CytoCell IGH/FGFR3 Translocation, Dual Fusion

Probe specification

• IGH, 14q32.33, Green
• FGFR3, 4p16.3, Red

The IGH/FGFR3 product consists of probes, labelled in green, covering the Constant, J, D and Variable segments of the IGH gene, and FGFR3 probes, labelled in red. The FGFR3 probe mix contains a 118kb probe telomeric to FGFR3, including the D4S2561E marker and a second probe covering the 126kb region centromeric to MMSET, including the D4S1182 marker.

Probe information

The FGFR3 (fibroblast growth factor receptor 3) gene is located at 4p16.3 and IGH (immunoglobulin heavy locus) at 14q32.33.

Approximately 50-60% of multiple myeloma (MM) cases are associated with translocations involving IGH and one of several partners including CCND1, NSD2 (MMSET) and FGFR3, CCND3, MAF or MAFB¹.

The t(4;14)(p16.3;q32.3) translocation is a recurrent translocation seen in 15% of MMs^2,3.

The translocation results in the dysregulation of two genes at 4p16; NSD2 (nuclear receptor binding SET domain protein 2) and FGFR3. The consequence of the translocation is increased expression of FGFR3 and NSD2. The translocation can be unbalanced, with 25% of cases losing the derivative chromosome 14, associated with the loss of FGFR3 expression^2,3.

The majority of the breakpoints on chromosome 4 occur between FGFR3 and NSD2. The breakpoint on chromosome 14 is almost exclusively in the switch region of constant genes. For the overexpression of both FGFR3 and NSD2 the breakpoint on chromosome 14 must be located between the μ enhancer and the 3’ IGH enhancers and between FGFR3 and NSD2. As a consequence, both derivative chromosomes contain an enhancer juxtaposed to an oncogene⁴.

This t(4;14) translocation is often cytogenetically cryptic and was poorly described before the advent of FISH techniques. The translocation has been associated with poorer survival in MM patients^{2, 3}.