Abstract
The precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL.
Highlights
Nodal marginal zone lymphomas (NMZL) represent one of three recognized entities within the category of marginal zone lymphomas (MZL), along with splenic marginal zone lymphomas (SMZL) and extranodal marginal zone lymphomas (ENMZL), with the latter tumors known as mucosaassociated lymphoid tissue (MALT) lymphomas
Analyses of antigen-receptor genes in human lymphoma represent a useful tool in understanding their pathogenesis and clonal history [7]
Somatic hypermutations seem to be restricted to B cells proliferating within the microenvironment of the germinal center (GC)
Summary
Nodal marginal zone lymphomas (NMZL) represent one of three recognized entities within the category of marginal zone lymphomas (MZL), along with splenic marginal zone lymphomas (SMZL) and extranodal marginal zone lymphomas (ENMZL), with the latter tumors known as mucosaassociated lymphoid tissue (MALT) lymphomas. NMZL, SMZL, and MALT all belong to the category of indolent small B cell lymphomas [1]. NMZL shares many histologic and immunologic features with extranodal MZL of MALT type, clinical characteristics, natural history, and prognosis suggest that nodal MZL should be considered a distinct entity [2]. Lack of typical markers and absence of a clear consensus for its molecular pathogenesis make the diagnosis of nodal marginal zone lymphoma (NMZL) a problematic subject [3]. The precise B cell of origin of NMZL remains poorly defined [4].
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