IgV and bcl6 somatic mutation analysis reveals the heterogeneity of cutaneous B-cell lymphoma, and indicates the presence of undisclosed local antigens

Abstract

Our understanding of the ontology of B-cell lymphomas (BCL) has been improved by the study of mutational status of IgV H and bcl6 genes, but only a few cases of cutaneous BCL have been examined for this status. We analyzed IgV H and bcl6 somatic mutations in 10 cutaneous BCL, classified as follicular (three primary and one secondary), primary marginal zone (two cases), and diffuse large BCL (three primary and one secondary). We observed a lower rate (o2%) of IgV H mutation in all marginal zone lymphomas, and a preferential usage of V H 2-70 (one primary follicular and two primary diffuse large BCL). Fewer than expected replacement mutations in framework regions (FR) were observed in three primary follicular lymphomas (FLs) and in all diffuse large BCL, indicating a negative antigen selection pressure. Ongoing mutations were observed in eight of 10 cases. Only two primary FLs and two diffuse large BCL showed bcl6 somatic mutation. These data support the heterogeneous nature of the different cutaneous BCL, and specifically the distinction between cutaneous follicular and marginal zone lymphomas. The biased usage of V H 2-70, the low rate of replacement mutation in the FR, and the presence of ongoing mutation imply that local antigens could modulate the growth of primary cutaneous BCL.

Analysis of immunoglobulin variable kappa gene mutations in cutaneous B-cell lymphoma

“…All follicular center lymphomas including those observed primarily in the skin demonstrate intraclonal heterogeneity of their expressed Ig variable genes which is a hallmark of ongoing somatic mutation [2][3][4]8]. This has been confirmed also in our study by the mutational status of a case of PCFCL.…”

“…It is evident from the analysis of Ig variable region genes in our and previous investigations that the cells of origin of the three subentities of CBCL investigated in our study have been exposed to the somatic mutation mechanism [2][3][4]. Such mutations are evidence of exposure to antigen and passage through the germinal center stage of development.…”

“…The WHO-EORTC classification for cutaneous lymphomas recognizes four types [1]: (1) primary cutaneous marginal-zone B-cell lymphoma (PCMZL); (2) primary cutaneous follicle center lymphoma (PCFCL); (3) primary cutaneous diffuse large B-cell lymphoma (PCDLBCL)-leg type; (4) primary cutaneous diffuse large B-cell lymphoma, other. Recent data for CBCL indicate a germinal center cell origin of these neoplasms by the analysis of the variable heavy chain (VH) region genes [2][3][4]. In our study, we analyzed the somatic hypermutation status of V kappa (Vk) gene segments in a group of CBCL including a case each of PCMZL, PCFCL and PCDLBCL-leg type.…”

The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and develops in a T-helper type 2 inflammatory environment

“…Reverse-transcribed PCR (RT-PCR) for t (11;18) demonstrated the absence of the API-MALT1 translocation in 11 cases tested (CM01, CM03, CM04, CM05, CM07, CM08, CM11, CM15, CM17, CM35, and CM37). Light chain restriction was established for all cases: CM01, 02, 03, 04, 06, 07, 08, 09, 11,14,15,16,17,18,20,22,26,31,34,35,36,37,43, and 44 expressed kappa, whereas CM05, 10,13,19,21,23,24,25,27,28,29,30,32,33,38,39,40,41, and 42 expressed lambda.…”

“…[24][25][26][27] To extend our previous findings on Ig usage by extranodal MZBCLs, we conducted a detailed Ig gene analysis of an extensive cohort of PCMZLs. Furthermore, we analyzed the inflammatory environment in which the PCMZLs arise.…”