Aberrant Somatic Hypermutation of Follicular Lymphoma Transformed To Diffuse Large B-Cell Lymphoma.

Abstract Follicular Lymphoma (FL) accounts for approximately 20–30% of all malignant lymphomas and the frequency of histological transformation (HT) into diffuse large B-cell lymphomas (DLBCL) varies from 10% to 70%. Many genetic lesions have already been described in histological transformation, but a mechanism of genome-wide instability during histological transformation (HT) has not been reported. We have shown that the somatic hypermutation process (SHM) physiologically aimed at mutating the immunoglobulin variable gene (IgV) aberrantly targets multiple proto-oncogenes in >50% of DLCBL (Pasqualucci et al., Nature 412:341, 2001). Consequently, multiple mutations are introduced in the 5′ region of genes including known proto-oncogenes such as PIM-1, PAX-5, Rho/TTF and c-MYC. To further investigate whether aberrant somatic hypermutation (ASHM) also occurs in histological transformation of follicular lymphoma in DLBCL we studied the mutational profile of these genes in a total of 26 cases consisting of 10 paired samples of follicular lymphoma together with the corresponding DLBCL and 6 single cases of transformed DLBCL. Genomic DNA from histologically confirmed, macrodissected tissue obtained from formalin fixed and paraffin embedded tissue or cryoconserved samples was directly sequenced. Mutations in one or more genes were detected in 6 of 10 (60%) cases of pre-HT follicular lymphoma and in 13 of 16 (81.2%) post-HT cases. Two ore more genes were affected in 1 of 10 (10%) of FL and in 7 of 16 (43.7%) cases with DLBCL. Mutations in PIM-1 occurred in 3 of 10 (30%) cases of follicular lymphoma and in 9 of 16 (56.2%) in DLBCL. For PAX-5, the distribution of the mutated cases between FL and DLBCL was 2 of 10 (20%) and 7 of 16 (43.7%), for RhoH/TTF 2 of 10 (20%) and 3 of 16 (18.7%) and for c-MYC none of 10 (0%) FL and 2 of 16 (12.5%) DLBCL. A total of 38 single base pair substitutions were found in 19 cases, 10 sequence variants in 6 FL cases and 28 sequence variants in 13 DLBCL cases. The mutations were of somatic origin and share features of the IgV SHM process including bias for transition over transversion, elevated ratio of G+C over A+T substitutions and restriction to the first 1-2Kb from the promoter initiation site. The mean mutation frequency in mutated follicular lymphoma was with 0.024 ×10−2/bp 1.4 fold lower compared to 0.032 ×10−2/bp in the transformed DLBCLs. Further in PIM-1 and c-MYC some of the mutations were found to affect coding exons, leading to amino acid exchanges, thus potentially altering gene function. These data support a role of aberrant SHM in the histological transformation of FL to overt DLBCL.

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Transformation of Follicular Lymphoma into Primary Mediastinal B-Cell Lymphoma-like Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2021-144892 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4479-4479

Author(s):

Tristan Loveday ◽

Gerben Duns ◽

Lisa M. Rimsza ◽

Karen Rech ◽

James R. Cook ◽

...

Keyword(s):

Gene Expression ◽

Follicular Lymphoma ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Sequence Variants ◽

