Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B-cell-derived mantle cell lymphoma
Stefanie Schneider
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorBarbara Crescenzi
Institute of Hematology, University of Perugia, Perugia, Italy
Search for more papers by this authorMarkus Schneider
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorStefano Ascani
Institute of Anatomic Pathology, University of Perugia, Perugia, Italy
Search for more papers by this authorSylvia Hartmann
Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany
Search for more papers by this authorMartin-Leo Hansmann
Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany
Search for more papers by this authorBrunangelo Falini
Institute of Hematology, University of Perugia, Perugia, Italy
Search for more papers by this authorCristina Mecucci
Institute of Hematology, University of Perugia, Perugia, Italy
R.K., E.T., and C.M. contributed equally to this work.
Search for more papers by this authorEnrico Tiacci
Institute of Hematology, University of Perugia, Perugia, Italy
R.K., E.T., and C.M. contributed equally to this work.
Search for more papers by this authorCorresponding Author
Ralf Küppers
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
R.K., E.T., and C.M. contributed equally to this work.
Correspondence to: Ralf Küppers, Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Virchowstr. 173, 45122 Essen, Germany, Tel.: +49-201-723-3384, Fax: +49-201-723-3386, E-mail: [email protected]Search for more papers by this authorStefanie Schneider
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorBarbara Crescenzi
Institute of Hematology, University of Perugia, Perugia, Italy
Search for more papers by this authorMarkus Schneider
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
Search for more papers by this authorStefano Ascani
Institute of Anatomic Pathology, University of Perugia, Perugia, Italy
Search for more papers by this authorSylvia Hartmann
Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany
Search for more papers by this authorMartin-Leo Hansmann
Senckenberg Institute of Pathology, University of Frankfurt, Medical School, Frankfurt, Germany
Search for more papers by this authorBrunangelo Falini
Institute of Hematology, University of Perugia, Perugia, Italy
Search for more papers by this authorCristina Mecucci
Institute of Hematology, University of Perugia, Perugia, Italy
R.K., E.T., and C.M. contributed equally to this work.
Search for more papers by this authorEnrico Tiacci
Institute of Hematology, University of Perugia, Perugia, Italy
R.K., E.T., and C.M. contributed equally to this work.
Search for more papers by this authorCorresponding Author
Ralf Küppers
Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Essen, Germany
R.K., E.T., and C.M. contributed equally to this work.
Correspondence to: Ralf Küppers, Institute of Cell Biology (Cancer Research), Faculty of Medicine, University of Duisburg-Essen, Virchowstr. 173, 45122 Essen, Germany, Tel.: +49-201-723-3384, Fax: +49-201-723-3386, E-mail: [email protected]Search for more papers by this authorAbstract
Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) VH gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post-)germinal center (GC) B cell. This also demonstrates the (post-)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function-impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.
Abstract
What's new?
When two phenotypically distinct, yet genetically related lymphomas occur in one patient (composite lymphomas), this represents a unique opportunity to study the multistep transformation process in the pathogenesis of B cell lymphomas. Here, the authors present a case consisting of a Hodgkin and a mantle cell lymphoma. The two lymphomas were clonally related and carried the genetic translocation with the cyclin D1 gene translocated into the IGH locus, a characteristic for a mantle cell lymphoma. They further showed an identical TP53 function-impairing mutation, and later independently acquired a TP53 heterozygous deletion (convergent evolution). The authors see this close genetic relationship as evidence for subclonal evolution of a Hodgkin lymphoma from a mantle cell lymphoma.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
| Filename | Description |
|---|---|
| ijc28422-sup-0001-suppfig1.jpg1.2 MB | Supporting Information Figure 1. Top left: Low power view of the hematoxylin-eosin staining, showing a somewhat nodular growth pattern. Top middle: Low power view of the CD30 staining, showing relatively numerous HRS cells. Top right: Low power view of the CD68 staining, showing some macrophages. Bottom left: High power view of the CD3 staining, showing T cells rosetting around a HRS cell. Bottom right: High power view of the CD21 staining, showing the follicular dendritic cell meshwork embedding a HRS cell. |
| ijc28422-sup-0002-suppfig2.jpg709.4 KB | Supporting Information Figure 2. HRS cells are negative for CD20 (except for a minority of cells - not shown), for CD79a and for CD45 (except for dubious, partial membrane staining in a minority of cells), whereas they express PAX5, IRF4 and CD15, as expected for cHL. Conversely, the nearby MCL cells display the reverse phenotype (except for PAX5). Interestingly, nuclear SOX11 expression is observed both in HRS cells (one is indicated by the arrow) and in the nearby MCL cells. |
| ijc28422-sup-0003-suppfig3.doc1.1 MB | Supporting Information Figure 3. TP53 sequences of HRS, MCL and non-tumor two-cell samples. Representative electropherograms of HRS, MCL and non-tumor cells are shown. The non-tumor cells demonstrate the germline configuration and the MCL cells a homozygous mutation state. For HRS cells examples of the different sequence results are shown indicating a heterozygous mutation state. Arrows indicate the mutation position. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1Kim H, Hendrickson R, Dorfman RF. Composite lymphoma. Cancer 1977; 40: 959-76.
