IgV_H mutations in blastoid mantle cell lymphoma characterize a subgroup with a tendency to more favourable clinical outcome

Abstract

Mantle cell lymphoma (MCL) is associated with a very unfavourable clinical course. This is particularly true for mantle cell lymphoma of the blastoid subtype (MCL-b). In order to define prognostic factors, we analysed the impact of immunoglobulin heavy chain variable (IgV H) gene somatic hypermutations on clinical outcome in a series of 21 cases of morphologically, phenotypically, and genotypically well-characterized MCL-b. Testing and estimation were performed using log-rank statistics and displayed on Kaplan-Meier graphs. Thirteen of 21 cases of MCL-b revealed a homology rate of > or = 99% compared to IgV H germ-line sequences in the databases and were scored as non-mutated. Eight of 21 cases (38%) of MCL-b were mutated. In MCL-b the mutation frequency was usually low and the mutation pattern was only rarely antigen-selected, in contrast to a control group of 11 cases with morphologically almost identical, but phenotypically and genotypically clearly distinguishable, diffuse large B cell lymphoma, derived, most likely, from germinal centre B cells. In our series of 21 MCL-b, positive IgV H mutational status, irrespective of varying homology thresholds, had no statistically significant prognostic impact on event-free or overall survival. However, mutated MCL-b tended to present more frequently at an earlier stage and without bone marrow involvement and to show lower rates of relapse and death, resulting in a more favourable clinical outcome.

Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma

“…The clinical significance of IGVH mutations in MCL is controversial. Most studies have shown no relationship to the outcome of the patients (28)(29)(30), whereas a tendency to longer survival of the hypermutated MCL has been observed in some series (30)(31)(32)(33). Most of these studies have used a cutoff of 2% to consider the tumor as hypermutated.…”

A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma

“…27,28 Cases with a homology rate lower than 98% when compared to the closest germ-line IGHVsequence in the IMGT database (https://imgt.cines.fr/) using the IMGT/V-QUEST software were considered mutated. 29 In addition, bone marrow and peripheral blood samples were analyzed in a central laboratory by polymerase chain reaction (PCR) at baseline for the presence of the chromosomal translocation t(11;14)(q13;32) and, in negative cases, for monoclonal IGHV rearrangement, which were to be used as molecular markers during the follow-up. The t(11;14) was evaluated as described elsewhere, 27 while monoclonal IGH rearrangements were assessed using the IGH Gene Clonality Assay targeting the FR3-JH segments (InVivoScribe Technologies, San Diego, CA, USA).…”

Genomic aberrations in mantle cell lymphoma detected by interphase fluorescence in situ hybridization. Incidence and clinicopathological correlations

“…[4][5][6] However, unlike in chronic lymphocytic leukemia, in MCL the variable heavy chain gene (VH) mutation status shows no association with ZAP-70 expression and its prognostic relevance is the subject of heated debate. [6][7][8] Additional genetic alterations that occur in subsets of MCL appear to disturb the cell cycle machinery and to interfere with cellular responses to DNA damage. In particular, cyclin D1 upregulation, genomic amplification of cyclin-dependent kinase 4 (CDK4), deletions of the CDK inhibitor p16INK4a, and overexpression of BMI-1, a transcriptional repressor of the p16INK4a locus, are associated with deregulation of cell cycling in MCL.…”