Identification of two novel translocations t(14;20)(q32;q12) and t(2;14)(q23;q32) involving immunoglobulin heavy chain gene locus in gastric lymphoma

Abstract

Gastric B-cell non-Hodgkin’s lymphoma (GL) is the most common extra-nodal lymphoma in Hong Kong Chinese. Many subtypes of B-cell lymphomas are associated with specific chromosomal translocations, which may play a pivotal role in the pathogenesis of disease. In lymphomas of mature B-cells, these translocations frequently involve the immunoglobulin (IG) loci, most often involving the immunoglobulin heavy chain (IgH) gene at band 14q32.3, and are usually caused by errors in two developmentally regulated DNA recombination processes: V(D)J and class switch recombination. Since studies on the chromosomal translocations in lymphoid malignancies have led to the discovery of novel proto-oncogenes, this study was carried out to provide opportunity for the identification of new genes that may play an important role in the pathogenesis of GL. Using the LSI IgH dual color, break apart rearrangement probe (Vysis Inc.) for interphase FISH, we first identified the GL cases with chromosomal breakage at either the J segments or within switch sequences of the IgH locus that is associated with 14q32 translocations involving a variety of other loci. To clone novel IgH translocation breakpoints at IgHJ, 5’ Sμ and 3’ to the Sμ, Sγ1-4, and Sα1-2 regions, we employed the long distance inverse-PCR (LDI-PCR) approach to the DNA extracted from the GL cases with translocation involving the IgH locus. IgH translocation breakpoints were then cloned and sequenced. To determine the frequency of each novel translocation identified in this study, specific primers were designed across the translocation breakpoints to perform direct PCR on genomic DNA of 58 GL cases. In addition, 39 cases of nodal and other non-gastric extra-nodal lymphomas were also investigated for the presence of these translocations. Significantly, two novel recurrent chromosomal translocations t(14;20)(q32;q12) and t(2;14)(q23;q32) were identified, involving the IgH J6 and IgH γ3 switch respectively. t(14;20)(q32;q12) was found to be present in 3.4% (2/58) of GL cases and in 5.1% (2/39) of other nodal and non-gastric extra-nodal cases. t(2;14)(q23;q32) was found to be only present in GL cases (17.2%; 10/58) and not in any other nodal and non-gastric extra-nodal cases. Current studies are being carried out to identify the specific genes in the proximity of these translocation breakpoints whose expression may be altered as the results of these translocations since the principal molecular consequences of IgH translocations are deregulation and/or overexpression of the incoming gene. These studies might help us to discover new oncogenes that may play an important role in the genesis of normal and malignant B-cells.