10.1002/1097-0142(197709)40:3<959::AID-CNCR2820400302>3.0.CO;2-3 CAS PubMed Web of Science® Google Scholar
- 2Jaffe ES, Zarate-Osorno A, Kingma DW, et al. The interrelationship between Hodgkin's disease and non-Hodgkin's lymphomas. Ann Oncol 1994; 5(Suppl 1): 7-11.
- 3Rosenquist R, Menestrina F, Lestani M, et al. Indications for peripheral light-chain revision and somatic hypermutation without a functional B-cell receptor in precursors of a composite diffuse large B-cell and Hodgkin's lymphoma. Lab Invest 2004; 84: 253-62.
- 4Rosenquist R, Roos G, Erlanson M, et al. Clonally related splenic marginal zone lymphoma and Hodgkin lymphoma with unmutated V gene rearrangements and a 15-yr time gap between diagnoses. Eur J Haematol 2004; 73: 210-4.
- 5Tinguely M, Rosenquist R, Sundstrom C, et al. Analysis of a clonally related mantle cell and Hodgkin lymphoma indicates Epstein-Barr virus infection of a Hodgkin/Reed-Sternberg cell precursor in a germinal center. Am J Surg Pathol 2003; 27: 1483-8.
- 6van den Berg A, Maggio E, Rust R, et al. Clonal relation in a case of CLL, ALCL, and Hodgkin composite lymphoma. Blood 2002; 100: 1425-9.
- 7Küppers R, Sousa AB, Baur AS, et al. Common germinal-center B-cell origin of the malignant cells in two composite lymphomas, involving classical Hodgkin's disease and either follicular lymphoma or B-CLL. Mol Med 2001; 7: 285-92.
- 8Bräuninger A, Hansmann ML, Strickler JG, et al. Identification of common germinal-center B-cell precursors in two patients with both Hodgkin's disease and non-Hodgkin's lymphoma. N Engl J Med 1999; 340: 1239-47.
- 9Küppers R, Zhao M, Hansmann ML, et al. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 1993; 12: 4955-67.
- 10Küppers R, Rajewsky K, Zhao M, et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci U S A 1994; 91: 10962-6.
- 11Kanzler H, Küppers R, Hansmann ML, et al. Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 1996; 184: 1495-505.
- 12Weniger MA, Melzner I, Menz CK, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene 2006; 25: 2679-84.
- 13Küppers R. The biology of Hodgkin's lymphoma. Nat Rev Cancer 2009; 9: 15-27.
- 14Küppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest 2012; 122: 3439-47.
- 15Jares P, Campo E. Advances in the understanding of mantle cell lymphoma. Br J Haematol 2008; 142: 149-65.
- 16Kridel R, Meissner B, Rogic S, et al. Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma. Blood 2012; 119: 1963-71.
- 17Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood 2011; 117: 26-38.
- 18Camacho E, Hernandez L, Hernandez S, et al. ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood 2002; 99: 238-44.
- 19Honma K, Tsuzuki S, Nakagawa M, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 2009; 114: 2467-75.
- 20Tiacci E, Döring C, Brune V, et al. Analyzing primary Hodgkin and Reed-Sternberg cells to capture the molecular and cellular pathogenesis of classical Hodgkin lymphoma. Blood 2012.
- 21Tiacci E, Orvietani PL, Bigerna B, et al. Tumor protein D52 (TPD52): a novel B-cell/plasma-cell molecule with unique expression pattern and Ca(2+)-dependent association with annexin VI. Blood 2005; 105: 2812-20.
- 22Shaffer LG, Slovak ML, Campbell LJ. An international system for human cytogenetic nomenclatureed. Basel: S. Karger, 2009.
- 23Schmitz R, Renne C, Rosenquist R, et al. Insights into the multistep transformation process of lymphomas: IgH-associated translocations and tumor suppressor gene mutations in clonally related composite Hodgkin's and non-Hodgkin's lymphomas. Leukemia 2005; 19: 1452-8.
- 24Bräuninger A, Küppers R, Spieker T, et al. Molecular analysis of single B cells from T-cell-rich B-cell lymphoma shows the derivation of the tumor cells from mutating germinal center B cells and exemplifies means by which immunoglobulin genes are modified in germinal center B cells. Blood 1999; 93: 2679-87.
