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Germinal center B-cell-like diffuse Large B-cell Lymphoma (GCB) DLBCL

Written2017-09Luis Miguel Juárez Salcedo, Samir Dalia
Principe de Asturias University Hospital, Madrid, Spain; (LMJC); Oncology and Hematology, Mercy Clinic Joplin, Joplin, MO, USA; (SD)

Abstract Review on Germinal center B-cell-like diffuse Large B-cell Lymphoma (GCB) DLBCL, with data on clinics, and genes.

Keywords Diffuse Large B-cell Lymphoma, Germinal center

(Note : for Links provided by Atlas : click)


ICD-Topo C420,C421,C424
ICD-Morpho 9680/3 Diffuse large B-cell lymphoma (DLBCL), NOS; Primary DLBCL of the CNS; Primary cutaneous DLBCL, leg type; EBV positive DLBCL of the elderly; DLBCL associated with chronic inflammation; B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma
Atlas_Id 2147
Other names(GCB) DLBCL

Clinics and Pathology

Disease Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% to 40% of all non-Hodgkin lymphoma (NHL) cases. (Sujobert P, et al., 2016) Gene expression profiling (GEP) studies have identified ≥ 2 distinct molecular subtypes, termed germinal center B-cell (GCB) and activated B-cell (ABC), which are believed to represent lymphomas arising from different stages of lymphoid differentiation. (Alizadeh AA, et al., 2000; Rosenwald A, et al., 2002) The GCB DLBCL represent approximately 50% of DLBCL. (Karmali R, et al., 2017).
GCB DLBCLs are thought to arise from normal germinal center B cells and show features that are consistent with germinal center B cell derivation. (Alizadeh AA, et al., 2000; Rosenwald A, et al., 2002) These harbor oncogenetic hits typical such as t(14:18) translocation, the mutations of epigenetic modifiers ( EZH2, KMT2D) or mutations in the genes encoding the S1PR2 receptor or its signal transduction protein GNA13. (Sehn L, et al., 2015)
This subtype has a cure rate of about 70 to 80% with currently available immune chemotherapy regimens like R-CHOP, R-DHAP, R-ICE or DA-EPOCH-R. (Thieblemont C, et al., 2011; Delarue R, et al., 2013; Cunningham D, et al., 2013)
Etiology GCB DLBCLs are believed to derived from lymphoid cells residing in the germinal center and therefore express genes normally detected in germinal center B cells, such as CD10, LMO2 and the transcriptional repressor Bcl6. (Béguelin W, et al., 2013; Sujobert P, et al., 2016; Lenz G et al. 2008) Approximately 30% to 40% of GCB DLBCLs have a t(14:18) translocation, 30% have REL amplifications, 20% have mutations of the histone methyltransferase EZH2 and 10% have a deletion of the PTEN, all of which are virtually never seen in ABC DLBCL. (Pfeifer M, et al., 2013; Morin RD, et al., 2011; Pasqualucci L, et al., 2011)
Epidemiology The median age is 70 years old (occur in children and adults). The incidence is between 25-30% of adult NHL's (western countries), with slight male predominance.
Pathology GC-DLBCL is described as CD-10 positive, Bcl-6 positive and MUM-1 negative. (Sujobert P, et al., 2016)
Treatment It is the most curable subtype, with a 5-year overall survival (OS) rate of nearly 75%. The GC subtype has a cure rate of about 70 to 80% with currently available therapies. The infusional regimen of dose-adjusted etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (DA-EPOCH-R) or Hyper CVAD-R, have yield promising results especially in the GC- DLBCL subtype. (Petrich AM, et al., 2014) Similarly, R-CHOP, R-DHAP and R-ICE could be valuable options of treatment. (Delarue R, et al., 2013; Cunningham D, et al., 2013). In the new era of targeted therapy, it could soon benefit from inhibitors of the EZH2, Bcl-2 and Bcl-6 oncoproteins.


GC-DLBCL largely express gene products, such as Bcl-6, GCSAM (HGAL) and LMO2 that define normal germinal center B cells within the germinal center light zone. (Alizadeh AA, et al., 2000; Rosenwald A, et al., 2002) Malignant GC-DLBCL clones continue to undergo somatic hypermutation of their variable immunoglobulin heavy chain gene and have often switched IgH classes that are mediated by AID, an enzyme that is characteristically expressed at high levels in germinal center B cells. (Lossos IS, et al., 2000) The GC-DLBCL subtype is characterized by low level of NF-kB activation and its survival is not dependent on NF-kB. (Davis RE, et al., 2001; Dal Porto JM, et al., 2004)
Translocation of BCL2and/or MYC genes, are commonly observed in GC-DLBCL. These translocation lead to constitutive activation of c-MYC and the anti-apoptotic Bcl-2 protein and to a malignant transformation by preventing terminal differentiation or blocking apoptosis. (Shaffer 3rd AL, et al., 2012) 20% have gain of function mutations of the histone methyltransferase EZH2, which is a master regulator of the GC-DLBCL phenotype and cooperates, partly with Bcl-2 and BCL6 to mediate lymphomagenesis. Is also characterized by downregulation of the phosphatase and tensin homologue (PTEN) and concomitant upregulation of phosphatidylinositol-3-kinase (PI3K) signaling pathway. (Sehn L, et al., 2015)


Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM
Nature 2000 Feb 3;403(6769):503-11
PMID 10676951
EZH2 is required for germinal center formation and somatic EZH2 mutations promote lymphoid transformation
Béguelin W, Popovic R, Teater M, Jiang Y, Bunting KL, Rosen M, Shen H, Yang SN, Wang L, Ezponda T, Martinez-Garcia E, Zhang H, Zheng Y, Verma SK, McCabe MT, Ott HM, Van Aller GS, Kruger RG, Liu Y, McHugh CF, Scott DW, Chung YR, Kelleher N, Shaknovich R, Creasy CL, Gascoyne RD, Wong KK, Cerchietti L, Levine RL, Abdel-Wahab O, Licht JD, Elemento O, Melnick AM
Cancer Cell 2013 May 13;23(5):677-92
PMID 23680150
Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles
Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D
Lancet 2013 May 25;381(9880):1817-26
PMID 23615461
Constitutive nuclear factor kappaB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells
Davis RE, Brown KD, Siebenlist U, Staudt LM
J Exp Med 2001 Dec 17;194(12):1861-74
PMID 11748286
Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial
Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A
Lancet Oncol 2013 May;14(6):525-33
PMID 23578722
Molecular Subtyping in Diffuse Large B Cell Lymphoma: Closer to an Approach of Precision Therapy
Karmali R, Gordon LI
Curr Treat Options Oncol 2017 Feb;18(2):11
PMID 28229364
MYC-associated and double-hit lymphomas: a review of pathobiology, prognosis, and therapeutic approaches
Petrich AM, Nabhan C, Smith SM
Cancer 2014 Dec 15;120(24):3884-95
PMID 25060588
PI3K/AKT addiction in subsets of diffuse large B-cell lymphoma
Pfeifer M, Lenz G
Cell Cycle 2013 Nov 1;12(21):3347-8
PMID 24091535
The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma
Rosenwald A, Wright G, Chan WC, Connors JM, Campo E, Fisher RI, Gascoyne RD, Muller-Hermelink HK, Smeland EB, Giltnane JM, Hurt EM, Zhao H, Averett L, Yang L, Wilson WH, Jaffe ES, Simon R, Klausner RD, Powell J, Duffey PL, Longo DL, Greiner TC, Weisenburger DD, Sanger WG, Dave BJ, Lynch JC, Vose J, Armitage JO, Montserrat E, López-Guillermo A, Grogan TM, Miller TP, LeBlanc M, Ott G, Kvaloy S, Delabie J, Holte H, Krajci P, Stokke T, Staudt LM; Lymphoma/Leukemia Molecular Profiling Project
N Engl J Med 2002 Jun 20;346(25):1937-47
PMID 12075054
Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity
Sehn LH, Gascoyne RD
Blood 2015 Jan 1;125(1):22-32
PMID 25499448
Pathogenesis of human B cell lymphomas
Shaffer AL 3rd, Young RM, Staudt LM
Annu Rev Immunol 2012;30:565-610
PMID 22224767
Molecular Classification of Diffuse Large B-cell Lymphoma: What Is Clinically Relevant? Hematol Oncol Clin North Am
Sujobert P, Salles G, Bachy E
Hematol Oncol Clin North Am. 2016 Dec;30(6):1163-1177. doi: 10.1016/j.hoc.2016.07.001.
PMID 27888873
The germinal center/activated B-cell subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory diffuse large B-cell lymphoma: a bio-CORAL study
Thieblemont C, Briere J, Mounier N, Voelker HU, Cuccuini W, Hirchaud E, Rosenwald A, Jack A, Sundstrom C, Cogliatti S, Trougouboff P, Boudova L, Ysebaert L, Soulier J, Chevalier C, Bron D, Schmitz N, Gaulard P, Houlgatte R, Gisselbrecht C
J Clin Oncol 2011 Nov 1;29(31):4079-87
PMID 21947824


This paper should be referenced as such :
Luis Miguel Juarez Salcedo, Samir Dalia
Germinal center B-cell-like diffuse Large B-cell Lymphoma (GCB) DLBCL
Atlas Genet Cytogenet Oncol Haematol. 2018;22(10):450-452.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other genes implicated (Data extracted from papers in the Atlas) [ 6 ]


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