Download Solid Tumour Section Lung: non-small cell carcinoma with inv(2)(p21p23)

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Solid Tumour Section
Mini Review
Lung: non-small cell carcinoma with
inv(2)(p21p23)
Hiroyuki Mano
Division of Functional Genomis, Jichi Medical University, 3311-1 Yakushiji, Shimotsukeshi, Tochigi 3290498, Japan (HM)
Published in Atlas Database: September 2008
Online updated version : http://AtlasGeneticsOncology.org/Tumors/inv2p21p23NSCCLungID5667.html
DOI: 10.4267/2042/44570
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Protein
1620 amino acids; 176 kDa; membrane-associated
tyrosine kinase receptor.
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.
Result of the chromosomal
anomaly
Hybrid Gene
Genetics
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
Note
Vast majority of EML4-ALK positive 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.
EML4
Location
2p21
Protein
981 amino acids; 109 kDa; microtubule associated
protein.
ALK
Location
2p23
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
681
Lung: non-small cell carcinoma with inv(2)(p21p23)
Mano H
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
EML4ALK(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).
References
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H,
Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, et al. Global
survey of phosphotyrosine signaling identifies oncogenic
kinases in lung cancer. Cell. 2007 Dec 14;131(6):1190-203
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. Identification of the transforming
EML4-ALK fusion gene in non-small-cell lung cancer. Nature.
2007 Aug 2;448(7153):561-6
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. Identification of novel isoforms of the
EML4-ALK transforming gene in non-small cell lung cancer.
Cancer Res. 2008 Jul 1;68(13):4971-6
Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H,
Okui M, Satoh Y, Okumura S, Nakagawa K, et al. EML4-ALK
fusion is linked to histological characteristics in a subset of lung
cancers. J Thorac Oncol. 2008 Jan;3(1):13-7
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.
Koivunen JP, Mermel C, Zejnullahu K, Murphy C, Lifshits E,
Holmes AJ, Choi HG, Kim J, Chiang D, et al. EML4-ALK fusion
gene and efficacy of an ALK kinase inhibitor in lung cancer.
Clin Cancer Res. 2008 Jul 1;14(13):4275-83
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. Multiplex RT-PCR
screening for EML4-ALK fusion transcripts. Clin Cancer Res.
2008; in press.
This article 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.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(9)
682