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Lung: Non-small cell carcinoma with inv(2)(p21p23) EML4/ALK

Written2008-09Hiroyuki Mano
Division of Functional Genomis, Jichi Medical University, 3311-1 Yakushiji, Shimotsukeshi, Tochigi 329-0498, Japan

(Note : for Links provided by Atlas : click)

Identity

ICD-Topo C340-C343,C348-C349 LUNG & BRONCHUS
Atlas_Id 5667
Phylum Lung, Heart, Skin, Other:Lung:Nonsmall cell carcinoma :Adenocarcinoma :inv(2)(p21p23)

Clinics and Pathology

Disease A subset of non-small cell lung cancer harbors the EML4-ALK fusion gene. Incidence of such tumors is 4-5% in non-small cell lung cancer among the Asian ethnic group, but may be lower among the others.

Genetics

Note Vast majority of EML4-ALKÐpositive lung cancer is negative for active EGFR and active KRAS.

Cytogenetics

Note inv(2)(p21p23)

Genes involved and Proteins

Note Inv(2)(p21p23) involves EML4 and ALK, generating the EML4-ALK and ALK-EML4 fusion genes.
Gene Name EML4
Location 2p21
Protein 981 amino acids; 109 kDa; microtubule associated protein.

Gene Name ALK
Location 2p23
Protein 1620 amino acids; 176 kDa; membrane-associated tyrosine kinase receptor.

Result of the chromosomal anomaly

Hybrid Gene
Note In lung cancer cells, 5'-part of EML4 is fused to intron 19 of ALK, generating EML4-ALK. While intron 19 of ALK is involved in the rearrangement in most of the cases, breakpoints within EML4 may diverge, giving rise to various isoforms of EML4-ALK. Detailed information of known variants is shown below.
EML4-ALK(E13;A20): Intron 13 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 13 of the former is fused to exon 20 of the latter (also referred to as variant 1).
EML4-ALK(E20;A20): Intron 20 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 20 of the former is fused to exon 20 of the latter (also referred to as variant 2).
EML4-ALK(E6;A20): Intron 6 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 6a of the former is fused to exon 20 of the latter. Alternative splicing of the messages gives rise to the E6a; A20 (variant 3a) and E6b; A20 (variant 3b) mRNAs, which contains exon 6a and 6a+6b of EML4, respectively.
EML4-ALK(E14;ins11;del49A20): Another rearrangement generates an EML4-ALK mRNA where exon 14 of EML4 is ligated to a fragment of 11 bp with unknown origin, and in turn connected to a nucleotide at position 50 of exon 20 of ALK (also referred to as variant 4 by Takeuchi et al.).
EML4-ALK(E15del19;del20A20): Another rearrangement generates an EML4-ALK mRNA where a part of exon 15 of EML4 is fused to a nucleotide at position 21 of exon 20 of ALK (also referred to as variant 4 by Koivunen et al.).
EML4-ALK(E2;A20) and EML4-ALK(E2;add117A20): Intron 2 of EML4 is ligated to intron 19 of ALK, generating an EML4-ALK mRNA where exon 2 of the former is fused to exon 20 of the latter (also referred to as variant 5a). From the same gene rearrangement, alternative splicing of messages further generates an mRNA where exon 2 of EML4 is connected to a position within intron 19 of ALK located 117 bp-upstream of exon 20 (also referred to as variant 5b).
Fusion Protein
Note All EML4-ALK fusion mRNAs encode proteins where a part of EML4 is fused to the cytoplasmic kinase domain of ALK. The amino-terminal coiled-coil domain within EML4 is necessary and sufficient for the transforming activity of EML4-ALK, probably through oligomerazing the fusion proteins.
  

Bibliography

Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
Choi YL, Takeuchi K, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Hamada T, Haruta H, Watanabe H, Kurashina K, Hatanaka H, Ueno T, Takada S, Yamashita Y, Sugiyama Y, Ishikawa Y, Mano H.
Cancer Res. 2008 Jul 1;68(13):4971-6.
PMID 18593892
 
EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers.
Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M, Choi YL, Niki T, Mano H, Ishikawa Y.
J Thorac Oncol. 2008 Jan;3(1):13-7.
PMID 18166835
 
EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer.
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E, Holmes AJ, Choi HG, Kim J, Chiang D, Thomas R, Lee J, Richards WG, Sugarbaker DJ, Ducko C, Lindeman N, Marcoux JP, Engelman JA, Gray NS, Lee C, Meyerson M, Janne PA.
Clin Cancer Res. 2008 Jul 1;14(13):4275-83.
PMID 18594010
 
Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ.
Cell. 2007 Dec 14;131(6):1190-203.
PMID 18083107
 
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H.
Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11.
PMID 17625570
 
Multiplex RT-PCR screening for EML4-ALK fusion transcripts.
Takeuchi K, Choi YL, Soda M, Inamura K, Togashi Y, Hatano S, Enomoto M, Takada S, Yamashita Y, Satoh Y, Okumura S, Nakagawa K, Ishikawa Y, Mano H.
Clin Cancer Res. 2008; in press.
 

Citation

This paper should be referenced as such :
Mano, H
Lung: non-small cell carcinoma with inv(2)(p21p23)
Atlas Genet Cytogenet Oncol Haematol. 2009;13(9):681-682.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Tumors/inv2p21p23NSCCLungID5667.html


Other genes implicated (Data extracted from papers in the Atlas) [ 1 ]

Genes EML4

Translocations implicated (Data extracted from papers in the Atlas)

 inv(2)(p21p23) EML4/ALK

External links

Mitelman database inv(2)(p21p23) EML4/ALK [Case List]    inv(2)(p21p23) EML4/ALK [Association List] Mitelman database (CGAP - NCBI)
arrayMap Topo ( C34) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
 
COSMIC_fusionEML4 (2p21) ALK (2p23.2)    [fusion1062] [fusion1063] [fusion1064] [fusion1065] [fusion1127] [fusion1128] [fusion1296] [fusion1297] [fusion1368] [fusion1376] [fusion1539] [fusion1540] [fusion1541] [fusion1542] [fusion1543] [fusion1544] [fusion1545] [fusion408] [fusion409] [fusion410] [fusion411] [fusion413] [fusion414] [fusion462] [fusion463] [fusion464] [fusion465] [fusion473] [fusion474] [fusion475] [fusion476] [fusion477] [fusion478] [fusion479] [fusion480] [fusion487] [fusion488] [fusion489] [fusion490] [fusion491] [fusion493] [fusion730] [fusion731] [fusion732] [fusion733] [fusion734]
Mitelman databaseEML4/ALK[MCList]    EML4 (2p21) ALK (2p23.2)   
Mitelman databaseEML4/ALK[MCList]    EML4 (2p21) ALK (2p23.2)   del(2)(p21p23)
TCGA_FusionEML4/ALK    EML4 (2p21) ALK (2p23.2)
TICdbEML4/ALK    EML4 (2p21) ALK (2p23.2)
 
Disease databaseLung: Non-small cell carcinoma with inv(2)(p21p23) EML4/ALK
REVIEW articlesautomatic search in PubMed
Last year articlesautomatic search in PubMed


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