VH mutation status and VDJ rearrangement structure in mantle cell lymphoma: correlation with genomic aberrations, clinical characteristics, and outcome

Abstract

Immunoglobulin variable heavy chain gene (V H ) mutation status and VDJ rearrangement structure were analyzed in 141 patients with mantle cell lymphoma (MCL) and correlated with biologic and clinical characteristics; 29% of the MCLs displayed mutated V H using a 98% germline homology cutoff. Striking differences occurred in the V H mutation subgroups with respect to the use of specific V genes. Rearrangements involving V4-34 and V3-21 were almost exclusively unmutated, whereas rearrangements using V4-59 and V3-23 were typically mutated. Significant association occurred between mutated V H with shorter CDR3 lengths and the use of J H 4b. V3-21 and V4-59 were involved in highly characteristic rearrangements, implying that antigen specificity might have been involved in MCL development. There was no evidence for isotype switch recombination or Bcl-6 expression in any MCL. ZAP70 expression was not different in V H -mutated or -unmutated MCL. Although the deletions 11q؊ and 17p؊ showed a balanced distribution, an overrepresentation was observed for trisomies ؉3q, ؉8q, and tetraploidy in the V H -unmutated subgroup and ؉12q in the V H -mutated subgroup. Clinically, mutated V H was associated with a higher rate of complete remission, but there was no correlation between V H mutation status and other clinical characteristics or overall survival. (Blood. 2003; 102:3003-3009)

Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma

“…24,25 In our studies, however, ZAP-70 was detected in only 13% mantle cell lymphoma cases. We also detected low level ZAP-70 protein expression in Mino, a mantle cell lymphoma cell line.…”

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

“…Similar findings were reported by other studies, with V H 3-21, V H 4-59 and V H 4-34 being most commonly implicated. 15,18 In our study, we also identified a strong bias for V H 4-59, but we identified V H 1-69 and V H 3-74 as the most frequent utilized V H regions, neither of which were highly represented in the previous studies. These discrepancies may be attributed to methodological differences, as described above.…”

“…We also have considered the possibility that different IGH primers may have bias toward amplifying different V H regions. Lastly, all of the four previous large studies were from European centers, [15][16][17][18] and we cannot exclude the possibility that the North American population (as in this study) may have different characteristics than their European counterparts.…”

“…24 Second, DNA templates were used uniformly in all cases in our study, whereas a mixture of RNA and DNA templates were used in most of the previous studies. 15,17,18 We believe that results from the use of RNA templates may yield different results from the use of DNA templates, as different rearranged IGH species may be transcribed at different rates and thus they may be represented differently at the RNA level. To this point, we have recently performed parallel studies using RNA template as well as DNA templates from 12 cases of mantle cell lymphoma, and our results are in keeping with this concept (manuscript in preparation).…”

“…[11][12][13][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 mantle cell lymphoma have relatively high rates of V H mutation. [15][16][17][18] In contrast to chronic lymphocytic leukemia, no strong correlation was identified between the degree of V H homology and patient survival, although one study revealed a significant correlation between the use of V H 3-21 and a better clinical outcome. 15 These studies also identified a bias in the utilization of specific V H gene segments in mantle cell lymphoma, with V H 3-21 being the most frequently utilized region.…”