Large B Cell Lymphoma ◽

Large B Cell ◽

Stat Pathway

Abstract Objectives: We identified a case of follicular lymphoma (FL) that transformed into a morphologic diffuse large B-cell lymphoma (DLBCL), which by gene expression profiling showed a primary mediastinal (PMBL)-like gene expression profile (GEP) (Lymph3Cx; Blood 2018;132:2401-5). A search identified 4 additional transformed FL (tFL) cases with a PMBL-like GEP, which we further studied to determine how similar these tFLs were to classic cases of PMBL. Methods: The morphology and previously reported immunophenotype were reviewed, and CD30, CD23, MAL, CD273/PDL2, and CD200 immunohistochemical stains (IHC) were performed. Whole exome sequencing (WES) and copy number analysis (CNA) to evaluate genes typically altered in FL and PMBL were performed. Results: None of the tFLs arose in the mediastinum or had a previous history of mediastinal disease. All cases showed typical centroblastic DLBCL cytology, with fine sclerosis typical of PMBL. 3/3 were GCB by the Hans IHC algorithm, 1/3 were MYC+, 3/3 BCL2+, 1/5 CD30+, 3/5 CD23+, 4/5 MAL+, 0/5 CD273/PDL2+, 1/5 CD200+, and 0/2 EBER+. Rearrangements of MYC, BCL2, or BCL6 were identified by FISH in 0/3, 1/3, and 2/3 cases, respectively. WES demonstrated sequence variants in genes associated with both FL (CREBBP [60%], KMT2D [40%], and TNFRSF14 [40%]) and PMBL (JAK-STAT pathway genes [80%], B2M [20%], and CD58 [20%]). 2 of the mutations identified in the tFLs have previously been shown to result in JAK-STAT activation (STAT6 p.E372K [PNAS 2016;113:13015-20] and SOCS1 p.F101L [Oncogene 2002;21:4351-62] identified in 1/5 cases each). CNA showed gains/amplification of REL in 3/5 cases, gains/amplification of STAT6 in 2/5, gains of large sections of chromosome 16, including IL4R, in 2/5, and both deletions and gains of 11q in 1/5. See Figure demonstrating the 5 cases on the Y-axis and the chromosomes on the X-axis. Conclusions: The tFLs in this small series seem to represent PMBL-like DLBCLs, rather than classic PMBLs, and have a blended pattern of immunophenotypic and genomic features between FL/DLBCL and PMBL. Although the cases express some PMBL-associated markers (CD23 and MAL), there is less frequent staining for others (CD30, CD273/PDL2, and CD200). The cases harbor both FL-associated and PMBL-associated sequence variants, including 40% with mutations known to activate the JAK-STAT pathway. This frequency of mutations in JAK-STAT pathway genes is higher than that seen in typical FL/DLBCL, but perhaps lower than in classic PMBL (Blood 2019;134:802-13). PMBL also frequently has gains/amplifications of 9p24.1, which was not seen in our cohort. However, gains/amplification of REL/2p, which is seen in approximately 50% of PMBL, was identified in 60% of the tFLs. The 11q aberration identified in 1 case would be unusual for PMBL, and is instead more commonly associated with a subset of aggressive lymphomas with Burkitt-like features (Haematologica 2019;104:1822-9). Recently, lymphomas with similar blended features between DLBCL and PMBL, which were not arising in the setting of tFL, have been reported (Duns G, et al. Blood 2021). Our study extends the types of biological transformations, in addition to more classic DLBCL, that can be seen in FL. These tFLs with blended PMBL-DLBCL biology may have implications for therapeutic decision making including targeted therapies used in PMBL. Figure 1 Figure 1. Disclosures Rimsza: NanoString Technologies: Other: Fee-for-service contract. Steidl: Curis Inc.: Consultancy; Trillium Therapeutics: Research Funding; Bayer: Consultancy; Epizyme: Research Funding; Seattle Genetics: Consultancy; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding.

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Transformation of follicular lymphoma to diffuse large B-cell lymphoma proceeds by distinct oncogenic mechanisms

Yearbook of Pathology and Laboratory Medicine ◽

10.1016/s1077-9108(08)70699-6 ◽

2008 ◽

Vol 2008 ◽

pp. 270-271

Author(s):

M. Djokic

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Changes in dynamics of excess mortality rates and net survival after diagnosis of follicular lymphoma or diffuse large B-cell lymphoma: comparison between European population-based data (EUROCARE-5)

The Lancet Haematology ◽

10.1016/s2352-3026(15)00155-6 ◽

2015 ◽

Vol 2 (11) ◽

pp. e481-e491 ◽

Cited By ~ 19

Author(s):

Morgane Mounier ◽

Nadine Bossard ◽

Laurent Remontet ◽

Aurélien Belot ◽

Pamela Minicozzi ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Excess Mortality ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Mortality Rates ◽

Population Based ◽

European Population ◽

Large B Cell Lymphoma ◽

Large B Cell

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Inactivating SOCS1 mutations are caused by aberrant somatic hypermutation and restricted to a subset of B-cell lymphoma entities

Blood ◽

10.1182/blood-2009-06-225839 ◽

2009 ◽

Vol 114 (20) ◽

pp. 4503-4506 ◽

Cited By ~ 81

Author(s):

