Molecular genetics related to non-Hodgkin lymphoma

Ming Guo 1 , Xianglin Mao 1 ,  and Xiaoqing Ding 1
  • 1 Department of Hematology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100078, China
Ming Guo, Xianglin Mao and Xiaoqing Ding

Abstract

Non-Hodgkin lymphoma (NHL) is a serious disease, with a high proportion of mortality. Molecular genetic abnormalities are very common in NHL, but specific characterization in accordance to molecular genetics for lymphoma subtypes is not yet completed. This article summarizes the relationship between B- and T-NHL and molecular genetics. We focus on NHL subtypes and emphasize its features to figure out what is exposed about NHL genetics. The basis of this method is collection of biological specimens for genomic and genetic analyses. This summary may help to prompt prediction of outcomes and guide therapy in the future.

1 Introduction

Lymphomas are hematological malignancies, which are divided into non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL). Non-Hodgkin lymphoma (NHL) is a lymphoma-derived malignancy that makes up about 90% of all malignant lymphoma [1]. According to its origin, NHL is classified into B-cell NHL and T-cell NHL. The most common types are follicular lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL) [2,3]. NHL mortality has increased in recent years and has become the seventh most frequently occurring cancer [4]. Although many therapies have emerged, for example the current combination of cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab chemotherapy [5], the fundamental molecular genetics are still unclear. This article will help elucidate the relationship between NHL and miRNAs and other molecular genetic mechanisms respectively.

2 Comprehensive miRNA sequence analysis in NHL patients

miRNAs (microRNA) are 17-25 nucleotide short RNA molecules. They participate in the regulation of gene expression and play critical roles in nearly all biological processes. miRNAs induce cleavage or translational processing of messenger RNAs with complementary miRNA binding sites [6]. Many types of miRNAs participate in cancer’s occurrence and development. For example diffuse large B-cell lymphoma (DLBCL), which is a serious form of NHL [5]. According to the derivation from different cells of origin, DLBCL is divided into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes [5]. Many miRNAs act as a marker of cancer for different subtypes. Such as miR-155, miR-21, and miR-221, which are expressed in DLBCL but not in non-malignant B-cells [7]. Some miRNAs exist in serum and act as an index of patient prognosis. For example, miR-21, miR-222, miR-23a and miR27a were not only identified to be related to prognosis but also survival of patients [8-11]. Allowing for different subtypes of DLBCL, which are ABC-DLBCL and GCB-DLBCL, differential analysis was performed for each miRNA by comparing expression value. Deep sequencing of miRNAs provides a method to obtain expression value [12]. About 23 miRNAs are upregulated in ABC-DLBCL and 30 miRNAs have higher expression in GCB-DLBCL [12].

As a reference indicates, there are many novel effects on NHL lines [13-14]. Abundant expression of miRNA in DLBCL is characterized by interaction with genes showing enrichment for biological process, which includes cell cycle, metabolism, chromatin modification, protein modification and organelle organization [15]. In this reference, Deep sequencing of miRNA (miRNA –seq) was used to study expression and dysregulation of candidate novel and known miRNAs. According to this report, 25 miRNA appeared to be related to survival of DLBCL patients. Among these 25 miRNAs, when miR-28-5p, miR-214-5p, miR-339-3p and miR-5586-5p are upregulated, the survival of patients increases. However, other miRNAs, such as miR-324-5p and NOVELMOO203M, occurring with higher level of expression are associated with increased mortality [16]. In order to study the relationship between miRNA expression and patient overall survival (OS) and progression-free-survival (PFS), log-rank tests on X-tile-derived low and high expression patient groups were performed [15]. It is reported that 58 miRNAs are associated with OS and 45 miRNAs are related to PFS. For example, miR-330 [16], miR-93, miR-148a, miR-151, miR-28 [17], miR-155 [18], miR-181a [18] etc. In view of the effect of miRNAs on cancer process, 15 miRNAs are identified as abundantly expressed in B-cells. One of these 15 miRNAs, miR-142, plays an important role in B-cell function [19]. Three of these 15 miRNAs, which are miR-3150b-3p, miR-6087, and miR-4491, are abundantly expressed in B-cells [20]. It is noteworthy that the miR-200 family, including miR-200a-3p, miR-200a-5p, miR-200b-3p, miR-200b-5p, miR-200c-3p and miR-200-5p are decreased significantly in expression in B-cells [21].

