inv(2)(p23q35) ATIC/ALK

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inv(2)(p23q35) ATIC/ALK

Written	2001-08	Jean-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 Name ALK (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 Name ATIC (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

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

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.

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

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 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

Gene Name	ALK (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 Name	ATIC (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

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) )

Mitelman database	inv(2)(p23q35)
arrayMap (UZH-SIB Zurich)	[select an item]

COSMIC_fusion	ATIC/ALK ATIC (2q35) ALK (2p23.2) [fusion444] [fusion445] [fusion446]
Mitelman database	ATIC/ALK [MCList] ATIC (2q35) ALK (2p23.2)
Mitelman database	ATIC/ALK [MCList] ATIC (2q35) ALK (2p23.2)
TICdb	ATIC/ALK ATIC (2q35) ALK (2p23.2)

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