igk and Lymphoma--Follicular

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas.

Topics: Aged; Aged, 80 and over; B-Lymphocytes; Biomarkers, Tumor; Cell Plasticity; DNA Mutational Analysis; Female; France; Gene Rearrangement, B-Lymphocyte, Heavy Chain; High-Throughput Nucleotide Sequencing; Hodgkin Disease; Humans; Immunoglobulin Heavy Chains; Immunoglobulins; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lymphoma, Follicular; Male; Middle Aged; Mutation; Phenotype; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6; Retrospective Studies

Topics: Child; China; Female; Gene Rearrangement; Humans; Immunoglobulins; Immunohistochemistry; Immunophenotyping; In Situ Hybridization, Fluorescence; Interferon Regulatory Factors; Ki-67 Antigen; Lymphoma, B-Cell; Lymphoma, Follicular; Male; Neprilysin; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-bcl-6

Primary cutaneous B-cell lymphomas (PCBCL) are rare. Marginal zone lymphomas and follicle center lymphomas (FCL) represent a majority of these cases, and a significant number of cases present with multiple lesions. It is unclear whether multiple lesions in PCBCL represent dissemination of a single clone or multiple new primary lymphomas. In the current study, we analyzed paired samples from 20 PCBCL patients at more than 1 site (16) or at the same site at different time points (4) and 12 patients with benign lymphoid infiltrates to investigate for the presence or absence of a clone, and if present, whether the clones were identical. Both IGH@ and IGK@ rearrangements were tested using the BIOMED-2 protocol. We identified a clone (IGH@ and/or IGK@) in 19 of 20 (95%) PCBCL patients and 2 of 12 (17%) benign lymphoid infiltrate patients. The B-cell clones were proven to be identical in 11 of 20 (55%) PCBCL patients, including 7 of 16(44%) biopsies from patients with 2 different sites and 4 of 4 biopsies (100%) from patients at the same site but different time points. In 4 cases (3 FCL and 1 marginal zone lymphoma), different clones were detected at different sites, suggesting the possibility of a second simultaneous primary lymphoma. Our results indicate that the presence of identical clones is highly suggestive of lymphoma. To our knowledge, this is the first report to investigate the detection of identical clones in 2 distinct biopsies in PCBCL patients. Although the study is small and the results need to be confirmed in a larger study, these findings suggest that a subset of PCBCL at different sites may represent different primary tumors rather than occurrence of a single disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD20; Biomarkers, Tumor; Case-Control Studies; Clone Cells; Female; Gene Rearrangement; Humans; Immunoglobulin Heavy Chains; Immunoglobulins; Immunohistochemistry; Lymphoma, B-Cell; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Follicular; Male; Middle Aged; Neoplasms, Multiple Primary; Polymerase Chain Reaction; Skin Neoplasms

B-cell clonality analysis is commonly performed by polymerase chain reaction (PCR) targeting the IGH genes although a high false-negative rate is recognized for germinal centre/post-germinal centre B-cell malignancies, especially follicular lymphoma. We assessed the diagnostic value of BIOMED-2 IGK assays and investigated the cause of IGH PCR failure in 77 patients with follicular lymphoma. Using the full set of BIOMED-2 reactions, clonal immunoglobulin gene rearrangements were detected in 74 (96%) cases. The clonality detection rate was 86% by two IGK reactions but only 68% by five IGH reactions (P < 0·001). Sequencing of the clonal PCR products showed significantly fewer somatic mutations in the rearranged IGKV (9/27 cases, 33%, mean mutation rate 0·5%) than IGHV (17/17 cases, 100%, rate 11·0%) (P < 0·01). All IGHV-IGHJ PCR failures occurred in cases with at least one mutation at the corresponding IGHV primer binding sites. t(14:18)(q32:q21)/IGH-BCL2 was detected in 50 of 71 (70%) cases and the presence of the translocation was not associated with the poor performance of IGH assays. Our results showed that BIOMED-2 IGK assays are significantly more sensitive than IGH assays in follicular lymphoma due to the fact that the rearranged IGKV is less frequently targeted by somatic hypermutation than IGHV, and therefore, are essential in routine clonality analysis of these lymphomas.

Topics: Adult; Aged; Aged, 80 and over; B-Lymphocytes; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 18; Clone Cells; Female; Gene Rearrangement, B-Lymphocyte; Humans; Immunoglobulin Heavy Chains; Immunoglobulins; Lymphoma, Follicular; Male; Middle Aged; Neoplastic Stem Cells; Paraffin Embedding; Polymerase Chain Reaction; Sensitivity and Specificity; Somatic Hypermutation, Immunoglobulin; Translocation, Genetic

Rearrangement of the BCL6 gene is found in follicular lymphomas and in diffuse large B cell lymphomas of follicular center cell origin. The breakpoints cluster mainly in a region spanning the first noncoding exon of the gene (the major breakpoint region). A second breakpoint cluster has also been identified upstream of the first BCL6 noncoding exon (the alternative breakpoint region [ABR]). To date, eight different rearrangements involving the ABR have been reported. Here, we describe a novel rearrangement involving a t(2;3)(p11;q27) translocation that affects the ABR in an unusual combination with the IGK locus.

Topics: Aged; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Gene Rearrangement; Humans; Immunoglobulins; Lymphoma, Follicular; Male; Polymerase Chain Reaction; Proto-Oncogene Proteins c-bcl-6; Translocation, Genetic

Topics: Base Sequence; Blotting, Southern; Cell Cycle Proteins; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 6; Cloning, Molecular; Endonucleases; Endoribonucleases; Gene Expression Regulation, Neoplastic; Gene Rearrangement; Humans; Immunoglobulins; Lymphoma, Follicular; Molecular Sequence Data; Proteins; Sequence Alignment; Translocation, Genetic