Anja Mottok ◽

Christoph Renné ◽

Marc Seifert ◽

Elsie Oppermann ◽

Wolf Bechstein ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Lymphoma ◽

Somatic Hypermutation ◽

B Cell Lymphoma ◽

Rare Mutations ◽

Large B Cell Lymphoma ◽

Mantle Cell ◽

Follicular Lymphomas ◽

Large B Cell

Abstract STATs are constitutively activated in several malignancies. In primary mediastinal large B-cell lymphoma and Hodgkin lymphoma (HL), inactivating mutations in SOCS1, an inhibitor of JAK/STAT signaling, contribute to deregulated STAT activity. Based on indications that the SOCS1 mutations are caused by the B cell–specific somatic hypermutation (SHM) process, we analyzed B-cell non-HL and normal B cells for mutations in SOCS1. One-fourth of diffuse large B-cell lymphoma and follicular lymphomas carried SOCS1 mutations, which were preferentially targeted to SHM hotspot motifs and frequently obviously inactivating. Rare mutations were observed in Burkitt lymphoma, plasmacytoma, and mantle cell lymphoma but not in tumors of a non–B-cell origin. Mutations in single-sorted germinal center B cells were infrequent relative to other genes mutated as byproducts of normal SHM, indicating that SOCS1 inactivation in primary mediastinal large B-cell lymphoma, HL, diffuse large B-cell lymphoma, and follicular lymphoma is frequently the result of aberrant SHM.

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Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma

Haematologica ◽

10.3324/haematol.2013.088740 ◽

2013 ◽

Vol 98 (12) ◽

pp. 1912-1920 ◽

Cited By ~ 85

Author(s):

F. Asmar ◽

V. Punj ◽

J. Christensen ◽

M. T. Pedersen ◽

A. Pedersen ◽

...

Keyword(s):

Dna Methylation ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Genome Wide ◽

Large B Cell

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Cutaneous annular lesions as the first sign of transformation of follicular lymphoma into diffuse large B-cell lymphoma

Indian Journal of Dermatology Venereology and Leprology ◽

10.4103/0378-6323.158660 ◽

2015 ◽

Vol 81 (5) ◽

pp. 495 ◽

Cited By ~ 3

Author(s):

Irene Palacios-Álvarez ◽

Concepción Román-Curto ◽

AlejandroMartín García-Sancho ◽

Ángel Santos-Briz ◽

JuanCarlos Santos-Durán ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Annular Lesions ◽

Large B Cell

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Genome-wide DNA methylation and RNA-seq analyses identify genes and pathways associated with doxorubicin resistance in a canine diffuse large B-cell lymphoma cell line

PLoS ONE ◽

10.1371/journal.pone.0250013 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0250013

Author(s):

Chia-Hsin Hsu ◽

Hirotaka Tomiyasu ◽

Chi-Hsun Liao ◽

Chen-Si Lin

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Rna Seq ◽

Doxorubicin Resistance ◽

Large B Cell Lymphoma ◽

Genome Wide ◽

Large B Cell

Doxorubicin resistance is a major challenge in the successful treatment of canine diffuse large B-cell lymphoma (cDLBCL). In the present study, MethylCap-seq and RNA-seq were performed to characterize the genome-wide DNA methylation and differential gene expression patterns respectively in CLBL-1 8.0, a doxorubicin-resistant cDLBCL cell line, and in CLBL-1 as control, to investigate the underlying mechanisms of doxorubicin resistance in cDLBCL. A total of 20289 hypermethylated differentially methylated regions (DMRs) were detected. Among these, 1339 hypermethylated DMRs were in promoter regions, of which 24 genes showed an inverse correlation between methylation and gene expression. These 24 genes were involved in cell migration, according to gene ontology (GO) analysis. Also, 12855 hypermethylated DMRs were in gene-body regions. Among these, 353 genes showed a positive correlation between methylation and gene expression. Functional analysis of these 353 genes highlighted that TGF-β and lysosome-mediated signal pathways are significantly associated with the drug resistance of CLBL-1. The tumorigenic role of TGF-β signaling pathway in CLBL-1 8.0 was further validated by treating the cells with a TGF-β inhibitor(s) to show the increased chemo-sensitivity and intracellular doxorubicin accumulation, as well as decreased p-glycoprotein expression. In summary, the present study performed an integrative analysis of DNA methylation and gene expression in CLBL-1 8.0 and CLBL-1. The candidate genes and pathways identified in this study hold potential promise for overcoming doxorubicin resistance in cDLBCL.

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