t(4;14)(p16;q32) IGH/FGFR3 and WHSC1

2005-05-01   Franck Viguié  

1.Laboratoire de Cytogenetique - Service dHematologie Biologique, Hopital Hotel-Dieu - 75181 Paris Cedex 04, France
2.Unité INSERM 393, Hopital Necker-Enfants Malades, 149 rue de Sèvres 75743, Paris Cedex 15, France (JB)
3.Unité INSERM 393, Hopital Necker-Enfants Malades, 149 rue de Sèvres 75743, Paris Cedex 15, France (JB)

Clinics and Pathology

Disease

Found in plasma cell leukaemia, multiple myeloma, plasmacytoma and monoclonal gammopathy of unknown significance (MGUS)

Phenotype stem cell origin

Malignant plasma cells have the phenotype of mature terminally differenciated B-cells; there origin may be a pluripotent stem cell.

Epidemiology

Poorly described before FISH, quite karyotypically undetectable: found initially in cell lines, it represents the second more frequent IgH associated rearrangement, after t(11;14); detected by interphase FISH or RT-PCR in 25% MM cell lines, 15-20% primary MM and 0-10% MGUS lines; might be frequent but karyotypically undetected.

Clinics

Found in MM cases with unfavorable prognosis, even in patients treated with high dose chemotherapy.

Cytogenetics

Cytogenetics morphological

May be undetectable (telomere-telomere translocation).

Cytogenetics molecular

Therefore molecular probes are indicated, and FISH is relevant.

Additional anomalies

Hypodiploid karyotype and -13 / 13q- in major part of cases.

Genes Involved and Proteins

Gene name
FGFR3 (Fibroblast Growth Factor Receptor 3)
Location
4p16.3
Atlas Image
c-FGFR3 (4p16.3) in normal cells: PAC 884J17 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Protein description
Member of the tyrosine-kinase FGF receptor family, contains an extracellular domain with Ig-like loops, a transmembrane domain, and intracellular tyrosine kinase domains; localisation: plasma membrane; tyrosine kinase receptor; role in signal transduction, activates multiple signaling pathways regulating cell proliferation and differentiation; constitutional point mutations resulting in ligand-independent activation, are responsible of familial dominant achondroplasia / thanatophoric dwarfism.
Gene name
IGH (Immunoglobulin Heavy)
Location
14q32.33
Gene name
NSD2
Location
4p16.3
Dna rna description
90 kb, 25 exons, 5 - 3 centromeric orientation - complex alternative splicing.
Protein description
136 KDa, 4 domains: PWWP domain (proline-tryptophan-tryptophan-prolin motif), HMG box (high mobility group), PHD-type (plant-homeodomain) zinc finger domain and SET (suppressor of variegation enhancer of zeste and Trithorax) domain. One full length 1365 aa isoenzyme and 4 possible truncated variants. Transcription factor, ubiquitously expressed but preferentially in growing embryonic tissues. Chromatin remodelling agent, regulates histones methylation.
Protein description
Constitutional deletion of one copy is responsible for Wolf-Hirschhorn syndrom by haplo-insufficiency.

Result of the Chromosomal Anomaly

Description

4p16.3 breakpoint in a 110 kb region between MMSET (centromeric) within the 5 introns, and FGFR3 (telomeric).
14q32 breakpoint in the IgH switch region involving JH + constant region.
Two fusions generated, FGFR3 brought under the influence of the Ig gene enhancer Ea on der(14); MMSET under the influence of enhancer Eµ on der(4). Both FGFR3 and MMSET genes are deregulated by the translocation and a IgH-MMSET fusion transcript, detectable by RT-PCR, is generated.No IgH-FGFR3 fusion protein, but promoter exchange between both partner genes; however, somatic mutations similar to what has been found in thanatophoric dwarfism have been identified in some cases; they may also contribute to abnormal FGFR3 activation.
According to the variable breakpoint inside MMSET gene, the translocation may generate either a full length MMSET protein or a NH2-terminal truncated one.

Oncogenesis

Overexpression and activation of FGFR3 provides an oncogenic signal enhancing cell proliferation and survival. The functional consequences of MMSET deregulation are not completely investigated. All t(4;14) positive cases express MMSET whereas 30% lack FGFR3 expression, sometimes correlated with loss of der(14), which tends to demonstrate that MMSET dysregulation should be the crucial oncogenic event.

