A molecular study of the t(4;14) in multiple myeloma.

The t(4;14) translocation is found in approximately 10% of myeloma patients and results in the deregulation of at least two genes, MMSET and fibroblast growth factor receptor 3 (FGFR3), with the formation of a fusion product between MMSET and the immunoglobulin heavy chain (IgH) locus and overexpression of FGFR3. We have analysed a series of 80 patient samples, comprising 67 multiple myeloma (MM) cases and 13 monoclonalgammopathy of undetermined significance (MGUS) cases, using RT-PCR to detect IgH-MMSET fusions. The t(4;14) translocation was detected in 7/67 (10%) myeloma cases and all seven expressed FGFR3 which was not seen in t(4;14)-negative myeloma cases. In the MGUS cases, a similar proportion of t(4;14)-positive cases was found (2/13; 15%), but none of these expressed FGFR3. All patients with detectable FGFR3 expressed both the FGFR3 IIIb and FGFR3 IIIc isoforms, the result of alternative splicing in the ligand binding domain, and exon-deleted variants of FGFR3. We also identified a cryptic splice site in MMSET which results in a 277 amino acid deletion downstream of the breakpoint on der(4). FGFR3 mutation analysis revealed no mutations in the presenting myeloma or MGUS samples. However, we also had access to paired presentation and relapse samples which had been taken from a patient 13 months apart. Both samples had the t(4;14) translocation and overexpressed FGFR3, but only the relapse sample possessed the K650E mutation in the kinase domain of FGFR3. This suggests that targeted mutation in the translocated FGFR3 gene when under the control of the immunoglobulin promoters can occur and may provide one mechanism for disease progression.