Immunoglobulin V_H somatic hypermutation in mantle cell lymphoma: Mutated genotype correlates with better clinical outcome

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 <98% 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 <98% homology. V_H1-69, V_H4-59 and V_H3-74 were utilized in 29 (55%) cases. Intraclonal evolution and non-productive V_H rearrangements were more frequent in the mutated group. Patients with the 'mutated' genotype had longer overall survival (P=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.