This data suggests that these miRNAs may participate in some specific function in B-cell lymphoma. These findings may provide us with a new understanding of NHL lymphoma biology and therapeutic schedule.

3 Molecular genetics of NHL in different subtypes

NHL commonly occurs along with molecular genetic abnormalities. Certain molecular genetic abnormalities in NHL are related to specific lymphoma subtypes, which are associated with prognosis or potential therapeutic targets. Different translocations and mutations can be characteristic of different subtypes of NHL. Currently, classification of NHL is based on morphology and immunophenotype. This article will give you a new insight into classification of NHL from specific genetic changes (Table 1), which may be helpful with prediction of outcome and guidance of therapy.

Table 1

B-cell Non-Hodgkin lymphoma genetics [41].

LymphomaGenetic change
Burkitt lymphoma (BL)t(8;14)(q24;q32)/MYC-IGH
t(2;8)(2q11;q24)/IGK-MYC
t(8;22)(q24;q11)/MYC-IGL
11q gain/loss
13q gain/loss
ID3 and/or TCF3 mutation
Diffuse large B-cell lymphoma (DLBCL)8q24 MYC rearrangements

t(14;18)(q32;q21) IGH-BCL2
3q27 BCL6 rearrangements

Double/tripe hit lymphoma (MYC/BCL2, MYC/BCL6, MYC/BCL2/BLC6)
IRF4 rearrangements

GCB/ABC type gene expression profiles
Follicular lymphoma (FL)t (14;18)(q32;q21)
IGH-BCL2 IRF4 rearrangements
TNFRSF14 mutation

3.1 Burkitt lymphoma

Burkitt lymphoma (BL) is characterized by overexpression of the oncogene MYC. This form results from translocation, combining the MYC locus at 8q24.21 with an immunoglobulin gene locus [22]. Although overexpression of MYC is driven by an immunoglobulin gene enhancer generally associated with BL, recurrent genetic abnormalities apart from MYC are reported. Abnormalities of chromosomes 1, 6, 7, 13, 17 and 22 are reported in pediatric BL [23-24]. In studies of BL samples, cytogenetic abnormalities have been reported. About 25-33% of BL patients have gained through translocation in 1q, 11-18% have gained in 3q and 14-18% have lost in 17q [25,26]. Meanwhile, 13q33.1-q34 and Xp22.33 are both lost. This molecular genetic abnormality in BL has become a good guidance for classification of NHL. Taking 25 cases of BL for example, nineteen of atypical BL cases were classified as BL by the molecular classifier. Furthermore, some cases diagnosed as DLBCL in terms of pathology were classified correctly.

3.2 Diffuse large B-cell lymphoma

DLBCL is defined via characterization of morphology and immunophenotype. This type of NHL is closely associated with BCL6, BCL2 and MYC translocations. If any two of these genetic translocations are referred to as double-hit lymphoma, prognosis for adult patients will be poor [27]. Therefore, studying double-hit lymphoma cases may have an effect on treatment decisions. DLBCL is classified into activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes, which is mentioned above. When the DLBCL gene is sequenced, it is found that MYD88, KLHL14, CD79B, SIGLEC10 are commonly upregulated in the ABC subtype; GNA13, BCL2, EZH2 predominantly in the GCB subtype [28]. Another novel finding demonstrates that mutation of EZH2 and KMT2D (MLL2) in the GCB subtype may impact histone modifications and transcriptional regulation in DLBCL patients [29, 30]. Primary mediastinal large B-cell lymphoma (PMBL) that mainly arises in the anterior mediastinum is more common in adolescent and young adult female patients [24]. Currently, it is indicated that when genomic gains of 9p24 [JAK2, CD274 (PDL1)] and PDCD1L (PD-L2)] and 2p15 (REL and BCL11A) are enhanced in PMBL, immune system and STAT3 will be activated [32]. As an uncommon lymphoma, PMBL is recognized distinctly from typical DLBCL, which is helpful with targeted therapies [33].

3.3 B lymphoblastic lymphoma

The more common type of B lymphoblastic lymphoma is B acute lymphoblastic leukemia (B-ALL), with B lymphoblastic lymphoma (B-LBL) being much more rare. Limited data for B-LBL results in limited therapies. B-LBL is treated according to B-ALL protocols [34]. Thus, it is urgent to distinguish B-ALL from B-LBL via genomic. A study shows that a translocation t(2;8) (p12;q12) related to the site of the ICK locus, 2p12 has become the characteristic of B-LBL. However, further work with larger sample sizes should be done to characterize the genomic features of B-LBL, which is very important for distinction from B-ALL.

3.4 Follicular lymphoma

Follicular lymphoma (FL) is an uncommon type of B-cell NHL. Most FL cases are characterized by t(14;18) translocation involving IGH and BCL2, which results in overexpression of BCL2 [24]. Generally, FL betides older adults and shows significant differences with younger patients in morphological, clinical and genetic features. Cases that occur in younger patients are characterized by mutation of TNFRSF14 at 1p36 in about 41% [36].

3.5 T lymphoblastic lymphoma

T lymphoblastic lymphoma (T-LBL) is the second most common NHL. Another similar subtype of T-cell lymphoma is T-cell Acute Lymphoblastic Leukemia (T-ALL). As WHO classification showed, these two types of lymphoma are both named as T lymphoblastic leukaemia/ lymphoma [37]. However, T-LBL patients demonstrate poor outcomes for therapy or relapse when treated the same as T-ALL. Therefore, it is necessary to evaluate large cohorts to find more detailed genetic characterization compared with T-ALL (Table 2). This article will list some examples detailing the different molecular genetics between T-LBL and T-ALL.

Table 2

T-LBL genetics [41].

Genetic changesSignificance
Absence of Bi-allelicImplies early T cell maturational arrest
TRG deletion (ABD)NS
NOTCHI-activating mutationMost common gene mutation
FBXW7 mutationDecrease NOTCHI degradation
PTEN mutationActivates PI3K-SKT cascade
KRAS and NRAS mutationNS
LOH6q16Distinct from LOH6q14-15 in T-ALL; affects CASP8AP2
Deletion or LOH of chromosome 9pAffects CDKN2A/CDKN2B loci, which encode multiple tumor suppressors

T-LBL, T cell lymphoblastic lymphoma; LOH, loss of heterozygosity; NS, not significant

About 56-69% abnormal karyotypes, with 3-5% hyperdiploid, 25-44% pseudodiploid and 22-25% hyperdiploid were shown in both T-LBL and T-ALL [38]. Translocation of the T-cell receptor (TCR) loci exists in both T-LBL and T-ALL. Transformation of expression occurs when oncogenes are combined with TCR regulatory regions on chromosomes 7q34 [TRB (TCR β)], 7q14 [TRG (TCR γ)], or 14q11 [TRD (TCR α) and TRD (TCR δ)] [39]. A recent study shows that 2-15% of pediatric T-LBL patients also have translocation of 9q34. Many of the oncogenes associated with T-ALL, such as NOTCHI, ABL1, SET and NUP214 also exists in 9q34. Thus, it is reasonable that translocation involving 9q34 are more common in T-ALL than T-LBL [38]. The gene FBXW7 is closely related to NOTCHI mutation. Reduced FBXW7 function via mutation, leads to the up regulation of the oncogene NOTCHI and thereby increases its signaling [40]. Although collecting the genetic characteristics related to gene expression for T-LBL remains a daunting task, the addition of new and helpful sequencing technologies and group efforts will make it within our reach.

4 Summary and further study

This article has summarized some of the key molecular genetics of NHL from miRNAs (DLBCL for example) and other types of molecular genetics (BL, DLBCL, B-and T-LBL, FL for examples). Some of these molecular genetic abnormalities involved translocation and mutation. All of these phenomenon play crucial roles in the progression, pathogenesis and prognosis of cancer. Difference in roles of each molecular genetic component also provides for us more information about the classification of NHL and guidance for therapeutic decision-making. Overall, NHL is very common in oncology and constitutes a large percentage of all neoplasia. NHL molecular characterization is not comprehensive for all subtypes due to a lack of adequate sampling. In order to improve therapeutic effects and outcomes for any subtype of NHL, a large cooperation and effort must be made to collect and share information about cutting-edge genomic and genetic analyses.

Conflict of interest

Authors declare nothing to disclose.

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  • [1]

    Ekstrom-Smedby K., Epidemiology and etiology of non-Hodgkin lymphoma–a review, Acta Oncol., 2006, 45, 258–271.

  • [2]

    Nogai H., Dorken B., Lenz G., Pathogenesis of non-Hodgkin’s lymphoma, Clin Oncol., 2011, 29, 1803–1811.

  • [3]

    Willis TG., Dyer MJ., The role of immunoglobulin translocations in the pathogenesis of B-cell malignancies, Blood, 2000, 96, 808–822.

  • [4]

    Qiao Z., Zhe Y., Zhuqing J., Cuiling L., Chen G., Huafei L., et al., ISL-1 is overexpressed in non-Hodgkin lymphoma and promotes lymphoma cell proliferation by forming a p-STAT3/p-c-Jun/ISL-1 complex, Mol. Cancer, 2014, 13-181.

  • [5]

    Alizadeh AA., Eisen MB., Davis RE., Ma C., Lossos IS., Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling, Nature, 2000, 403, 503–11.

  • [6]

    Roehle A., Hoefig KP., Repsilber D., Thorns C., Ziepert M., Wesche KO., et al., MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas, Br. J. Haematol., 2008, 142, 732–44.

  • [7]

    Lawrie CH., Soneji S., Marafioti T., Charles H., Cooper CDO., Palazzo S., et al., MicroRNA expression distinguishes between germinal center B cell-like and activated B cell-like subtypes of diffuse large B cell lymphoma, Cancer, 2007, 121, 1156–61.

  • [8]

    Lawrie CH., Chi J., Taylor S., Tramonti D., Ballabio E., Palazzo S., et al., Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma, Cell. Mol. Med., 2009, 13, 1248–60.

  • [9]

    Montes-Moreno S., Martinez N., Sanchez-Espiridión B., Diaz Uriate R., Rodriquez ME., Saez A., et al., miRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy, Blood, 2011, 118, 1034–40.

  • [10]

    Alencar AJ., Malumbres R., Kozloski GA., MicroRNAs are independent predictors of outcome in diffuse large B-cell lymphoma patients treated with R-CHOP, Clin. Cancer Res., 2011, 17, 4125–35.

  • [11]

    Tamura K., Stechel G., Peterson D., Filipski A., Kumar S., MEGA6: Molecular Evolutionary Genetics Analysis version 6.0, Mol. Biol. Evol., 2013, 30 (12), 2725-9.

  • [12]

    Jima DD., Zhang J., Jacobs C., Richards KL., Dunphy CH., Choi WW., et al., Deep sequencing of the small RNA transcriptome of normal and malignant human B cells identifies hundreds of novel microRNAs, Blood, 2010, 116, 118–27.

  • [13]

    Basso K., Sumazin P., Morozov P., Identification of the human mature B cell miRNome, Immunity, 2009, 30, 744–52.

  • [14]

    Emilia L Lim., Diane L Trinh., David W Scott., Comprehensive miRNA sequence analysis reveals survival differences in diffuse large B-cell lymphoma patients, Genome Biol., 2015, 16, 18.

  • [15]

    Ott CE., Horbett D., Schwill S., MicroRNAs differentially expressed in postnatal aortic development downregulate elastin via 3’ UTR and coding-sequence binding sites, PLoS One, 2011, 6, 16250.

  • [16]

    Camp RL., Dolled-Filhart M., Rimm DL., X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization, Clin. Cancer Res., 2004, 10, 7252–9.

  • [17]

    Lawrie CH., Chi J., Taylor S., Tramonti D., Ballabio E., Palazzo S., et al., Expression of microRNAs in diffuse large B cell lymphoma is associated with immunophenotype, survival and transformation from follicular lymphoma, Cell. Mol. Med., 2009, 13, 1248–60.

  • [18]

    Montes-Moreno S., Martinez N., Sanchez-Espiridión B., miRNA expression in diffuse large B-cell lymphoma treated with chemoimmunotherapy, Blood, 2011, 118, 1034–40.

  • [19]

    Roehle A., Hoefig KP., Repsilber D., MicroRNA signatures characterize diffuse large B-cell lymphomas and follicular lymphomas, Br. J. Haematol., 2008, 142, 732–44.

  • [20]

    Tarantul V., Nikolaev A., Hannig H., Kalmyrzaev B., Muchoyan I., Maximov V., et al., Detection of Abundantly Transcribed Genes and Gene Translocation in Human Immunodeficiency Virus-Associated Non-Hodgkin’s Lymphoma, Clin. Cancer Res., 2011, 17, 4125–35.

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    Shaffer AL., Young RM., Staudt LM., Pathogenesis of human B cell lymphomas, Annu. Rev. Immunol., 2012, 30, 565–610.

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    Haecker I., Gay LA., Yang Y., Herpesvirus miRNA function in primary effusion lymphomas, PLoS Pathog., 2012, 8, e1002884.

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    Caramuta S., Lee L., Ozata DM., Akçakaya P., Georgii-Hemming P., Xie H., et al., Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma, Blood Cancer J., 2013, 3, e152.

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    Swerdlow S.H., Campo E., Harris N.L., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, WHO 2008.

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    Lones M.A., Sanger W.G., Le Beau., Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children’s Cancer Group Study CCG-E08, J. Pediatric Hematol. Oncol., 2004, 26, 169–178.

  • [26]

    Onciu M., Schlette E., Zhou Y., Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma, Cancer, 2006, 107, 1084–1092.

  • [27]

    Poirel H.A., Cairo M.S., Heerema N.A., Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study, Leukemia, 2009, 23, 323–331.

  • [28]

    Schiffman J.D., Lorimer P.D., Rodic, V., Genome wide copy number analysis of paediatric Burkitt lymphoma using formalin-fixed tissues reveals a subset with gain of chromosome 13q and corresponding miRNA over expression, Haematology, 2011, 155, 477–486.

  • [29]

    Scholtysik R., Kreuz M., Klapper W., Burhardt B., Feller AC., Hummel M., et al., Detection of genomic aberrations in molecularly defined Burkitt’s lymphoma by array-based, high resolution, single nucleotide polymorphism analysis, Haematologica, 2010, 95, 2047–2055.

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    Zhang J., Grubor V., Love C.L.., Genetic heterogeneity of diffuse large B-cell lymphoma, Proc. Natl. Acad. Sci. USA, 2013, 110, 1398–1403.

  • [31]

    Morin R.D., Johnson N.A., Severson T.M.., Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large Bcell lymphomas of germinal-center origin, Nat. Genet., 2010, 42, 181–185.

  • [32]

    Morin R.D., Mendez-Lago M., Mungall A.J., Goya R., Mungall KL., Corbett RD., er al., Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma, Nature, 2011, 476, 298–303.

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