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t(2;5)(p23;q35) SQSTM1/ALK

Written2011-11Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C420,C421,C424 BLOOD, BONE MARROW, & HEMATOPOIETIC SYS
Atlas_Id 1584
Note Not to be confused with the t(2;5)(p23;q35) with NPM1-ALK involvement.

Clinics and Pathology

Disease ALK-positive large B-cell lymphoma (ALK+ LBCL)
Phenotype / cell stem origin One case to date, a 67-year-old male patient (Takeuchi et al., 2011).
Cytology Anti-ALK immunohistochemistry showed a diffuse cytoplasmic staining pattern, in contrast with the nuclear and cytoplasmic pattern usually sen in the NPM1-ALK fusion gene/protein.
Prognosis Complete remission was obtained, but the patient relapsed four months later.

Genes involved and Proteins

Gene Name ALK
Location 2p23
Protein ALK is composed of an extracellular region (containing two MAM (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu) and one LDLa (low-density lipoprotein receptor) domains, and one glycin-rich region), a transmembrane domain, and an intracellular region (composed of a tyrosine kinase domain. Membrane receptor tyrosine kinase.
Germinal mutations In familial neuroblastoma.
Somatic mutations Fusion proteins in anaplastic large cell lymphoma, some diffuse large B-cell lymphomas, inflammatory myofibroblastic tumours, and some non-small cell lung cancers. Somatic mutations in sporadic neuroblastoma (review in Allouche, 2010).
Gene Name SQSTM1
Location 5q35.3
Protein SQSTM1 (sequestosome1), also called p62, is a scaffolding protein with several interaction domains; it is composed of an OPR domain (octicosapeptide repeat (PB1 dimerization domain)), a Zn finger, a LIM protein-binding region, a TRAF6-binding motif, a PEST sequence (proline, glutamic acid, serine, and threonine rich), a LIR motif (LC3 interaction region, SGGDDDWTHLSS), a second PEST sequence, a KIR (keap1 interacting region), and an UBA (ubiquitin-associated) domain. Interacts with Caspase-8 and the apoptosis, machinery, MAPK kinases such as MAP2K5 (15q23), LCK (1p34), NBR1 (17q21), PRKCI (3q26), PAWR (12q21), RIPK1 (6p25), TRAF6 (11p12) and NTRK1 (1q23) and the NF-kappaB pathway, KEAP1 (19p13), GABARAPL1 (12p13), MAP1LC3A/LC3 (20q11), and ubiquitin. Mediates the interaction between TRAF6 and CYLD (16q12). Implicated in the activation of the transcription factor NF-kappaB. Involved in the autophagy-lysosome pathway. Plays a role in the formation of cytoplasmic proteinaceous inclusions in various pathologic situations where autophagy is inactivated (Geetha and Wooten, 2002; Lamark et al., 2009; Moscat and Diaz-Meco, 2009; Moscat et al., 2009; Ichimura and Komatsu, 2010; Komatsu and Ichimura, 2010; Moscat and Diaz-Meco, 2011).
Germinal mutations Mutated in Paget's disease of bone.

Result of the chromosomal anomaly

Hybrid gene
Description Exon 5 of SQSTM1 fused to the ALK exon 20.
  
Fusion Protein
 
Description Fuses the PB1 dimerization domain of SQSTM1 to the tyrosine kinase domain of ALK, resulting in a constitutive activation of the ALK kinase domain.
  

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

ALK (anaplastic lymphoma receptor tyrosine kinase)
Allouche M.
Atlas Genet Cytogenet Oncol Haematol. February 2010. URL: http://AtlasGeneticsOncology.org/Genes/ALK.html
 
Structure and functional properties of the ubiquitin binding protein p62.
Geetha T, Wooten MW.
FEBS Lett. 2002 Feb 13;512(1-3):19-24.
PMID 11852044
 
Selective degradation of p62 by autophagy.
Ichimura Y, Komatsu M.
Semin Immunopathol. 2010 Dec;32(4):431-6. Epub 2010 Sep 3. (REVIEW)
PMID 20814791
 
Physiological significance of selective degradation of p62 by autophagy.
Komatsu M, Ichimura Y.
FEBS Lett. 2010 Apr 2;584(7):1374-8. Epub 2010 Feb 12. (REVIEW)
PMID 20153326
 
NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets.
Lamark T, Kirkin V, Dikic I, Johansen T.
Cell Cycle. 2009 Jul 1;8(13):1986-90. Epub 2009 Jul 30.
PMID 19502794
 
Feedback on fat: p62-mTORC1-autophagy connections.
Moscat J, Diaz-Meco MT.
Cell. 2011 Nov 11;147(4):724-7. (REVIEW)
PMID 22078874
 
Identification of a novel fusion, SQSTM1-ALK, in ALK-positive large B-cell lymphoma.
Takeuchi K, Soda M, Togashi Y, Ota Y, Sekiguchi Y, Hatano S, Asaka R, Noguchi M, Mano H.
Haematologica. 2011 Mar;96(3):464-7. Epub 2010 Dec 6.
PMID 21134980
 

Citation

This paper should be referenced as such :
Huret, JL
t(2;5)(p23;q35) SQSTM1/ALK
Atlas Genet Cytogenet Oncol Haematol. 2012;16(4):293-294.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Anomalies/t0205p23q35ID1584.html


Translocations implicated (Data extracted from papers in the Atlas)

 t(2;5)(p23;q35) SQSTM1/ALK

External links

arrayMap (UZH-SIB Zurich)SQSTM1 (5q35.3) ALK (2p23.2)

SQSTM1 (5q35.3) ALK (2p23.2)

SQSTM1 (5q35.3) ALK (2p23.2)

Mitelman databaset(2;5)(p23;q35) [Case List]    t(2;5)(p23;q35) [Association List] Mitelman database (CGAP - NCBI)
arrayMap[select an item]
 
COSMIC_fusionSQSTM1/ALK SQSTM1 (5q35.3) ALK (2p23.2)   [fusion1051]   [fusion1052]  
Mitelman databaseSQSTM1/ALK [MCList]  SQSTM1 (5q35.3) ALK (2p23.2)
TICdbSQSTM1/ALK  SQSTM1 (5q35.3) ALK (2p23.2)
 
Disease databaset(2;5)(p23;q35) SQSTM1/ALK
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed
All articlesautomatic search in PubMed


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