Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B‐cell‐derived mantle cell lymphoma

Abstract

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) V H 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.A composite lymphoma (CL) is defined by the simultaneous or sequential presence of two distinct types of lymphomas, e.g. a B-cell non-Hodgkin lymphoma (NHL) and a Hodgkin lymphoma (HL) or two different NHL, in the same patient. 1,2Often, CL show a clonal relationship. [3][4][5][6][7][8] In most cases analyzed, the immunoglobulin (Ig) V genes of the two lymphoma entities carried both shared and distinct somatic mutations. This suggests that the common precursor of the two lymphomas underwent a germinal center (GC) reaction, where somatic hypermutation of IgV genes takes place 9 (explaining the shared mutations), and that the two lymphomas then developed from different members of the progeny of this common precursor (explaining the distinct mutations).Classical HL (cHL) is characterized by the occurrence of rare Hodgkin and Reed/Sternberg (HRS) tumor cells embedded in a mixed cellular infiltrate. HRS cells mostly derive from GC B cells. 10,11 The signaling pathways NF-jB and

Independent Mechanisms Lead to Genomic Instability in Hodgkin Lymphoma: Microsatellite or Chromosomal Instability

“…In this study, functional yeast assays revealed the non-functionality of TP53 in three cell lines and DNA sequencing revealed the same mutations previously described in L1236, HDLM2, and L428 [ 21 ]. This re-evaluation of the TP53 status in HL using a sensitive technique reinforces the concept that TP53 mutation may be involved in the pathology of some cases of HL [ 29 ] and perhaps in the genomic instability observed in this disease, as well as the occurrence of late complications, such as secondary cancer following HL treatment [ 30 ] or HL as a secondary event [ 6 ]. It may be informative to investigate the TP53 status in lymph nodes derived from relapsing or refractory HL patients.…”

“…The TP53 status of HL has been the subject of debate and remains controversial [ 21 ]. The lack of proven TP53 mutations in lymph nodes contrasts with the levels of its expression which are often high [ 6 ]. The disruption of this process can promote tumor progression and resistance to treatment [ 28 ].…”

“…We observed no significant effects of radiation for L1236. Future studies will require delineation of the in vivo radiation sensitivity of NS-HL versus MC-HL patients, including the role of TP53 and MSI in the response to treatment [ 6 ].…”

“…Several aberrantly activated pathways have been identified in HRS cells [ 2 ]. Nevertheless, no recurrent chromosomal rearrangements have been found [ 3 , 4 ] and the functional status of TP53 is still a matter of debate [ 5 , 6 ]. However, genomic instability has been described as a characteristic of HRS cells and a driving force of the aggressiveness of HL [ 7 , 8 , 9 ].…”

Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives

“…Reevaluation of the P53 status in HL cell lines has demonstrated the presence of deletions within exon 4 in the L428 cell line and a nearly complete loss of exons 10–11 in the L1236 and exons 8–11 in the HDLM-2 cell lines. These data suggest that mutation of TP53 may be involved in the pathology of some cases of HL [ 53 ] and perhaps in the genomic instability observed during in the course of HL, as well as in the frequent occurrence of late complications, such as secondary cancer [ 54 ] or HL as a secondary event [ 55 ]. The correlation between TP53 status and high-grade progression in B-cell lymphoma has been previously established [ 56 , 57 ].…”