inv(2)(p23q35) ATIC/ALK

2001-08-01   Jean-Loup Huret  

1.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

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

    Result of the Chromosomal Anomaly

    Description

    5 ATIC- 3 ALK791 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) )

    Highly cited references

    Pubmed IDYearTitleCitations
    107023932000ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).48
    286593372017Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene.48
    113953962001The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells.44
    278468612016Intraosseous inflammatory myofibroblastic tumor of the mandible with a novel ATIC-ALK fusion mutation: a case report.33
    369106602023Case report: ATIC-ALK fusion in infant-type hemispheric glioma and response to lorlatinib.28
    334898092020Coexistence of a novel CCNY-ALK and ATIC-ALK double-fusion in one patient with ALK-positive NSCLC and response to crizotinib: a case report.13
    382796252024Variant ALK-fusion positive anaplastic large cell lymphoma (ALCL): A population-based paediatric study of the NHL-BFM study group.0
    107060822000A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.0
    185728092008[ATIC-ALK-positive anaplastic large cell lymphoma: a case report and review of the literature].0
    382669182024Molecular Screening in Anaplastic Lymphoma Kinase-Positive Anaplastic Large Cell Lymphoma: Anaplastic Lymphoma Kinase Analysis, Next-Generation Sequencing Fusion Gene Detection, and T-Cell Receptor Immunoprofiling.0
    107068872000Inv(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.0
    109949992000Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.0
    391098872025Anaplastic large cell lymphoma with ATIC::ALK in leukemic phase and associated with hemophagocytic lymphohistiocytosis.0
    388842662024Crizotinib therapy for congenital embryonal rhabdomyosarcoma associated with an ATIC-ALK gene fusion.0
    195452842009Distribution of NPM1-ALK and X-ALK fusion transcripts in paediatric anaplastic large cell lymphoma: a molecular-histological correlation.0
    332460762021Minimal Residual Disease Monitoring Using a 3'ALK Universal Probe Assay in ALK-Positive Anaplastic Large-Cell Lymphoma: ddPCR, an Attractive Alternative Method to Real-Time Quantitative PCR.0
    152086562004Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells.0
    146318062003[Anaplastic large-cell lymphoma: review].0
    386562572025Inflammatory Myofibroblastic Tumor of the Esophagus and Stomach Successfully Treated With ALK Inhibitor in a Pediatric Patient: A Case Report and Concise Review of Literature.0
    260535612015ALK-positive primary cutaneous T-cell-lymphoma (CTCL) with unusual clinical presentation and aggressive course.0
    255011142014Variant translocation partners of the anaplastic lymphoma kinase (ALK) gene in two cases of anaplastic large cell lymphoma, identified by inverse cDNA polymerase chain reaction.0
    150803012004Assessment of t(2;5)(p23;q35) translocation and variants in pediatric ALK+ anaplastic large cell lymphoma.0
    174643202007Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma.0
    121125242002Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor.0

    Article Bibliography

    Pubmed IDLast YearTitleAuthors
    107023932000ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35).Colleoni GW et al
    109949992000Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas.Drexler HG et al
    105529611999Lymphomas expressing ALK fusion protein(s) other than NPM-ALK.Falini B et al
    90538411997Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.Iwahara T et al
    107068872000Inv(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 et al
    113803912001Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma.Morris SW et al
    110900482000CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.Stein H et al
    107060822000A new variant anaplastic lymphoma kinase (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma.Trinei M et al
    97635511998The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.Wlodarska I et al

    Summary

    Fusion gene

    ATIC/ALK ATIC (2q35) ALK (2p23.2) COF 444 445 446|ATIC/ALK ATIC (2q35) ALK (2p23.2) M|ATIC/ALK ATIC (2q35) ALK (2p23.2) M inv(2)(p23q35)|ATIC/ALK ATIC (2q35) ALK (2p23.2) TIC

    Citation

    Jean-Loup Huret

    inv(2)(p23q35) ATIC/ALK

    Atlas Genet Cytogenet Oncol Haematol. 2001-08-01

    Online version: http://atlasgeneticsoncology.org/haematological/1172/inv(2)(p23q35)-atic-alk