Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2017

Open Access 01-12-2017 | Research

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

Authors: Meng Zhou, Hengqiang Zhao, Wanying Xu, Siqi Bao, Liang Cheng, Jie Sun

Published in: Molecular Cancer | Issue 1/2017

Login to get access

Abstract

Background

Diffuse 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.

Methods

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.

Results

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.

Conclusions

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.
Appendix
Available only for authorised users
Literature
1.
Tilly H, Gomes da Silva M, Vitolo U, Jack A, Meignan M, Lopez-Guillermo A, Walewski J, Andre M, Johnson PW, Pfreundschuh M, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26 Suppl 5:v116–125.CrossRefPubMed
2.
Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105:1684–92.CrossRefPubMedPubMedCentral
3.
Wright G, Tan B, Rosenwald A, Hurt EH, Wiestner A, Staudt LM. A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2003;100:9991–6.CrossRefPubMedPubMedCentral
4.
Abramson JS, Shipp MA. Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. Blood. 2005;106:1164–74.CrossRefPubMed
5.
Pan H, Jiang Y, Boi M, Tabbo F, Redmond D, Nie K, Ladetto M, Chiappella A, Cerchietti L, Shaknovich R, et al. Epigenomic evolution in diffuse large B-cell lymphomas. Nat Commun. 2015;6:6921.CrossRefPubMedPubMedCentral
6.
Younes A. Prognostic Significance of Diffuse Large B-Cell Lymphoma Cell of Origin: Seeing the Forest and the Trees. J Clin Oncol. 2015;33:2835–6.CrossRefPubMed
7.
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403:503–11.CrossRefPubMed
8.
Cai YD, Huang T, Feng KY, Hu L, Xie L. A unified 35-gene signature for both subtype classification and survival prediction in diffuse large B-cell lymphomas. PLoS One. 2010;5:e12726.CrossRefPubMedPubMedCentral
9.
Lawrie CH, Soneji S, Marafioti T, Cooper CD, Palazzo S, Paterson JC, Cattan H, Enver T, Mager R, Boultwood J, et al. MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma. Int J Cancer. 2007;121:1156–61.CrossRefPubMed
10.
Visco C, Li Y, Xu-Monette ZY, Miranda RN, Green TM, Li Y, Tzankov A, Wen W, Liu WM, Kahl BS, et al. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study. Leukemia. 2012;26:2103–13.CrossRefPubMedPubMedCentral
11.
Shaknovich R, Geng H, Johnson NA, Tsikitas L, Cerchietti L, Greally JM, Gascoyne RD, Elemento O, Melnick A. DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma. Blood. 2010;116:e81–89.CrossRefPubMedPubMedCentral
12.
Monti S, Savage KJ, Kutok JL, Feuerhake F, Kurtin P, Mihm M, Wu B, Pasqualucci L, Neuberg D, Aguiar RC, et al. Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. Blood. 2005;105:1851–61.CrossRefPubMed
13.
Lenz G, Wright GW, Emre NC, Kohlhammer H, Dave SS, Davis RE, Carty S, Lam LT, Shaffer AL, Xiao W, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci U S A. 2008;105:13520–5.CrossRefPubMedPubMedCentral
14.
15.
Fatica A, Bozzoni I. Long non-coding RNAs: new players in cell differentiation and development. Nat Rev Genet. 2014;15:7–21.CrossRefPubMed
16.
Fatima R, Akhade VS, Pal D, Rao SM. Long noncoding RNAs in development and cancer: potential biomarkers and therapeutic targets. Mol Cell Ther. 2015;3:5.CrossRefPubMedPubMedCentral
17.
18.
Yang J, Lin J, Liu T, Chen T, Pan S, Huang W, Li S. Analysis of lncRNA expression profiles in non-small cell lung cancers (NSCLC) and their clinical subtypes. Lung Cancer. 2014;85:110–5.CrossRefPubMed
19.
Zhao W, Luo J, Jiao S. Comprehensive characterization of cancer subtype associated long non-coding RNAs and their clinical implications. Sci Rep. 2014;4:6591.CrossRefPubMedPubMedCentral
20.
Su X, Malouf GG, Chen Y, Zhang J, Yao H, Valero V, Weinstein JN, Spano JP, Meric-Bernstam F, Khayat D, Esteva FJ. Comprehensive analysis of long non-coding RNAs in human breast cancer clinical subtypes. Oncotarget. 2014;5:9864–76.CrossRefPubMedPubMedCentral
21.
Liu YR, Jiang YZ, Xu XE, Yu KD, Jin X, Hu X, Zuo WJ, Hao S, Wu J, Liu GY, et al. Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer. Breast Cancer Res. 2016;18:33.CrossRefPubMedPubMedCentral
