title: Immunoglobulin VH 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 <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(H)1-69, V(H)4-59 and V(H)3-74 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.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, Alberta, Canada. Raymondl@cancerboard.ab.ca
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
authors.forename: Shilo V
authors.initials: SV
authors.lastname: Lefresne
authors.forename: Bevin
authors.initials: B
authors.lastname: Franko
authors.forename: David
authors.initials: D
authors.lastname: Hui
authors.forename: Imran
authors.initials: I
authors.lastname: Mirza
authors.forename: Adnan
authors.initials: A
authors.lastname: Mansoor
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Yupo
authors.initials: Y
authors.lastname: Ma
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D015322:Gene Rearrangement, B-Lymphocyte; D050438:Genes, Immunoglobulin Heavy Chain; D005838:Genotype; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D053208:Kaplan-Meier Estimate; D020522:Lymphoma, Mantle-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D012689:Sequence Homology, Nucleic Acid; D027041:Somatic Hypermutation, Immunoglobulin; D016896:Treatment Outcome
chemical_list: D007135:Immunoglobulin Variable Region