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inv(2)(p23q35) ATIC/ALK

Written2001-08Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
Atlas_Id 1172

Clinics and Pathology

Disease
  • Translocations involving 2p23 are found in more than half cases of anaplasic large cell lymphoma (ALCL), a high grade non Hodgkin lymphoma (NHL). They involve ALK, and are therefore called ALK+ ALCL.
  • The most frequent ALK+ ALCL being the the t(2;5)(p23;q35) with NPM1 -ALK fusion protein, which localises both in the cytoplasm and in the nucleus.
  • The inv(2)(p23q35) is very rare., and, like other t(2;Var) involving various partners and ALK, the fusion protein has a cytoplasmic localization; they are therefore called "cytoplasm only" ALK+ ALCL.
    • Phenotype / cell stem origin CD30+; ALK+
    Epidemiology at least 7 known cases, aged 12 yrs to 52 yrs (med 23 yrs); no sex unbalance so far, in contrast with the general feature found in ALK+ ALCL
    Clinics ALK+ ALCL without the t(2;5) (so called cytoplasmic only ALK cases) show clinical features similar to those of classical ALK+ ALCL: young age, male predominance, presentation with advanced disease, systemic symptoms, frequent involvement of extranodal sites, and a good prognosis. Nothing in particular is known concerning inv(2) cases, as cases are not fully documented
    Prognosis not well documented

    Cytogenetics

    Cytogenetics Morphological difficult to identify, as breakpoints lie in telomeric regions; an apparent i(2q) -when present- in ALCL should ring the bell; in some other cases, with numerous anomalies, there is no apparent breakpoint on chromosomes 2.
    Cytogenetics Molecular FISH analyses are thereof essential
    Additional anomalies ider(2)(q10)inv(2) has been found in some cases, carrying 2 additional copies of the ATIC-ALK hybrid gene, as detected with FISH; frequent complex karyotypes

    Genes involved and Proteins

    Gene NameALK (anaplastic lymphoma receptor tyrosine kinase)
    Location 2p23.2
    Protein 1620 amino acids; 177 kDa; glycoprotein (200 kDa mature protein) ; membrane associated tyrosine kinase receptor
    Gene NameATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase)
    Location 2q35
    Protein 591 amino acids, 64 kDa; bifunctional purine biosythesis:9th and 10th step of the de novo purine synthesis

    Result of the chromosomal anomaly

    Hybrid gene
    Description 5' ATIC- 3' ALK
      
    Fusion Protein
    Description 791 amino acids, 87 kDa. 229 N-term amino acid from ATIC containing the IMPCH domain and the dimerization domain fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain).
    Expression Localisation cytoplasmic localisation (in contrast with the t(2;5)(p23;q35) with NPM1-ALK, which localizes both in the cytoplasm and in the nucleus).
    Oncogenesis ATIC seems to provoke the dimerization of ATIC-ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase, as for NPM1-ALK (see t(2;5)(p23;q35) )
      

    Bibliography

    ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).
    Colleoni GW, Bridge JA, Garicochea B, Liu J, Filippa DA, Ladanyi M
    The American journal of pathology. 2000 ; 156 (3) : 781-789.
    PMID 10702393
     
    Anaplastic large cell lymphomas, Primary systemic (T/Null cell type).
    Delsol G, Ralfkiaer E, Stein H, Wright D, Jaffe E
    World Health Organization (WHO) Classification of Tumors..
     
    Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.
    Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks WG
    Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2000 ; 14 (9) : 1533-1559.
    PMID 10994999
     
    Lymphomas expressing ALK fusion protein(s) other than NPM-ALK.
    Falini B, Pulford K, Pucciarini A, Carbone A, De Wolf-Peeters C, Cordell J, Fizzotti M, Santucci A, Pelicci PG, Pileri S, Campo E, Ott G, Delsol G, Mason DY
    Blood. 1999 ; 94 (10) : 3509-3515.
    PMID 10552961
     
    Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.
    Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa T, Mori S, Ratzkin B, Yamamoto T
    Oncogene. 1997 ; 14 (4) : 439-449.
    PMID 9053841
     
    Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis.
    Ma Z, Cools J, Marynen P, Cui X, Siebert R, Gesk S, Schlegelberger B, Peeters B, De Wolf-Peeters C, Wlodarska I, Morris SW
    Blood. 2000 ; 95 (6) : 2144-2149.
    PMID 10706887
     
    Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma.
    Morris SW, Xue L, Ma Z, Kinney MC
    British journal of haematology. 2001 ; 113 (2) : 275-295.
    PMID 11380391
     
    CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.
    Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K, Pileri S, Falini B
    Blood. 2000 ; 96 (12) : 3681-3695.
    PMID 11090048
     
    A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.
    Trinei M, Lanfrancone L, Campo E, Pulford K, Mason DY, Pelicci PG, Falini B
    Cancer research. 2000 ; 60 (4) : 793-798.
    PMID 10706082
     
    The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.
    Wlodarska I, De Wolf-Peeters C, Falini B, Verhoef G, Morris SW, Hagemeijer A, Van den Berghe H
    Blood. 1998 ; 92 (8) : 2688-2695.
    PMID 9763551
     

    Citation

    This paper should be referenced as such :
    Huret, JL
    inv(2)(p23q35)
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(4):277-278.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Anomalies/inv2p23q35ID1172.html

    Other genes implicated (Data extracted from papers in the Atlas) [ 3 ]

    Genes ALK ALK ATIC

    Translocations implicated (Data extracted from papers in the Atlas)

     inv(2)(p23q35) ATIC/ALK

    External links

    ATIC (2q35) ALK (2p23.2)

    ATIC (2q35) ALK (2p23.2)

    ATIC (2q35) ALK (2p23.2)

    ATIC (2q35) ALK (2p23.2)

    Mitelman databaseinv(2)(p23q35) [Case List]    inv(2)(p23q35) [Transloc-MCList] ATIC/ALK [Fusion-MCList]
    arrayMap (UZH-SIB Zurich)[select an item]
     
    COSMIC_fusionATIC/ALK ATIC (2q35) ALK (2p23.2)   [fusion444]   [fusion445]   [fusion446]  
    Mitelman databaseATIC/ALK [MCList]  ATIC (2q35) ALK (2p23.2)
    Mitelman databaseATIC/ALK [MCList]  ATIC (2q35) ALK (2p23.2)
    TICdbATIC/ALK  ATIC (2q35) ALK (2p23.2)
     
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed
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