Immunoglobulin V somatic hypermutation in mantle cell lymphoma: mutated genotype correlates with better clinical outcome

Abstract

Mantle cell lymphoma is an aggressive B-cell lymphoma for which the biology is incompletely understood. Previous studies have reported that somatic hypermutation of the variable region of the immunoglobulin heavy chain gene (V H ), as commonly defined as o98% homology, can be detected in approximately one-third of mantle cell lymphoma, although the V H mutation status has not been found to significantly correlate with patient survival. In this study, we assessed V H mutation in 55 mantle cell lymphomas using a method slightly different from those used in the previous studies, and we came to different conclusions. Using DNA extracted from formalin-fixed/paraffin-embedded tumors in all cases, we identified monoclonal IGH bands in 54 of 55 cases with the FR1c/J H primer; a monoclonal IGH band was amplified using another IGH primer set, FR256/J H , in the remaining case. Cloning was performed in all cases, and an average of six clones were sequenced and analyzed for each case. Intraclonal heterogeneity was detected in 45 (82%) cases. Further analysis was performed in 53 cases, in which a predominant IGH species was identified. Most (32 of 53 cases, 60%) cases were 'mutated', with o98% homology. V H 1-69, V H 4-59 and V H 3-74 were utilized in 29 (55%) cases. Intraclonal evolution and nonproductive V H rearrangements were more frequent in the mutated group. Patients with the 'mutated' genotype had longer overall survival (P ¼ 0.017, Log rank) that is independent of the international prognostic index. To conclude, our data suggest that the V H mutation frequency in mantle cell lymphoma may be higher than previously believed. Importantly, using our methodology, we found that the V H mutation status may be a useful prognostic marker for these patients. Mantle cell lymphoma is a distinct clinicopathologic entity recognized by the World Health Organization Classification Scheme. 1 The genetic hallmark of this disease is the chromosomal abnormality, the t(11;14)(q13;q32), which results in cyclin D1 overexpression. 2 Using transgenic mouse models, two research groups have shown that enforced cyclin D1 expression in B cells is not sufficient for lymphomagenesis. 3,4 Recent studies, including a number of oligonucleotide array studies, revealed additional biochemical abnormalities in mantle cell lymphoma, such as defects in the apoptotic pathway, cell cycle progression and DNA repair. [5][6][7][8][9][10] To further understand the biology of this type of B-cell neoplasm, one approach is to examine the somatic hypermutation of the variable region of the immunoglobulin heavy chain (V H ) gene. In chronic lymphocytic leukemia, it has been shown that a subset of cases has relatively high levels of V H somatic mutation, and mutated cases were associated with better clinical outcome when using o98% homology as the cutoff. 11-14 More recently, several large studies were performed to examine the V H mutation status in mantle cell lymphoma; using o98% homology (compared to the germline sequences) as the cutoff, it was found that 29-34% of

Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma

“…They also suggest that NF-κΒ and STAT3 pathways may cooperate to play an important role in MCL proliferation, as described in diffuse large B-cell lymphoma. Some studies identified IGHV mutational status as a relevant prognostic factor in MCL, 3,[26][27][28] suggesting an involvement of antigen stimulation in the course of the disease. In these studies, patients with mutated IGHV appeared to have a better clinical outcome.…”

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.…”

Somatic hypermutation signature in B-cell low-grade lymphomas

“…8 Besides the biological relevance of SHM, there is a broad base of evidence to suggest that IgVH SHM is a clinically significant phenomenon in various types of B-cell lymphoma, as demonstrated by studies reporting that cases of hypermutated CLL 9 and splenic marginal zone lymphoma (SMZL) have a better prognosis, 10 while cases of hypermutated mantle cell lymphoma (MCL) display specific clinicopathological features (leukemic course, longer survival). [11][12][13][14] There were two aims of the current study. First, we wished to identify a set of markers that could be analyzed by immunohistochemical assays, since this could have a potential clinical value for analyzing SHM status.…”

“…The study focuses on small B-cell lymphomas in which the presence of Ig somatic hypermutation has been reported to be a biological variable of clinical significance, such as CLL, MCL and SMZL, as noted above. [9][10][11][12][13][14] Furthermore, expression profiling was used in patients' samples to identify genes that may play a role in the process of SHM.…”