Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

t(4;14)(p16;q32)

Identity

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

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.

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.
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
Location 14q32
Gene Name MMSET (multiple myeloma SET domain), also kown as WHSC1 (Wolf-Hirschorn syndrome candidate 1)
Location 4p16.3
Dna / Rna 90 kb, 25 exons, 5' - 3' 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

Hybrid gene
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.
  
Fusion Protein
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 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.
  

External links

Other databaset(4;14)(p16;q32) Mitelman database (CGAP - NCBI)

Other genes implicated (Data extracted from papers in the Atlas)

Genes FGFR3 IGH TACC3 WHSC1

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, Schrck 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
 
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed

Contributor(s)

Written03-1998Jean-Loup Huret and Jacky Bonaventure
Updated05-2005Frank 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 .
Viguié F . t(4;14)(p16;q32). Atlas Genet Cytogenet Oncol Haematol. May 2005 .
URL : http://AtlasGeneticsOncology.org/Anomalies/t04142059.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/37437/1/03-1998-t04142059.pdf   [ Bibliographic record ]
http://documents.irevues.inist.fr/bitstream/2042/38220/1/05-2005-t04142059.pdf   [ Bibliographic record ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Apr 16 12:06:39 CEST 2014


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.