Highly cited references

Pubmed IDYearTitleCitations
98657131998High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies.24
244968252014Impact of C-Myc gene-related aberrations in newly diagnosed myeloma with bortezomib/dexamethasone therapy.11
236274522013Plasma cell enrichment enhances detection of high-risk cytogenomic abnormalities by fluorescence in situ hybridization and improves risk stratification of patients with plasma cell neoplasms.8
177047432007Molecular cytogenetic aberrations in patients with multiple myeloma studied by interphase fluorescence in situ hybridization.8
211202052010Clinical utility of FISH analysis in addition to G-banded karyotype in hematologic malignancies and proposal of a practical approach.6
275320152016Target fluorescence in-situ hybridization (Target FISH) for plasma cell enrichment in myeloma.4
216118372012Fluorescence in situ hybridization analysis of chromosome aberrations in 60 Chinese patients with multiple myeloma.4
211562292010Correlation of cytomorphology, immunophenotyping, and interphase fluorescence in situ hybridization in 381 patients with monoclonal gammopathy of undetermined significance and 301 patients with plasma cell myeloma.4
198372762009FGFR3 amplification in the absence of IGH@-FGFR3 fusion t(4;14) in myeloma.2
327606482020Near tetrapoloid karyotype with translocation t(11;14) in a Moroccan patient with amyloid light-chain amyloidosis and multiple myeloma.1
293328702017[Autologous peripheral blood stem cell transplantation for double-refractory myeloma with K-RAS and N-RAS mutations].1
182844152009Molecular cytogenetic aberrations in 21 Chinese patients with plasma cell leukemia.1
356574042022Plasmablastic myeloma in Taiwan frequently presents with extramedullary and extranodal mass mimicking plasmablastic lymphoma.0
354224112022Presentation and Impact of Double and Triple hit Cytogenetics in Patients With Multiple Myeloma in the Real World.0
352487832022Clinical characteristics and survival outcomes of newly diagnosed multiple myeloma patients presenting with extramedullary disease: A retrospective study.0
324477822020High-risk cytogenetics in multiple myeloma: Further scrutiny of deletions within the IGH gene region enhances risk stratification.0
312404682019Multiple myeloma with IGH-FGFR3 rearrangement progressing as testicular plasmacytoma during carfilzomib treatment.0
302952562018[Detection of the Cytogenetic Aberrations in Multiple Myeloma by Using Microrray Comparative Genomic Hybridization].0
286416402017[Application of CD138 Immunomagnetic Sorting Myeloma Cells Combined with Fluorescence in Situ Hybridization for Detecting Cytogenetic Abnormalities of Multiple Myeloma].0
265240362015[Detection of Molecular Cytogenetic Aberrations by Fluorescence in Situ Hybridization in Different Bone Marrow Samples of Multiple Myeloma].0
211763602010[Comparative study of genetic aberrations in human multiple myeloma cell lines and newly diagnosed MM by fluorescence in situ hybridization].0
208057032010[A case of central nervous system myelomatosis with complex chromosome aberrations].0
174985612007Simultaneous translocations of FGFR3/MMSET and CCND1 into two different IGH alleles in multiple myeloma: lack of concurrent activation of both proto-oncogenes.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
89430381996Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma.Bergsagel PL et al
97871351998The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts.Chesi M et al
153558952004A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma.Dring AM et al
155436172005Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses.Fabris S et al
103977391999Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by double-color fluorescent in situ hybridization.Finelli P et al
109456092000Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by reverse transcription-polymerase chain reaction analysis of IGH-MMSET fusion transcripts.Malgeri U et al
93546761997A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene.Richelda R et al
124336792003A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript.Santra M et al

Summary

Atlas Image
t(4;14)(p16;q32) FISH - Courtesy Hossein Mossafa.

Citation

Franck Viguié

t(4;14)(p16;q32) IGH/FGFR3 and WHSC1

Atlas Genet Cytogenet Oncol Haematol. 2005-05-01

Online version: http://atlasgeneticsoncology.org/haematological/2059/t(4;14)(p16;q32)-igh-fgfr3-and-whsc1

Historical Card

1998-03-01 t(4;14)(p16;q32) IGH/FGFR3 and WHSC1 by  Jean-Loup Huret,Jacky Bonaventure 

Unité INSERM 393, Hopital Necker-Enfants Malades, 149 rue de Sèvres 75743, Paris Cedex 15, France (JB)