EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
A fusion gene, echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK), with transforming activity has recently been identified in a subset of non-small cell lung cancer (NSCLC), but its pathogenetic, diagnostic, and therapeutic roles remain unclear. Both frequency and type of EML4-ALK transcripts were investigated by reverse transcription PCR in 120 frozen NSCLC specimens from Italy and Spain; non-neoplastic lung tissues taken far from the tumor were used as controls. In cases carrying the fusion transcript, we determined EML4-ALK gene and protein levels using fluorescence in situ hybridization, Western blotting, and immunoprecipitation. We also analyzed ALK protein levels in paraffin samples from 662 NSCLC specimens, including the 120 cases investigated in the molecular studies. EML4-ALK transcripts (variants 1 and 3) were detected in 9 of 120 NSCLC samples but were not specific for NSCLC since they were also found in non-cancerous lung tissues taken far from the tumor. Notably, no transcripts were detected in matching tumor samples from these patients. Fluorescence in situ hybridization analysis of cases expressing EML4-ALK transcripts showed that only a minority of cells harbored the EML4-ALK gene. None of these cases was found to express the EML4-ALK protein as examined by immunohistochemistry, Western blotting, and immunoprecipitation. The EML4-ALK transcript cannot be regarded as a specific diagnostic tool for NSCLC. Our results show therefore that the causal role and value of EML4-ALK as a therapeutic target remain to be defined.
Martelli
Maria Paola
MP
Institute of Hematology, University of Perugia, Perugia, Italy.
Sozzi
Gabriella
G
Hernandez
Luis
L
Pettirossi
Valentina
V
Navarro
Alba
A
Conte
Davide
D
Gasparini
Patrizia
P
Perrone
Federica
F
Modena
Piergiorgio
P
Pastorino
Ugo
U
Carbone
Antonino
A
Fabbri
Alessandra
A
Sidoni
Angelo
A
Nakamura
Shigeo
S
Gambacorta
Marcello
M
Fernández
Pedro Luis
PL
Ramirez
Jose
J
Chan
John K C
JK
Grigioni
Walter Franco
WF
Campo
Elias
E
Pileri
Stefano A
SA
Falini
Brunangelo
B
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion