Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.
Soda
Manabu
M
Division of Functional Genomics, Jichi Medical University, Tochigi 329-0498, Japan.
Choi
Young Lim
YL
Enomoto
Munehiro
M
Takada
Shuji
S
Yamashita
Yoshihiro
Y
Ishikawa
Shunpei
S
Fujiwara
Shin-ichiro
S
Watanabe
Hideki
H
Kurashina
Kentaro
K
Hatanaka
Hisashi
H
Bando
Masashi
M
Ohno
Shoji
S
Ishikawa
Yuichi
Y
Aburatani
Hiroyuki
H
Niki
Toshiro
T
Sohara
Yasunori
Y
Sugiyama
Yukihiko
Y
Mano
Hiroyuki
H
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D007446:Chromosome Inversion / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; C522504:EML4-ALK fusion protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases