Hypermutation in mantle cell lymphoma does not indicate a clinical or biological subentity

Abstract

Mantle cell lymphoma is a prime example of a well-defined entity based on morphology, phenotype, genetics and also clinical features. Although most patients have an adverse clinical course, some have a better survival than others. The most consistently reported adverse prognostic parameter is a high mitotic rate. Recently, it has been shown that hypermutation in the immunoglobulin heavy-chain gene occurs in a subset of mantle cell lymphomas. It is, however, unclear whether the mutational status is stable over time within a given case, whether hypermutation might be influenced by therapy and how it is related to other relevant biological features of mantle cell lymphoma. In this study, we analyzed 23 typical mantle cell lymphoma cases with respect to mutational status and compared the results with clinicopathological and genetic data to determine whether the presence of mutation indicates a subentity with clinical or pathological relevance. We found somatic hypermutation in 26% of our cases and, interestingly, one case showed ongoing somatic hypermutation. In tumor cells of both mutated and unmutated cases, we found a preferential usage of V H 3-21 (23%) and V H 4-34 (19%). No significant correlations were found between mutation status and the other morphological and genetic features analyzed. In conclusion, our results provide additional evidence that mutation status in mantle cell lymphoma is better interpreted as a feature within the spectrum of disease that seems to have little clinical or pathological relevance.

Genomic and Gene Expression Profiling Defines Indolent Forms of Mantle Cell Lymphoma

“…The clinical significance of IGVH mutations in MCL is controversial. Most studies have shown no relationship to the outcome of the patients (28)(29)(30), whereas a tendency to longer survival of the hypermutated MCL has been observed in some series (30)(31)(32)(33). Most of these studies have used a cutoff of 2% to consider the tumor as hypermutated.…”

Is there a role for antigen selection in mantle cell lymphoma? Immunogenetic support from a series of 807 cases

“…[12][13][14][15][16][17][18] In all published series, the classification of MCL cases based on SHM status was based on the 2% identity cut-off from the closest IGHV germ line gene, following the example of CLL, where this cut-off proved to be an accurate prognosticator of patient survival. 20 This approach should be viewed with caution for the following reasons.…”

“…In fresh or fresh-frozen samples, PCR amplification of IGHV-IGHD-IGHJ rearrangements was performed using IGHV leader primers or consensus primers for the IGHV framework region (FR) 1 region along with appropriate IGHJ gene primers, as described previously 9,12,[15][16][17] or following the BIOMED-2 protocol. 23 In formalin-fixed, paraffin-embedded material, deparaffinization was done according to standard methods, and gDNA was extracted using the QIAamp tissue kit (QIAGEN) following the manufacturer's recommendations.…”

“…19p232 Against this, virtually all aforementioned studies have reported the existence of a subset of MCL patients with mutated IGHV genes, variably accounting for from 16%-38% of cases. [12][13][14][15][16][17][18] This poses a conundrum, given the prevailing views about MCL ontogeny. In all studies, assignment to the "mutated" IGHV subset followed the 2% cut-off value for deviation from the closest IGHV germ line gene, which is widely used for prognostication in CLL.…”

“…However, their relative frequencies differed between studies, probably because of relatively small cohort sizes (the largest available study included 141 cases). [12][13][14][15][16][17] Moreover, there is evidence suggesting potential associations with molecular and clinical features for cases expressing certain IGHV genes (eg,. 12,13,[16][17][18] All relevant studies consistently showed that in the majority of MCL cases the clonotypic IGHV genes were either unmutated or exhibited a low impact of SHM activity.…”