TY - JOUR
T1 - EML4-ALK Rearrangement in Non-Small Cell Lung Cancer and Non-Tumor Lung Tissues
AU - Martelli, Maria Paola
AU - Sozzi, Gabriella
AU - Hernandez, Luis
AU - Pettirossi, Valentina
AU - Navarro, Alba
AU - Conte, Davide
AU - Gasparini, Patrizia
AU - Perrone, Federica
AU - Modena, Piergiorgio
AU - Pastorino, Ugo
AU - Carbone, Antonino
AU - Fabbri, Alessandra
AU - Sidoni, Angelo
AU - Nakamura, Shigeo
AU - Gambacorta, Marcello
AU - Luis Fernandez, Pedro
AU - Ramirez, Jose
AU - Chan, John K. C.
AU - Grigioni, Walter Franco
AU - Campo, Elias
AU - Pileri, Stefano A.
AU - Falini, Brunangelo
PY - 2009/2
Y1 - 2009/2
N2 - A fusion gene, enchinoderm 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 I 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. (Am J Pathol 2009, 174:661-670; DOI: 10.2353/ajpath.2009.080755)
AB - A fusion gene, enchinoderm 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 I 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. (Am J Pathol 2009, 174:661-670; DOI: 10.2353/ajpath.2009.080755)
KW - ANAPLASTIC LYMPHOMA KINASE
KW - FUSION GENE
KW - ALK KINASE
KW - NPM
KW - IDENTIFICATION
KW - PROTEINS
KW - TRANSCRIPTS
KW - INHIBITOR
KW - MUTATIONS
KW - TPM3-ALK
U2 - 10.2353/ajpath.2009.080755
DO - 10.2353/ajpath.2009.080755
M3 - Article
SN - 0002-9440
VL - 174
SP - 661
EP - 670
JO - Am. J. Pathol.
JF - Am. J. Pathol.
IS - 2
ER -