Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by double-color fluorescent in situ hybridization

Chromosomal translocations involving the immunoglobulin heavy chain (IGH) l ocus at chromosome 14q32 represent a common mechanism of oncogene activatio n in lymphoid malignancies. In multiple myeloma (MM), variable chromosome p artners have been identified by conventional cytogenetics, including the 11 q13, 8q24, 18q21, and 6p21 loci. We and others have recently reported a nov el, karyotypically undetectable chromosomal translocation t(4;14)(p16.3;q32 ) in MM-derived cell lines, as well as in primary tumors. The 4p16.3 breakp oints are relatively scattered and located less than 100 kb centromeric of the fibroblast growth factor receptor 3 (FGFR3) gene or within the recently identified WHSC1 gene, both of which are apparently deregulated by the tra nslocation. To assess the frequency of the t(4; 14)(p16.3; q32) translocati on in MM, we performed a double-color fluorescent in situ hybridization (FI SH) analysis of interphase nuclei with differently labeled probes specific for the IGH locus (a pool of plasmid clones specific for the IGH constant r egions) or 4p16.3 (yeast artificial chromosome (YAC) 764-H1 spanning the re gion involved in breakpoints). Thirty MM patients, the MM-derived cell line s KMS-11 and OPM2, and six normal controls were examined, The identificatio n of a t(4:14) translocation, evaluated as the presence of a der(14) chromo some, was based on the colocalization of signals specific for the two probe s; a cutoff value of 15% (mean + 3 standard deviation [SD]) derived from th e interphase FISH of the normal controls (range, 5% to 11%; mean +/- SD, 8. 16 +/- 2,2) was used for the quantification analysis. In interphase FISH, f ive patients (one in clinical stage I, two in stage II, one in stage III, a nd a plasma cell leukemia) were found to be positive (approximate to 15%). FISH metaphases with split or colocalized signals were detected in only two of the translocated cases and confirmed the pattern found in the interphas e nuclei. Furthermore, in three of the five cases with the translocation, F ISH analysis with the IGH joining probe (JH) showed the presence of the rec iprocal product of the translocation [der(4) chromosome]. Overall, our stud y indicates that the t(4;14)(p16.3;q32) chromosomal translocation is a recu rrent event in MM tumors and may contribute towards the detection of this l esion and our understanding of its pathogenetic and clinical implications i n MM. (C) 1999 by The American Society of Hematology.