IGH, 14q32.33, Green
FGFR3, 4p16.3, Red
The IGH/FGFR3 Plus product consists of probes, labelled in green, proximal to the Constant, and within the Variable segment of the IGH region 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.
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 (WHSC1) and FGFR3, CCND3, MAF or MAFB1.
The t(4;14)(p16.3;q32.3) translocation is a recurrent translocation seen in 15% of MMs2,3.
The translocation results in the dysregulation of two genes at 4p16; WHSC1 (Wolf-Hirschhorn syndrome candidate 1) and FGFR3. The consequence of the translocation is increased expression of FGFR3 and WHSC1. The translocation can be unbalanced, with 25% of cases losing the derivative chromosome 14, associated with the loss of FGFR3 expression2,3.
The majority of the breakpoints on chromosome 4 occur between FGFR3 and WHSC1. The breakpoint on chromosome 14 is almost exclusively in the switch region of constant genes. For the overexpression of both FGFR3 and WHSC1 the breakpoint on chromosome 14 must be located between the μ enhancer and the 3’IGH enhancers and between FGFR3 and WHSC1. 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 patients2,3.
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