- 25Küppers R. Molecular single-cell PCR analysis of rearranged immunoglobulin genes as a tool to determine the clonal composition of normal and malignant human B cells. Methods Mol Biol 2004; 271: 225-38.
- 26Montesinos-Rongen M, Roers A, Kuppers R, et al. Mutation of the p53 gene is not a typical feature of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Blood 1999; 94: 1755-60.
- 27Philipp C, Edelmann J, Buhler A, et al. Mutation analysis of the TNFAIP3 (A20) tumor suppressor gene in CLL. Int J Cancer 2011; 128: 1747-50.
- 28Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206: 981-9.
- 29Stanelle J, Döring C, Hansmann ML, et al. Mechanisms of aberrant GATA3 expression in classical Hodgkin lymphoma and its consequences for the cytokine profile of Hodgkin and Reed/Sternberg cells. Blood 2010; 116: 4202-11.
- 30Jungnickel B, Staratschek-Jox A, Bräuninger A, et al. Clonal deleterious mutations in the IkappaBalpha gene in the malignant cells in Hodgkin's lymphoma. J Exp Med 2000; 191: 395-402.
- 31Jares P, Colomer D, Campo E. Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 2012; 122: 3416-23.
- 32Stein H, Marafioti T, Foss HD, et al. Down-regulation of BOB.1/OBF.1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription. Blood 2001; 97: 496-501.
- 33Mozos A, Royo C, Hartmann E, et al. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype. Haematologica 2009; 94: 1555-62.
- 34Greiner TC, Moynihan MJ, Chan WC, et al. p53 mutations in mantle cell lymphoma are associated with variant cytology and predict a poor prognosis. Blood 1996; 87: 4302-10.
- 35Hernandez L, Fest T, Cazorla M, et al. p53 gene mutations and protein overexpression are associated with aggressive variants of mantle cell lymphomas. Blood 1996; 87: 3351-9.
- 36Caleo A, Sanchez-Aguilera A, Rodriguez S, et al. Composite Hodgkin lymphoma and mantle cell lymphoma: two clonally unrelated tumors. Am J Surg Pathol 2003; 27: 1577-80.
- 37Hayes SJ, Banerjee SS, Cook Y, et al. Composite mantle-cell lymphoma and classical Hodgkin lymphoma. Histopathology 2006; 48: 621-3.
- 38Papathomas TG, Venizelos I, Dunphy CH, et al. Mantle cell lymphoma as a component of composite lymphoma: clinicopathologic parameters and biologic implications. Hum Pathol 2012; 43: 467-80.
- 39Anagnostopulos I, Isaacson PG, Stein H. Lymphocyte-rich classical Hodgkin lymphoma. In: S Swerdlow, E Campo, NL Harris, ES Jaffe, SA Pileri, H Stein. WHO classification of tumours of haematopoietic and lymphoid tissuesed. Lyon, France: International Agency for Research on Cancer (IARC), 2008: 332-3.
- 40Kanzler H, Küppers R, Helmes S, et al. Hodgkin and Reed-Sternberg-like cells in B-cell chronic lymphocytic leukemia represent the outgrowth of single germinal-center B-cell-derived clones: potential precursors of Hodgkin and Reed-Sternberg cells in Hodgkin's disease. Blood 2000; 95: 1023-31.
- 41de Leval L, Vivario M, De Prijck B, et al. Distinct clonal origin in two cases of Hodgkin's lymphoma variant of Richter's syndrome associated With EBV infection. Am J Surg Pathol 2004; 28: 679-86.
- 42Weill JC, Weller S, Reynaud CA. Human marginal zone B cells. Annu Rev Immunol 2009; 27: 267-85.
- 43Küppers R. New insights into the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program 2012; 2012: 328-34.
- 44Mao Z, Quintanilla-Martinez L, Raffeld M, et al. IgVH mutational status and clonality analysis of Richter's transformation: diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution. Am J Surg Pathol 2007; 31: 1605-14.
- 45Duan H, Xiang H, Ma L, et al. Functional long-range interactions of the IgH 3' enhancers with the bcl-2 promoter region in t(14;18) lymphoma cells. Oncogene 2008; 27: 6720-8.
- 46Fernandez V, Salamero O, Espinet B, et al. Genomic and gene expression profiling defines indolent forms of mantle cell lymphoma. Cancer Res 2010; 70: 1408-18.
- 47Navarro A, Clot G, Royo C, et al. Molecular subsets of mantle cell lymphoma defined by the IGHV mutational status and SOX11 expression have distinct biologic and clinical features. Cancer Res 2012; 72: 5307-16.
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