1.73E-08", "0.507"], ["ENSG00000240666.2", "MME-AS1", "Chr 3: 155,158,370-155,183,285 (−)", "4.33E-15", "1.01E-11", "0.666"]], "row_count": 18, "column_count": 6, "numeric_cells": 96, "header_rows": 1, "locator": "section[12]/table-wrap[1]#Tab2"}}, {"id": "asset:table:pmid:28103885:3", "role": "table", "format": "jats-table", "media_type": "application/vnd.jats.table+json", "uri": null, "sha256": "sha256:6f38212adea253f6e4d7433ce489bc4ebfb1f6c8ba66fd3273037af57050f879", "bytes": 1698, "access": "open", "state": "verified", "reader": "read_table", "reader_status": "available", "identifier": "section[14]/table-wrap[1]#Tab3", "version": null, "note": "Univariate and multivariate Cox regression analysis of overall survival in each dataset", "structure": {"pmcid": "PMC5248456", "section_index": 14, "section_title": "Further validation of lncRNA-based molecular signature in the internal validation cohort and entire GSE31312 cohort", "row_count": 18, "column_count": 7}, "table": {"label": "Table 3", "caption": "Univariate and multivariate Cox regression analysis of overall survival in each dataset", "rows": [["Variables", "Univariate analysis", "Multivariate analysis"], ["HR", "95% CI of HR", "P value", "HR", "95% CI of HR", "P value"], ["GSE31312 cohort (n = 426)"], ["SubSigLnc-17 (ABC vs. GCB)", "1.638", "1.19-2.254", "0.002", "1.422", "0.997-2.028", "0.052"], ["Age (> = 60 vs. <60)", "2.01", "1.41-2.864", "1.12E-04", "1.946", "1.315-2.881", "8.79E-04"], ["Gender (Male vs. Female)", "0.959", "0.697-1.32", "0.798", "0.843", "0.597-1.189", "0.331"], ["Stage (III/IV vs. I/II)", "2.314", "1.646-3.251", "1.35E-06", "1.707", "1.135-2.567", "0.01"], ["LDH (High vs. Normal)", "2.035", "1.362-3.04", "5.19 E-04", "1.475", "0.973-2.236", "0.067"], ["No. of extranodal sites (≥2 vs. < 2)", "2.247", "1.598-3.16", "3.23E-06", "1.778", "1.213-2.605", "0.003"], ["ECOG (≥2 vs. < 2)", "2.195", "1.556-3.097", "7.48E-06", "1.584", "1.065-2.355", "0.023"], ["GSE10846 cohort (n = 350)"], ["SubSigLnc-17 (ABC vs. GCB)", "2.364", "1.673-3.341", "1.10E-06", "2.093", "1.391-3.149", "3.94E-04"], ["Age (> = 60 vs. <60)", "2.099", "1.464-3.009", "5.50E-05", "1.988", "1.31-3.016", "0.001"], ["Gender (Male vs. Female)", "1.017", "0.724-1.429", "0.922", "0.993", "0.676-1.46", "0.972"], ["Stage (III/IV vs. I/II)", "1.747", "1.239-2.464", "0.001", "1.147", "0.762-1.727", "0.51"], ["LDH (High vs. Normal)", "2.643", "1.791-3.899", "9.72E-07", "2.038", "1.341-3.096", "8.59E-04"], ["No. of extranodal sites (≥2 vs. < 2)", "1.899", "1.087-3.317", "0.024", "1.183", "0.58-2.415", "0.644"], ["ECOG (≥2 vs. < 2)", "2.968", "2.091-4.214", "1.19E-09", "1.907", "1.246-2.918", "0.003"]], "row_count": 18, "column_count": 7, "numeric_cells": 96, "header_rows": 2, "locator": "section[14]/table-wrap[1]#Tab3"}}], "gaps": ["asset:data:geo:GSE10846 not downloaded", "asset:data:geo:GSE10846 licence not read", "asset:data:geo:GSE31312 not 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