Atlas of Genetics and Cytogenetics in Oncology and Haematology
t(4;14)(p16;q32)
| Clinics and Pathology |
| Disease | found in plasma cell leukaemia, multiple myeloma, plasmacytoma and monoclonal gammopathy of unknown significance (MGUS) |
| Phenotype / cell stem 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 IMAGE |
| 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 |
| Location | 4p16.3 |
 | |
| c-FGFR3 (4p16.3) in normal cells: PAC 884J17 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics. Laboratories willing to validate the probes are wellcome: contact M Rocchi | |
| Protein | 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 MMSET (multiple myeloma SET domain), also kown as WHSC1 (Wolf-Hirschorn syndrome candidate 1) |
| Location | 14q32 4p16.3 |
| Dna / Rna | 90 kb, 25 exons, 5¹ - 3¹ centromeric orientation - complex alternative splicing |
| Protein | 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. 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 5¹ 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. |
| Description | 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 FGFR 3 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. |
| External links |
| Other database | t(4;14)(p16;q32) | Mitelman database (CGAP - NCBI) | |
| Other database | t(4;14)(p16;q32) | CancerChromosomes (NCBI) |
| To be noted |
| Additional cases are needed to delineate the epidemiology of this rare entity: you are welcome to submit a paper to our new Case Report section. |
| Bibliography |
| Promiscuous translocations into immunoglobulin heavy chain switch regions in multiple myeloma. |
| Bergsagel PL, Chesi M, Nardini E, Brents LA, Kirby SL, Kuehl WM |
| Proceedings of the National Academy of Sciences of the United States of America. 1996 ; 93 (24) : 13931-13936. |
| PMID 8943038 |
| Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. |
| Chesi M, Nardini E, Brents LA, Schrˆck E, Ried T, Kuehl WM, Bergsagel PL |
| Nature genetics. 1997 ; 16 (3) : 260-264. |
| PMID 9207791 |
| A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. |
| Richelda R, Ronchetti D, Baldini L, Cro L, Viggiano L, Marzella R, Rocchi M, Otsuki T, Lombardi L, Maiolo AT, Neri A |
| Blood. 1997 ; 90 (10) : 4062-4070. |
| PMID 9354676 |
| The t(4;14) translocation in myeloma dysregulates both FGFR3 and a novel gene, MMSET, resulting in IgH/MMSET hybrid transcripts. |
| Chesi M, Nardini E, Lim RS, Smith KD, Kuehl WM, Bergsagel PL |
| Blood. 1998 ; 92 (9) : 3025-3034. |
| PMID 9787135 |
| Detection of t(4;14)(p16.3;q32) chromosomal translocation in multiple myeloma by double-color fluorescent in situ hybridization. |
| Finelli P, Fabris S, Zagano S, Baldini L, Intini D, Nobili L, Lombardi L, Maiolo AT, Neri A |
| Blood. 1999 ; 94 (2) : 724-732. |
| PMID 10397739 |
| Detection 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, Baldini L, Perfetti V, Fabris S, Vignarelli MC, Colombo G, Lotti V, Compasso S, Bogni S, Lombardi L, Maiolo AT, Neri A |
| Cancer research. 2000 ; 60 (15) : 4058-4061. |
| PMID 10945609 |
| A subset of multiple myeloma harboring the t(4;14)(p16;q32) translocation lacks FGFR3 expression but maintains an IGH/MMSET fusion transcript. |
| Santra M, Zhan F, Tian E, Barlogie B, Shaughnessy J Jr |
| Blood. 2003 ; 101 (6) : 2374-2376. |
| PMID 12433679 |
| A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma. |
| Dring AM, Davies FE, Fenton JA, Roddam PL, Scott K, Gonzalez D, Rollinson S, Rawstron AC, Rees-Unwin KS, Li C, Munshi NC, Anderson KC, Morgan GJ |
| Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (17) : 5692-5701. |
| PMID 15355895 |
| Characterization of oncogene dysregulation in multiple myeloma by combined FISH and DNA microarray analyses. |
| Fabris S, Agnelli L, Mattioli M, Baldini L, Ronchetti D, Morabito F, Verdelli D, Nobili L, Intini D, Callea V, Stelitano C, Lombardi L, Neri A |
| Genes, chromosomes & cancer. 2005 ; 42 (2) : 117-127. |
| PMID 15543617 |
| Contributor(s) |
| Written | 03-1998 | Jean-Loup Huret and Jacky Bonaventure |
| Updated | 05-2005 | Frank Viguié |
| Citation |
| This paper should be referenced as such : |
| Huret JL and Bonaventure J . t(4;14)(p16;q32). Atlas Genet Cytogenet Oncol Haematol. March 1998 . URL : http://AtlasGeneticsOncology.org/Genes/t04142059.html |
| Viguié F . t(4;14)(p16;q32). Atlas Genet Cytogenet Oncol Haematol. May 2005 . URL : http://AtlasGeneticsOncology.org/Genes/t04142059.html |
| © Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Sep 24 21:06:41 2008 |
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