22.
Sun J, Cheng L, Shi H, Zhang Z, Zhao H, Wang Z, Zhou M. A potential panel of six-long non-coding RNA signature to improve survival prediction of diffuse large-B-cell lymphoma. Sci Rep. 2016;6:27842.CrossRefPubMedPubMedCentral
23.
Brazao TF, Johnson JS, Muller J, Heger A, Ponting CP, Tybulewicz VL. Long noncoding RNAs in B-cell development and activation. Blood. 2016;128:e10–19.CrossRefPubMedPubMedCentral
24.
Petri A, Dybkaer K, Bogsted M, Thrue CA, Hagedorn PH, Schmitz A, Bodker JS, Johnsen HE, Kauppinen S. Long Noncoding RNA Expression during Human B-Cell Development. PLoS One. 2015;10:e0138236.CrossRefPubMedPubMedCentral
25.
Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B, Goldschmidt N, Iqbal J, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359:2313–23.CrossRefPubMed
26.
Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF, Bernd HW, Cogliatti SB, Dierlamm J, Feller AC, et al. A biologic definition of Burkitt’s lymphoma from transcriptional and genomic profiling. N Engl J Med. 2006;354:2419–30.CrossRefPubMed
27.
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ, Scherf U, Speed TP. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics. 2003;4:249–64.CrossRefPubMed
28.
Cheadle C, Vawter MP, Freed WJ, Becker KG. Analysis of microarray data using Z score transformation. The Journal of molecular diagnostics. 2003;5:73–81.CrossRefPubMedPubMedCentral
29.
30.
Zhou M, Guo M, He D, Wang X, Cui Y, Yang H, Hao D, Sun J. A potential signature of eight long non-coding RNAs predicts survival in patients with non-small cell lung cancer. J Transl Med. 2015;13:231.CrossRefPubMedPubMedCentral
31.
Zhou M, Zhao H, Wang Z, Cheng L, Yang L, Shi H, Yang H, Sun J. Identification and validation of potential prognostic lncRNA biomarkers for predicting survival in patients with multiple myeloma. J Exp Clin Cancer Res. 2015;34:102.CrossRefPubMedPubMedCentral
32.
Du Z, Fei T, Verhaak RG, Su Z, Zhang Y, Brown M, Chen Y, Liu XS. Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. Nat Struct Mol Biol. 2013;20:908–13.CrossRefPubMedPubMedCentral
33.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Methodol. 1995;57:289–300.
34.
Yanagisawa K, Tomida S, Shimada Y, Yatabe Y, Mitsudomi T, Takahashi T. A 25-signal proteomic signature and outcome for patients with resected non-small-cell lung cancer. J Natl Cancer Inst. 2007;99:858–67.CrossRefPubMed
35.
da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009;4:44–57.CrossRef
36.
37.
38.
Li R, Qian J, Wang YY, Zhang JX, You YP. Long noncoding RNA profiles reveal three molecular subtypes in glioma. CNS Neurosci Ther. 2014;20:339–43.CrossRefPubMed
39.
Chen H, Xu J, Hong J, Tang R, Zhang X, Fang JY. Long noncoding RNA profiles identify five distinct molecular subtypes of colorectal cancer with clinical relevance. Mol Oncol. 2014;8:1393–403.CrossRefPubMed
Metadata
Title
Discovery and validation of immune-associated long non-coding RNA biomarkers associated with clinically molecular subtype and prognosis in diffuse large B cell lymphoma
Authors
Meng Zhou
Hengqiang Zhao
Wanying Xu
Siqi Bao
Liang Cheng
Jie Sun
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2017
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-017-0580-4

Other articles of this Issue 1/2017

Molecular Cancer 1/2017 Go to the issue

Research

Hypoxia-inducible microRNA-224 promotes the cell growth, migration and invasion by directly targeting RASSF8 in gastric cancer

Research

Syndecan-1 is a novel molecular marker for triple negative inflammatory breast cancer and modulates the cancer stem cell phenotype via the IL-6/STAT3, Notch and EGFR signaling pathways

Research

Oncogenic miR-210-3p promotes prostate cancer cell EMT and bone metastasis via NF-κB signaling pathway

Review

Circles reshaping the RNA world: from waste to treasure

Research

MicroRNA-608 inhibits proliferation of bladder cancer via AKT/FOXO3a signaling pathway

Research

Long noncoding RNA MALAT1 regulates autophagy associated chemoresistance via miR-23b-3p sequestration in gastric cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits