Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:High-Grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Kate Berry, MBBS, BBus (Hons), Pathology Queensland

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Mature B-cell neoplasms
Type Large B-cell lymphomas
Subtype(s) Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements

Related Terminology

Acceptable High-grade B-cell lymphoma with MYC and BCL2 rearrangements; high-grade B-cell lymphoma with MYC, BCL2, and BCL6 rearrangements
Not Recommended N/A

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE: ABL1 EXAMPLE: BCR::ABL1 EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: Common (CML) EXAMPLE: D, P, T EXAMPLE: Yes (WHO, NCCN) EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).

EXAMPLE: CIC EXAMPLE: CIC::DUX4 EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5. EXAMPLE: t(4;19)(q25;q13) EXAMPLE: Common (CIC-rearranged sarcoma) EXAMPLE: D EXAMPLE:

DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).

EXAMPLE: ALK EXAMPLE: ELM4::ALK


Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1

EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18. EXAMPLE: N/A EXAMPLE: Rare (Lung adenocarcinoma) EXAMPLE: T EXAMPLE:

Both balanced and unbalanced forms are observed by FISH (add references).

EXAMPLE: ABL1 EXAMPLE: N/A EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways. EXAMPLE: N/A EXAMPLE: Recurrent (IDH-wildtype Glioblastoma) EXAMPLE: D, P, T
editv4:Chromosomal Rearrangements (Gene Fusions)
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This subtype of B-cell lymphoma is defined by a rearrangement of the MYC proto-oncogene, located on chromosome 8q24.  In 39-65% of cases the translocation partner is an immunoglobulin gene, most commonly the IGH region on chromosome 14q32 with the IGK (2p12) and IGL (22q11.2) gene loci less frequently involved[1][2][3][4][5][6]. Non-IG gene partners include 9p13 and 3q27.3 (BCL6)[4]. Additionally, all cases must harbour a BCL2 (18q21.3) and/or BCL6 (3q27.3) rearrangement.

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
t(8;14)(q24;q32) IGH-MYC der(14) 28%[7]
t(8;22)(q24;q11) MYC-IGL der(8) 7%[7]
t(2;8)(p12;q24) MYC-IGK der(8)
t(14;18)(q32;q21.3) IGH-BCL2 der(14)
t(2;18)(p11;q21.3) BCL2-IGK
t(18;22)(q21.3;q11) BCL2-IGL
t(3;14)(q27;q32) IGH-BCL6
End of V4 Section


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

In general, patients with germinal centre B type DLBCL have been shown to have a better prognosis than those with ABC-type tumours[8]. However, despite the fact that the majority of HGBL DH/TH tumours are of GCB subtype, concurrent MYC and BCL2 and/or BCL6 rearrangement confers significantly worse outcomes than tumours without concurrent translocations[9][3][10][8][11], with median progression free and overall survival of approximately 10 and 22 months, respectively, despite treatment[9][12]. The extremely poor outcomes in these patients are postulated to result from the synergistic dysregulation of both genes, leading to MYC-induced growth promotion and inhibition of apoptosis resulting from BCL2 rearrangement[9]. Amongst HGBL DH/TH patients, advanced stage, central nervous system involvement, leucocytosis and LDH>3 times the upper limit of normal are all associated with poorer outcomes[12]  There appears to be no significant survival difference between patients with double hit (either BCL2 or BCL6) tumours and those with a triple hit[2][4][11].

The partner gene involved in MYC translocation also affects prognosis, with an IG partner gene conferring a significantly shorter progression free and overall survival[2][7]. Patients with double hit lymphoma with an IG-MYC translocation have significantly worse survival than patients with a non-IG partner gene and patients without a double hit, even in studies in which double hit has not shown to be independently associated with poorer outcomes overall. Several studies [2][11] have shown that, regardless of double or triple hit status, DLBCL patients with MYC rearrangement to an IG partner have a shorter overall survival than patients without MYC rearrangement and in one large study patients with double or triple hit lymphoma with MYC translocation to a non-IG partner did not show any significant difference in outcomes to patients with DLBCL without MYC rearrangement[11]. This reinforces the need for identification of the MYC translocation partner via appropriate FISH probe selection.

Further investigation of HGBL DH/TH via gene expression profiling in newer studies has reinforced that heterogeneity in outcomes exists amongst these patients, and that further sub classification via gene expression profiling and/or mutation analysis may be necessary to provide accurate prognostication.

Song et al[13] in a study of 87 cases of de novo DLBCL of germinal centre type treated with R-CHOP defined a subset of cases as “double-hit” on the basis of gene expression profiling (DHsig+), with most but not all cases showing double- or triple-hits on FISH. In this cohort, patients with DHsig+ and TP53 mutation had the worst overall and progression free survival, with good overall survival in DHsig+ patients without TP53 abnormalities. These mutations have been postulated to lead to a highly aggressive phenotype through evasion of apoptosis driven by BCL2 in the absence of TP53 mediation[14].

First-line treatment for HGBL is rituximab in combination with intensive chemotherapy, most commonly CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) with or without CNS prophylaxis[15]. Some studies have shown intensive induction regimens such as R-EPOCH to be associated with an improved response rate and progression free survival[12][16]. In vitro studies of novel targeted agents such as BET inhibitors both alone and in combination with BCL-2 and MDM2-p53 inhibitors have shown promising results[17] and further investigation of targeted therapies are needed to improve the otherwise dismal overall prognosis of these tumours.

End of V4 Section

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE: No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8

EXAMPLE:

Unknown

EXAMPLE: D, P EXAMPLE:

Common recurrent secondary finding for t(8;21) (add references).

EXAMPLE:

17

EXAMPLE: Amp EXAMPLE:

17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]

EXAMPLE:

ERBB2

EXAMPLE: D, P, T EXAMPLE:

Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

editv4:Genomic Gain/Loss/LOH
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High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements almost invariably display a complex karyotype with many cytogenetic abnormalities[1][3][5]. Gains of chromosomes 8q and 12q are more common in HGBL-DH/TH than in cases with isolated MYC translocation[4]. 12q12-q15 copy-number gain is significantly more common in HGBL with MYC and BCL2 translocation than in cases with BCL6 translocation[5].

Other common aberrations include[5]

Chromosome Number Gain/Loss/Amp/LOH Region
3 Gain p12.1-q29
7 Gain p22.3-p11.1
12 Gain p13.33-q21.31
1 Loss p36.33-p36.32
6 Loss q22.1-q23.2
15 Loss q14-q21.3
1-3 LOH 1p32.3-3p21.31
End of V4 Section

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:

Co-deletion of 1p and 18q

EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference). EXAMPLE: Common (Oligodendroglioma) EXAMPLE: D, P
EXAMPLE:

Microsatellite instability - hypermutated

EXAMPLE: Common (Endometrial carcinoma) EXAMPLE: P, T

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)
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Due to the relatively recent classification of HGBL with MYC and BCL2 and/or BCL6 translocation as a specific pathological entity, combined with small sample sizes, comprehensive data on gene mutation prevalence is not currently available. However, several studies have shown the mutational profile of HGBL DH/TH to differ significantly from that of DLBCL, NOS. Frequently mutations are associated with apoptosis and cell cycle pathways known to be associated with poor prognosis in DLBCL patients, including SOCS1 non-truncating mutations and mutations in CREBBP and FOX01[18]. HGBL DH/TH also shows a significantly higher number of IGH and MYC mutations than DLBCL with isolated MYC translocation[4]. MYC hotspot mutations occur more frequently in cases in which the MYC translocation partner is an immunoglobulin gene, and are associated with high MYC protein expression[19]. Amongst the most frequently mutated genes, somatic CREBBP mutations have been shown to inhibit TP53 tumour suppressor activity through activation of the BCL6 oncoprotein[18]. KMT2D mutations consist primarily of frameshift deletions and stop gain alterations with subsequent loss of protein function[18].

Amongst HGBL DH/TH cases, the nature of the secondary translocation also affects the mutational landscape, with TP53 mutations, associated with significantly worse overall survival, occurring more frequently in HGBL with MYC and BCL2 translocation than cases with MYC and BCL6 translocations or triple-hit tumours[14].

In one study[19], both HGBL with MYC and BCL2 translocations and triple-hit cases had a higher mutational load and more frequent mutations in BCL2, KMTD2, CREBBP, EZH2 and TNFRSF14 than DLBCL with isolated MYC translocation. These mutations are cardinal features of follicular lymphoma and are also commonly seen in DLBCL, NOS. In addition, BCL2 translocated cases harboured additional mutations (MYC, GNA13, TP53, P2RY8, PIM1, CCND3, B2M, EBF1 and S1PR2) associated with high-grade transformation of follicular lymphoma, suggesting a possible derivation from follicular lymphoma following acquisition of a MYC translocation.

Overall, HGBL with MYC and BCL6 translocation shows a different and more heterogenous mutation profile to those with MYC and BCL2 translocation. BCL10 and NOTCH2 mutations are most commonly enriched in MYC/BCL6 translocated cases[19].

As HGBL is a genetically heterogenous disease, a multitude of gene mutations have been identified at varying levels of prevalence. The table below summarises the most common mutations identified from a number of studies[19][18][14][13][20][21], including only those with a prevalence greater than 20% in the data analysed.

Gene Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence (COSMIC/TCGA/Other)
BCL2 Oncogene GOF 57% (72/126)
KMT2D Tumour suppressor LOF 54% (68/126)
CREBBP Tumour suppressor LOF 47% (59/126)
MYC Oncogene GOF 42% (53/126)
GNAI2 Oncogene GOF 40% (2/5)
IGLL5 Not fully characterised 40% (8/20)
EZH2 Oncogene GOF 39% (49/126)
TNFRSF14 Tumour suppressor LOF 33% (35/106)
SOCS1 Tumour suppressor/oncogene LOF/GOF 29% (33/112)
FOXO1 Oncogene GOF 29% (34/117)
IRF8 Oncogene GOF 29% (28/97)
TP53 Tumour suppressor LOF 25% (27/106)
DTX1 Tumour suppressor LOF 25% (23/92)
XPO1 Oncogene GOF 25% (2/8)
PIM1 Oncogene GOF 25% (25/101)
GNA13 Tumour suppressor LOF 25% (26/106)
HIST1H1E Oncogene GOF 24% (24/101)
ID3 Tumour suppressor LOF 23% (7/31)
BCL7A Tumour suppressor LOF 20% (1/5)
C10orf12 Not fully characterised 20% (1/5)
P2RY8 Oncogene GOF 20% (18/92)
End of V4 Section

Epigenomic Alterations

Although the role of epigenomics in HGBL specifically has been incompletely described, many of the genes most frequently mutated in HGBL have been shown to be epigenetic determinants in DLBCL. Such genes include EZH2, KMT2D and CREBBP, which encode proteins that are involved in two epigenetic switches at the promoter and enhancer regions of genes involved in the germinal centre reaction. These switches regulate the movement of germinal centre B-cells between the dark and light zones of the germinal centre and require the addition or removal of specific histone post-translational modifications to up- or down-regulate the target gene.[22]

BCL6 is an important regulatory gene, repressing, often in combination with EZH2, the expression of a multitude of genes involved in cell cycle regulation whilst affinity maturation is ongoing.  EZH2 encodes a histone methyltransferase which affects H3K27 methylation and its most common gain-of-function mutation has been shown in mouse models to cause a global increase of H3K27 trimethylation but with accompanying decreased expression of H3K27me3 at multiple loci[23]. When there is constitutive expression of BCL6 and a concurrent EZH2 mutation driving the repression of the promoter region of a common target gene, such as is sometimes observed in DLBCL, such repression may become permanent, leading to an oncogenic state.[22]

Similarly, inactivating CREBBP mutations within germinal centre B-cells prevent enhancer reactivation and, due to the role of CREBBP in acetylation of BCL6 and p53, impairs the cells’ ability to regulate these genes. Thus, inactivating CREBBP mutations can trap cells in the germinal centre reaction, being unable to differentiate whilst being exposed to mutagenic and therefore potentially oncogenic conditions.[22] CREBBP and EP300, both histone acetyltransferases, are frequently mutated in DBLCL and mutations have been shown to promote oncogenesis by both inducing H3K27 deacetylation and activating the NOTCH signalling pathway, which is critical to the regulation of B-cell proliferation, migration and survival in lymphoma[24].

KMT2D mutants promote lymphomagenesis in part by impeding H3K4 methylation, driving enhanced proliferation in germinal centres and impeding terminal differentiation of B cells[25]. The extent to which KMT2D loss promotes lymphomagenesis appears to be affected by dysregulation of the expression of a number of other genes, including BCL2 and AICDA. KMT2D loss, in combination with increased BCL2 expression, has been shown in mouse models to increase lymphoma incidence from that of mice with wild type KMT2D, and the effect is greater for those with homozygous deletions[26][25]. Similarly the overexpression of AICDA, which encodes activation-induced cytidine deaminase (AID), an enzyme involved in somatic hypermutation, class switch recombination and gene conversion in the process of immunoglobulin diversification, has been shown in mice models to be associated with increased lymphoma incidence only in combination with KMT2D loss, and to be associated with more aggressive phenotypes than tumours with KMT2D deletion alone[25].

Genes and Main Pathways Involved

Put your text here and fill in the table (Instructions: Please include references throughout the table. Do not delete the table.)

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations EXAMPLE: Histone modification, chromatin remodeling EXAMPLE: Abnormal gene expression program
editv4:Genes and Main Pathways Involved
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MYC is a proto-oncogene located at chromosome 8q24.2 which has been implicated in a variety of human cancers through its role as a regulator of multiple functions including cellular proliferation, DNA and protein synthesis and metabolism[27]. In the process of B cell maturation, MYC is involved in multiple different intracellular pathways governing angiogenesis, differentiation and metabolism[28]. MYC, not normally expressed by naïve B cells, is upregulated upon antigen stimulation and is crucial for germinal centre development, but is then subsequently suppressed by BCL6 and BLIMP1[29]. MYC translocation leads to increased MYC expression compared to non-translocated cases, regardless of translocation partner[30]. Translocation of MYC to an immunoglobulin locus leads to overexpression of the MYC protein due to IG promoter driven constitutively active transcription[31]. MYC expression in lymphoma promotes cell proliferation and induces genomic instability[31][32], however whilst MYC contributes to oncogenic changes, it can also paradoxically promote apoptosis and increase the expression of tumour suppressor TP53[33][28]. MYC overexpression in isolation is insufficient to promote lymphomagenesis[33][28], and MYC translocation is postulated to occur as a secondary genetic abnormality contributing to oncogenesis and an aggressive phenotype[1][28].

BCL2, an oncogene at chromosome 18q21.3, acts to inhibit apoptosis to maintain cellular viability, but is, in normal cells, itself downregulated by the BH3 family of proteins[34]. BCL2 overexpression resulting from chromosomal translocation confers apoptosis resistance to B-cells and allows them to proliferate within the germinal centre in which the BCL2 protein is not normally expressed[35]. BCL2 dysregulation acts synergistically with increased MYC translation to drive oncogenesis[34].

BCL6, located on chromosome 3q27.3 encodes a protein which suppresses the activity of P53, MYC and BCL2 and thus acts as a transcriptional repressor, contributing to the regulation of activation, differentiation and apoptosis in the germinal centre reaction[33][36][37]. In normal B-cell development, expression of the BCL6 protein is restricted to the germinal centre stage of differentiation[37]. Chromosomal translocations of BCL6 involve promoter substitution, where heterologous promoters from other chromosomes are relocated to the 5' end of the BCL6 gene[37]. Commonly, these promoters show persistent activity in post germinal centre B-cells, causing abnormal BCL6 expression by prevention of its physiological downregulation[37]. It is postulated that deregulated BCL6 expression contributes to lymphomagenesis by promoting a tolerance to DNA damage and hence oncogenic mutations[37].

End of V4 Section

Genetic Diagnostic Testing Methods

Histologically, HGBL with MYC and BCL2 and/or BCL6 rearrangements is often indistinguishable from other high-grade lymphomas and the only method to ensure detection of all cases is universal investigation of DLBCL, NOS by MYC FISH with further testing for BCL2 and BCL6 translocations where MYC rearrangement is detected[1][38][34][15]. In environments with restricted resources, limiting screening to GCB subtype tumours would limit FISH testing to 50-62% of the DLBCL population, whilst still detecting >99% of tumours with MYC and BCL2 translocation[38].

Use of a MYC break-apart probe or IG/MYC dual fusion probe as the sole method of detection of MYC rearrangement has the potential to yield false-negative results in cases of 8q24 breakpoints occurring very close to the MYC gene region and non-IG MYC-rearrangement partners, respectively, and concurrent use of both break apart and IGH/MYC dual fusion probes is therefore recommended if possible[38][8][39][40][41]. Use of IGL/MYC and/or IGK/MYC dual fusion probes can follow, if required, to confirm the presence or absence of an IG fusion partner, which has implications for prognostication.

There are, however, limitations to FISH testing. A subset of HGBCL DH/TH harbour MYC and/or BCL2 rearrangements that are cryptic to FISH, for example via cryptic enhancer insertions near MYC of insufficient size to separate the break apart probes sufficiently for detection by FISH[39]. Such cases, identified via whole genome sequencing, were in one study found to account for 19% of all HGBL DH/TH tumours, with the authors recommending the use of gene expression profiling rather than FISH to identify HGBL DH/TH cases[39]. Furthermore, false-positive or false-negative FISH results can occur due to probe type or different numbers of malignant lymphoid cells in different specimens (eg BM aspirate vs FFPE tissue) as well as inter-observer variability[3].

Several authors[13][20][42][21] have proposed refined molecular subtypes of DLBCL based on gene expression profiling and/or mutation status, within which subtypes not all tumours are double- or triple- hit on the basis of FISH. In addition to overcoming translocations cryptic to FISH, several of these gene signatures have been shown to provide additional information on prognosis with one study showing that double hit lymphomas lacking the molecular high grade signature showed outcomes no worse than other germinal centre B-cell like cases[21].

Familial Forms

There is currently no known familial association.

Additional Information

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Links

HAEM4:High-Grade B-cell Lymphoma

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References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)

  1. ↑ 1.0 1.1 1.2 1.3 Cite error: Invalid <ref> tag; no text was provided for refs named :0
  2. ↑ 2.0 2.1 2.2 2.3 Cite error: Invalid <ref> tag; no text was provided for refs named :7
  3. ↑ 3.0 3.1 3.2 3.3 Cite error: Invalid <ref> tag; no text was provided for refs named :2
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Cite error: Invalid <ref> tag; no text was provided for refs named :8
  5. ↑ 5.0 5.1 5.2 5.3 Cite error: Invalid <ref> tag; no text was provided for refs named :4
  6. ↑ Pedersen, Mette Ø.; et al. (2014-01). "MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations". European Journal of Haematology. 92 (1): 42–48. doi:10.1111/ejh.12212. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 Chong, Lauren C.; et al. (2018-10-23). "High-resolution architecture and partner genes of MYC rearrangements in lymphoma with DLBCL morphology". Blood Advances. 2 (20): 2755–2765. doi:10.1182/bloodadvances.2018023572. ISSN 2473-9529. PMC 6199666. PMID 30348671.CS1 maint: PMC format (link)
  8. ↑ 8.0 8.1 8.2 Visco, C.; et al. (2013-02-01). "Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study". Haematologica. 98 (2): 255–263. doi:10.3324/haematol.2012.066209. ISSN 0390-6078. PMC 3561433. PMID 22929980.CS1 maint: PMC format (link)
  9. ↑ 9.0 9.1 9.2 Cite error: Invalid <ref> tag; no text was provided for refs named :1
  10. ↑ Xia, Yang; et al. (2020). "The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma". Acta Haematologica. 143 (6): 520–528. doi:10.1159/000505892. ISSN 0001-5792.
  11. ↑ 11.0 11.1 11.2 11.3 Rosenwald, Andreas; et al. (2019-12-10). "Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium". Journal of Clinical Oncology. 37 (35): 3359–3368. doi:10.1200/JCO.19.00743. ISSN 0732-183X.
  12. ↑ 12.0 12.1 12.2 Cite error: Invalid <ref> tag; no text was provided for refs named :3
  13. ↑ 13.0 13.1 13.2 Song, Joo Y.; et al. (2021-03-15). "Double-hit Signature with TP53 Abnormalities Predicts Poor Survival in Patients with Germinal Center Type Diffuse Large B-cell Lymphoma Treated with R-CHOP". Clinical Cancer Research. 27 (6): 1671–1680. doi:10.1158/1078-0432.CCR-20-2378. ISSN 1078-0432.
  14. ↑ 14.0 14.1 14.2 Gebauer, Niklas; et al. (2015-01-02). "TP53 mutations are frequent events in double-hit B-cell lymphomas with MYC and BCL2 but not MYC and BCL6 translocations". Leukemia & Lymphoma. 56 (1): 179–185. doi:10.3109/10428194.2014.907896. ISSN 1042-8194.
  15. ↑ 15.0 15.1 Chaganti, Sridhar; et al. (2016). "Guidelines for the management of diffuse large B-cell lymphoma". British Journal of Haematology. 174 (1): 43–56. doi:10.1111/bjh.14136. ISSN 1365-2141.
  16. ↑ Oki, Yasuhiro; et al. (2014-09). "Double hit lymphoma: the MD Anderson Cancer Center clinical experience". British Journal of Haematology. 166 (6): 891–901. doi:10.1111/bjh.12982. Check date values in: |date= (help)
  17. ↑ Deng, Manman; et al. (2021-02). "Aggressive B-cell Lymphoma with MYC/TP53 Dual Alterations Displays Distinct Clinicopathobiological Features and Response to Novel Targeted Agents". Molecular cancer research: MCR. 19 (2): 249–260. doi:10.1158/1541-7786.MCR-20-0466. ISSN 1557-3125. PMC 8092941 Check |pmc= value (help). PMID 33154093 Check |pmid= value (help). Check date values in: |date= (help)
  18. ↑ 18.0 18.1 18.2 18.3 Cite error: Invalid <ref> tag; no text was provided for refs named :9
  19. ↑ 19.0 19.1 19.2 19.3 Cite error: Invalid <ref> tag; no text was provided for refs named :12
  20. ↑ 20.0 20.1 Wright, George W.; et al. (2020-04). "A Probabilistic Classification Tool for Genetic Subtypes of Diffuse Large B Cell Lymphoma with Therapeutic Implications". Cancer Cell. 37 (4): 551–568.e14. doi:10.1016/j.ccell.2020.03.015. Check date values in: |date= (help)
  21. ↑ 21.0 21.1 21.2 Sha, Chulin; et al. (2019-01-20). "Molecular High-Grade B-Cell Lymphoma: Defining a Poor-Risk Group That Requires Different Approaches to Therapy". Journal of Clinical Oncology. 37 (3): 202–212. doi:10.1200/JCO.18.01314. ISSN 0732-183X. PMC 6338391. PMID 30523719.CS1 maint: PMC format (link)
  22. ↑ 22.0 22.1 22.2 Bakhshi, Tanner J.; et al. (2020-12). "Genetic and epigenetic determinants of diffuse large B-cell lymphoma". Blood Cancer Journal. 10 (12). doi:10.1038/s41408-020-00389-w. ISSN 2044-5385. Check date values in: |date= (help)
  23. ↑ Souroullas, George P.; et al. (2016-06). "An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation". Nature Medicine. 22 (6): 632–640. doi:10.1038/nm.4092. ISSN 1546-170X. PMC 4899144. PMID 27135738. Check date values in: |date= (help)
  24. ↑ Huang, Yao-Hui; et al. (2021-01-11). "CREBBP/EP300 mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-associated macrophage polarization via FBXW7-NOTCH-CCL2/CSF1 axis". Signal Transduction and Targeted Therapy. 6 (1). doi:10.1038/s41392-020-00437-8. ISSN 2059-3635.
  25. ↑ 25.0 25.1 25.2 Ortega-Molina, Ana; et al. (2015-10). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature Medicine. 21 (10): 1199–1208. doi:10.1038/nm.3943. ISSN 1546-170X. PMC 4676270. PMID 26366710. Check date values in: |date= (help)
  26. ↑ Zhang, Jiyuan; et al. (2015-09-14). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature Medicine. 21 (10): 1190–1198. doi:10.1038/nm.3940. ISSN 1078-8956.
  27. ↑ Cheah, Chan Yoon; et al. (2015-03). "A clinician's guide to double hit lymphomas". British Journal of Haematology. 168 (6): 784–795. doi:10.1111/bjh.13276. Check date values in: |date= (help)
  28. ↑ 28.0 28.1 28.2 28.3 Korać, Petra; et al. (2017-04-04). "Role of MYC in B Cell Lymphomagenesis". Genes. 8 (4): 115. doi:10.3390/genes8040115. ISSN 2073-4425. PMC 5406862. PMID 28375188.CS1 maint: PMC format (link)
  29. ↑ Karube, Kennosuke; et al. (2015-04). "MYC alterations in diffuse large B-cell lymphomas". Seminars in Hematology. 52 (2): 97–106. doi:10.1053/j.seminhematol.2015.01.009. ISSN 1532-8686. PMID 25805589. Check date values in: |date= (help)
  30. ↑ Bertrand, P.; et al. (2007-03). "Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas". Leukemia. 21 (3): 515–523. doi:10.1038/sj.leu.2404529. ISSN 0887-6924. PMID 17230227. Check date values in: |date= (help)
  31. ↑ 31.0 31.1 Sesques, Pierre; et al. (2017-01-19). "Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements". Blood. 129 (3): 280–288. doi:10.1182/blood-2016-02-636316. ISSN 0006-4971.
  32. ↑ Meyer, Natalie; et al. (2008-12). "Reflecting on 25 years with MYC". Nature Reviews Cancer. 8 (12): 976–990. doi:10.1038/nrc2231. ISSN 1474-175X. Check date values in: |date= (help)
  33. ↑ 33.0 33.1 33.2 Riedell, Peter A.; et al. (2018-12-15). "Double hit and double expressors in lymphoma: Definition and treatment". Cancer. 124 (24): 4622–4632. doi:10.1002/cncr.31646. ISSN 0008-543X.
  34. ↑ 34.0 34.1 34.2 Riedell, Peter A.; et al. (2018-12-15). "Double hit and double expressors in lymphoma: Definition and treatment". Cancer. 124 (24): 4622–4632. doi:10.1002/cncr.31646. ISSN 0008-543X.
  35. ↑ Tomita, Naoto (2011). "BCL2 and MYC Dual-Hit Lymphoma/Leukemia". Journal of Clinical and Experimental Hematopathology. 51 (1): 7–12. doi:10.3960/jslrt.51.7. ISSN 1880-9952.
  36. ↑ Basso, Katia; et al. (2010). "BCL6: master regulator of the germinal center reaction and key oncogene in B cell lymphomagenesis". Advances in Immunology. 105: 193–210. doi:10.1016/S0065-2776(10)05007-8. ISSN 1557-8445. PMID 20510734.
  37. ↑ 37.0 37.1 37.2 37.3 37.4 Basso, Katia; et al. (2012-04-13). "Roles of BCL6 in normal and transformed germinal center B cells". Immunological Reviews. 247 (1): 172–183. doi:10.1111/j.1600-065x.2012.01112.x. ISSN 0105-2896.
  38. ↑ 38.0 38.1 38.2 Cite error: Invalid <ref> tag; no text was provided for refs named :6
  39. ↑ 39.0 39.1 39.2 Hilton, Laura K.; et al. (2019-10-31). "The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH". Blood. 134 (18): 1528–1532. doi:10.1182/blood.2019002600. ISSN 0006-4971. PMC 6839951. PMID 31527075.CS1 maint: PMC format (link)
  40. ↑ Muñoz-Mármol, Ana M; et al. (2013-09). "MYC status determination in aggressive B-cell lymphoma: the impact of FISH probe selection". Histopathology. 63 (3): 418–424. doi:10.1111/his.12178. Check date values in: |date= (help)
  41. ↑ May, Philippa C.; et al. (2010-04). "Detection of cryptic and variant IGH-MYC rearrangements in high-grade non-Hodgkin's lymphoma by fluorescence in situ hybridization: implications for cytogenetic testing". Cancer Genetics and Cytogenetics. 198 (1): 71–75. doi:10.1016/j.cancergencyto.2009.12.010. Check date values in: |date= (help)
  42. ↑ Ennishi, Daisuke; et al. (2019-01-20). "Double-Hit Gene Expression Signature Defines a Distinct Subgroup of Germinal Center B-Cell-Like Diffuse Large B-Cell Lymphoma". Journal of Clinical Oncology. 37 (3): 190–201. doi:10.1200/JCO.18.01583. ISSN 0732-183X. PMC 6804880. PMID 30523716.CS1 maint: PMC format (link)


Notes

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*Citation of this Page: “Diffuse large B-cell lymphoma / high grade B-cell lymphoma with MYC and BCL2 rearrangements”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 07/3/2025, https://ccga.io/index.php/HAEM5:Diffuse_large_B-cell_lymphoma_/_high_grade_B-cell_lymphoma_with_MYC_and_BCL2_rearrangements.

Other Sections

Cancer Sub-Classification/Subtype


High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements


Definition/Description of Disease


High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is a clinically aggressive lymphoma with poor prognosis. It is defined as a distinct entity which includes mature B cell neoplasms harbouring both MYC and BCL2 and/or BCL6 rearrangements, as detected by a cytogenetic/molecular method such as FISH, except for cases of proven follicular lymphoma in the absence of a concurrent high-grade component, or where the disease is classified as B-lymphoblastic leukaemia/lymphoma[1].


Synonyms/Terminology


“Double-Hit Lymphoma (HGBL-DH)” in cases with MYC and BCL2 OR BCL6 rearrangement.

“Triple-Hit Lymphoma (HGBL-TH)” in cases with MYC, BCL2 AND BCL6 rearrangement.

Obsolete: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma


Epidemiology/Prevalence


  • HGBL DH/TH accounts for 3-9% of diffuse large B-cell lymphoma and approximately 13.3% of the germinal centre B-cell-like subtype[1][2][3][4][5][6]
  • HGBL DH/TH accounts for approximately 1.7% of activated B-cell-like diffuse large B-cell lymphoma[2]
    • These tumours overwhelmingly show concurrent MYC and BCL6 translocations, and the existence of activated B-cell-like high grade B cell lymphoma with BCL2 translocation is controversial[2]
  • MYC translocations occur concurrently with BCL2 translocations in 57-87% of cases and with BCL6 translocations in 5-30% of cases. MYC, BCL2 and BCL6 translocations ("triple hit") are present in 7-15%[7][8][9]
  • The diagnosis is slightly more common in males
  • Median age at diagnosis is 6th to 7th decade[1][10]
  1. ↑ 1.0 1.1 1.2 Kluin PM, et al,, (2017). High-grade B-cell lymphoma, in World Health Organisation Classificaiton of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p330-334.
  2. ↑ 2.0 2.1 2.2 Scott, David W.; et al. (2018-05-03). "High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with diffuse large B-cell lymphoma morphology". Blood. 131 (18): 2060–2064. doi:10.1182/blood-2017-12-820605. ISSN 1528-0020. PMC 6158813. PMID 29475959.
  3. ↑ Akyurek, Nalan; et al. (2012-09-01). "Prognostic significance of MYC , BCL2 , and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab: MYC , BCL2 , BCL6 Rearrangements in DLBCL". Cancer. 118 (17): 4173–4183. doi:10.1002/cncr.27396.
  4. ↑ Copie-Bergman, Christiane; et al. (2015-11-26). "MYC-IG rearrangements are negative predictors of survival in DLBCL patients treated with immunochemotherapy: a GELA/LYSA study". Blood. 126 (22): 2466–2474. doi:10.1182/blood-2015-05-647602. ISSN 0006-4971.
  5. ↑ Kim, Heyjin; et al. (2020-09-01). "Diagnostic Approach for Double-Hit and Triple-Hit Lymphoma Based on Immunophenotypic and Cytogenetic Characteristics of Bone Marrow Specimens". Annals of Laboratory Medicine. 40 (5): 361–369. doi:10.3343/alm.2020.40.5.361. ISSN 2234-3806. PMC PMC7169621 Check |pmc= value (help). PMID 32311849 Check |pmid= value (help).CS1 maint: PMC format (link)
  6. ↑ Cucco, Francesco; et al. (2020-05). "Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit". Leukemia. 34 (5): 1329–1341. doi:10.1038/s41375-019-0691-6. ISSN 0887-6924. PMC PMC7192846 Check |pmc= value (help). PMID 31844144. Check date values in: |date= (help)CS1 maint: PMC format (link)
  7. ↑ Aukema, S. M.; et al. (2014-04-01). "Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma". Haematologica. 99 (4): 726–735. doi:10.3324/haematol.2013.091827. ISSN 0390-6078. PMC 3971083. PMID 24179151.CS1 maint: PMC format (link)
  8. ↑ Petrich, Adam M.; et al. (2014-10-09). "Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: a multicenter retrospective analysis". Blood. 124 (15): 2354–2361. doi:10.1182/blood-2014-05-578963. ISSN 0006-4971.
  9. ↑ Evrard, Solène M.; et al. (2019-04). "Targeted next generation sequencing reveals high mutation frequency of CREBBP, BCL2 and KMT2D in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements". Haematologica. 104 (4): e154–e157. doi:10.3324/haematol.2018.198572. ISSN 0390-6078. PMC 6442958. PMID 30309852. Check date values in: |date= (help)CS1 maint: PMC format (link)
  10. ↑ Miyaoka, Masashi; et al. (2018-02). "Clinicopathological and genomic analysis of double-hit follicular lymphoma: comparison with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements". Modern Pathology. 31 (2): 313–326. doi:10.1038/modpathol.2017.134. ISSN 1530-0285. Check date values in: |date= (help)
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