Ongoing immunoglobulin somatic mutation in germinal center B cell-like but not in activated B cell-like diffuse large cell lymphomas

Abstract

B cell diffuse large cell lymphoma (B-DLCL) is a heterogeneous group of tumors, based on significant variations in morphology, clinical presentation, and response to treatment. Gene expression profiling has revealed two distinct tumor subtypes of B-DLCL: germinal center B cell-like DLCL and activated B cell-like DLCL. In a separate study, we determined that B-DLCL can also be subdivided into two groups based on the presence or absence of ongoing Ig gene hypermutation. Here, we evaluated the correlation between these B-DLCL subtypes established by the two different methods. Fourteen primary B-DLCL cases were studied by gene expression profiling using DNA microarrays and for the presence of ongoing mutations in their Ig heavy chain gene. All seven cases classified as germinal center B cell-like DLCL by gene expression showed the presence of ongoing mutations in the Ig genes. Five of the seven cases classified by gene expression as activated B cell-like DLCL had no ongoing somatic mutations, whereas, in the remaining two cases, a single point mutation was observed in only 2 of 15 and 21 examined molecular clones of variable heavy (V(H)) chain gene, respectively. These two cases were distantly related to the rest of the activated B cell-like DLCL tumors by gene expression. Our findings validate the concept that lymphoid malignancies are derived from cells at discrete stages of normal lymphocyte maturation and that the malignant cells retain the genetic program of those normal cells.

Figure 1

Clustering of B-DLCL specimens and their relationship to normal B lymphocyte differentiation and activation. (A) Hierarchical clustering of B-DLCL specimens and germinal center B cells using a previously reported set of 380 genes, selectively expressed in GC B-like DLCL and Activated B-like DLCL as was previously reported (3). (Germinal center B-like DLCL in orange and Activated B-like DLCL in blue). The 12 B-DLCL specimens studied for the presence of ongoing somatic mutations of immunoglobulin gene are indicated in red. (B) Gene expression data from germinal center, activated and resting blood B cells, as was previously reported (3). Each row represents a separate cDNA clone on the microarray and each column a separate mRNA sample.