The genetic variability of the V_H genes in follicular lymphoma: the impact of the hypermutation mechanism

Abstract

Summary. Follicular lymphoma (FL) cells have inherited an activated hypermutation mechanism from their origin of germinal centre B cells. Based on today's knowledge of the intrinsic properties related to this mechanism and the V H base composition, reconsideration of previous reports should be made on a broader range of samples. The present study examined the mutation pattern of the V H genes expressed by 55 cases of FL. FL V H genes showed evidence of antigenic selection in 30% of cases with 88% carrying a functional sIg and 78´2% showing intraclonal variation. V H family and gene segment utilization was found to be roughly similar to that of normal B lymphocytes. FL V H genes revealed extensive variations. 17% of the V H exons harboured a total of ®ve deletions, three duplications and two insertions as compared to the most homologous germline counterpart. The V H genes of one tumour displayed three populations with varying CDR3 length at diagnosis. At relapse, emergence of a differently mutated gene, additional mutations reminiscent of ongoing mutations or no variation was prominent. From this study the heterogeneity of FLs is well established and ongoing mutations are seen in the scope of the activated status of the hypermutation mechanism rather than antigen-stimulated tumour growth.

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations

“…19 Tsuiji et al 20 reported IgM þ memory B cells more frequently express VH3 family genes than do naive B cells. Noppe et al 21 reported VH usage in nodal follicular lymphoma cases as VH3 70%, VH4 19% and VH1 11%; Bahler et al 22 reported it as VH3 67%, VH4 22% and VH1 8%. From their data, duodenal follicular lymphomas of our series showed a higher usage of VH4 and VH5 than did nodal cases.…”

Universal N-glycosylation sites introduced into the B-cell receptor of follicular lymphoma by somatic mutation: a second tumorigenic event?

“…No sites were found in FR2 in either V H or V L in keeping with the internal location of this region in the antibody protein. To broaden the analysis, the location of sites in the published V H genes of an additional 69 FL 5,6,8 were analysed (Figure 2b). The focusing of V H sites within CDR2 and CDR3 (41 and 29% of sites, respectively) was confirmed.…”

“…In all, 18% of sites were created through an essential aa replacement at both positions 1 and 3 of the motif, but only in a minority (9%) by an essential aa replacement at position 3 alone. A more detailed analysis of the generation of N-glycosylation sites in the V H CDR2 was performed and included sequences from cited references 5,6,8 (Table 2). All 47 sequences with CDR2 motifs used V H 3 (n ¼ 35) and V H 4 (n ¼ 12) genes.…”

“…To date, this mutation has not been reported in normal controls, lymphoid disorders or in patients with secondary erythrocytosis. [1][2][3][4][5][6][7][8][9][10] In this study, we have analyzed bone marrow or peripheral blood samples from 349 patients (PV, n ¼ 84; ET, n ¼ 243; IMF, n ¼ 22) referred to our diagnostic service for cytogenetic analysis and/or exclusion of the BCR-ABL fusion from several hospitals in the north of Spain between 1996 and 2005. Our study group thus includes the largest series of ET cases reported to date for JAK2 analysis.…”

“…[3][4][5][6][7][8] Table 1 The incidence of novel N-glycosylation sites in the V genes of patients with follicular lymphoma…”