The Ig Heavy Chain Gene Is Frequently Involved in Chromosomal Translocations in Multiple Myeloma and Plasma Cell Leukemia as Detected by In Situ Hybridization

Abstract

Chromosome rearrangement of 14q32.33 has recurrently occurred with variable partner sites, including 11q13.3, 8q24.1, 18q21.3, and 6p21.1 in multiple myeloma (MM). To assess the actual incidence of 14q32.33 translocation and to elucidate its implication in the pathogenesis of MM, we studied 42 patients with MM, plasma cell leukemia, or plasmacytoma and 5 with monoclonal gammopathy with undetermined significance (MGUS) by G-banding and molecular cytogenetic methods. Using double-color fluorescence in situ hybridization (DCFISH) with 2 Ig heavy chain (IgH) gene probes, a yeast artificial chromosome (YAC) clone containing variable region, and a phage clone containing γ constant region, 14q32.33 translocation was detected as split signals of the IgH gene in 31 patients with plasma cell malignancies and 3 with MGUS. In contrast, of 40 patients who were assessed by G-banding, 3 (7.5%) showed the 14q+ chromosome. DCFISH detected a split of the IgH gene on interphase nuclei in 34 (73.9%) of 46 patients analyzed, whereas on metaphase spreads, it was in 22 (51.2%) of 43 patients analyzed. Interphase DCFISH was particularly useful to detect 14q32.33 translocation in 17 (65.4%) of 26 patients with normal karyotypes. Donor sites were identified in 11 of 22 patients demonstrated as carrying 14q32.33 translocation by metaphase FISH. Chromosome t(11; 14)(q13.3; q32.33) was detected in 5 patients, t(8; 14)(q24.1; q32.33) in 2, t(14; 18)(q32.33; q21.3) in 2, and t(7; 14)(q32.1; q32.33) in 1. A complex 14q32.33 translocation involving 3q and 16q24 was detected in 1 patient. Myeloma cells with t(7; 14) showed myelomonocytoid surface antigen. Because rearrangements of 14q32.33 were closely associated with translocation of proto-oncogenes into the IgH gene, our findings indicate that 14q32.33 translocation with various partner chromosomes is a critical event in the pathogenesis of MM and MGUS.

Diagnosis of Burkitt lymphoma in due time: a practical approach

“…A positive C‐MYC status was found in six of six cases (100%) with a cBL morphology and in 10 of 18 cases (55.6%) with a aBL morphology, but also in nine of 15 cases (60%) with a DLBCL morphology. In summary, C‐MYC rearrangement was found to be an invariable feature of cBL and highly characteristic, but not specific for BL, confirming previous reports (Sigaux et al , 1984; De Jong et al , 1988; Thangavelu et al , 1990; Ladanyi et al , 1991; Nishida et al , 1997; Kramer et al , 1998; Akasaka et al , 2000; Nakamura et al , 2002; Barth et al , 2004; Mauch et al , 2004; Haralambieva et al , 2005).…”

“…BL characteristically carry a reciprocal translocation t(8;14)(q24;q32) or one of its variants resulting in the deregulation of the C‐MYC proto‐oncogene (Dalla‐Favera et al , 1982; Hecht & Aster, 2000). However, this molecular marker is not specific for BL, as it is also detected in approximately 15% of DLBCL as well as in secondary precursor B‐lymphoblastic leukaemia/lymphoma, aggressive lymphoma secondary to follicular lymphoma, and in some cases of multiple myeloma (Sigaux et al , 1984; De Jong et al , 1988; Thangavelu et al , 1990; Ladanyi et al , 1991; Nishida et al , 1997; Kramer et al , 1998; Akasaka et al , 2000; Nakamura et al , 2002; Barth et al , 2004; Mauch et al , 2004; Haralambieva et al , 2005). Thus, a clear‐cut definition of BL and its delimitation from DLBCL is blurred, leaving the pathologist with the open question of how to classify highly proliferative peripheral blastic B‐cell lymphoma (HPBCL) with some but not all features of BL and, even more irritatingly, leaving the clinician with the unsolved problem of how to treat these patients.…”

Molecular cytogenetic aberrations in 21 Chinese patients with plasma cell leukemia

“…As PCL is a tumor of PCs, which have undergone the processes of somatic hypermutation and isotype switch recombination in germinal centers, the translocations may have occurred during the recombination of switch regions in isotype switching. It was reported that IgH translocations are present in about 80% patients with PCL detected by interphase FISH (Nishida et al. , 1997).…”

Chromosomal and genetic abnormalities in myeloma

“…Whether STs are an early oncogenic change, a late ‘trigger’ of disease progression or a non‐pathogenic marker of genetic instability has been an interesting question with important implications on our understanding of myeloma pathogenesis. If STs are oncogenic, their presence in 50–75% of primary MM tumours (Nishida et al ., 1997; Avet‐Loiseau et al ., 1998; Sawyer et al ., 1998; Ho et al ., 2001) and the heterogeneity of chromosomal partners and partner oncogenes would imply that STs cannot be the only oncogenic factor, and a number of mechanisms must be involved. This heterogeneity was proposed as one of the arguments against STs being a unifying oncogenic change (Avet‐Loiseau et al ., 1998).…”