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

摘要

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 (VH), as commonly defined as VH mutation status has not been found to significantly correlate with patient survival. In this study, we assessed VH 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/JH primer; a monoclonal IGH band was amplified using another IGH primer set, FR256/JH, 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 VH1-69, VH4-59 and VH3-74 were utilized in 29 (55%) cases. Intraclonal evolution and non-productive VH 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 VH mutation frequency in mantle cell lymphoma may be higher than previously believed. Importantly, using our methodology, we found that the VH mutation status may be a useful prognostic marker for these patients.