Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene.
BACKGROUND
A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has recently been identified in nonsmall-cell lung cancers (NSCLCs). We screened for EML4-ALK fusion genes and examined the clinicopathological and genetic characteristics of fusion-harboring NSCLC tumors.


METHODS
We examined 313 NSCLC samples from patients who underwent resection at our hospital between May 2001 and July 2005. We screened for the fusion genes using reverse-transcription polymerase chain reaction (RT-PCR) assay and confirmed the results with direct sequencing. We also examined mutations in the epidermal growth factor receptor (EGFR), KRAS, and ERBB2 genes.


RESULTS
Five EML4-ALK fusion genes were detected (four from 111 female samples and one from 202 male samples; 1.6% overall). All five genes were found in adenocarcinomas and accounted for 2.4% of the 211 adenocarcinoma samples. One EML4-ALK fusion was variant 1, and two were variant 3. In addition, we also found two new fusion variants. Patients with fusion-positive tumors were nonsmokers or light smokers. Among the 211 adenocarcinomas, mutations in EGFR, KRAS, and ERBB2 were detected in 105, 29, and 7 tumors, respectively. Interestingly, all of the fusion-positive NSCLCs had no mutations within these genes.


CONCLUSIONS
EML4-ALK fusion genes were observed predominantly in adenocarcinomas, in female or nonsmoking populations. Additionally, the EML4-ALK fusions were mutually exclusive with mutations in the EGFR, KRAS, and ERBB2 genes.
Takahashi
Tsuyoshi
T
Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Sonobe
Makoto
M
Kobayashi
Masashi
M
Yoshizawa
Akihiko
A
Menju
Toshi
T
Nakayama
Ei
E
Mino
Nobuya
N
Iwakiri
Shotaro
S
Sato
Kiyoshi
K
Miyahara
Ryo
R
Okubo
Kenichi
K
Manabe
Toshiaki
T
Date
Hiroshi
H
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000368:Aged; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics
D066246:ErbB Receptors; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human