Abstract
BackgroundThe anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. Fusion partners of ALK include NPM, EML4, TPM3, ATIC, TFG, CARS, and CLTC. Characterization of ALK fusion patterns and their resulting clinicopathological profiles could be of great benefit in better understanding the biology of lung cancer.ResultsRACE-coupled PCR sequencing was used to assess ALK fusions in a cohort of 103 non-small cell lung carcinoma (NSCLC) patients. Within this cohort, the EML4-ALK fusion gene was identified in 12 tumors (11.6%). Further analysis revealed that EML4-ALK was present at a frequency of 16.13% (10/62) in patients with adenocarcinomas, 19.23% (10/52) in never-smokers, and 42.80% (9/21) in patients with adenocarcinomas lacking EGFR and KRAS mutations. The EML4-ALK fusion was associated with non-smokers (P = 0.03), younger age of onset (P = 0.03), and adenocarcinomas without EGFR/KRAS mutations (P = 0.04). A trend towards improved survival was observed for patients with the EML4-ALK fusion, although it was not statistically significant (P = 0.20). Concurrent deletion in EGFR exon 19 and fusion of EML4-ALK was identified for the first time in a Chinese female patient with an adenocarcinoma. Analysis of ALK expression revealed that ALK mRNA levels were higher in tumors positive for the EML-ALK fusion than in negative tumors (normalized intensity of 21.99 vs. 0.45, respectively; P = 0.0018). However, expression of EML4 did not differ between the groups.ConclusionsThe EML4-ALK fusion gene was present at a high frequency in Chinese NSCLC patients, particularly in those with adenocarcinomas lacking EGFR/KRAS mutations. The EML4-ALK fusion appears to be tightly associated with ALK mRNA expression levels. RACE-coupled PCR sequencing is a highly sensitive method that could be used clinically for the identification of EML4-ALK-positive patients.
Highlights
The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer
The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase (RTK) that has been discovered to be present in a number of fusion proteins consisting of the intracellular kinase domain of ALK and the aminoterminal portions of different genes [1,2]
More than nine different variants of the echinoderm microtubule associated protein-like 4" (EML4)-ALK fusion have been identified. These variants consist of exons 20 to 29 of ALK fused to EML4 exon 13, exon 20 (V2), exon 6 (V3a), exon 6 with an 11 amino acid insertion (V3b), exon 14 with an additional 11 nucleotide insertion of unknown origin at nucleotide 50 in exon 20 of ALK (V4), exon 2 (V5), exon (V6), exon with the fusion beginning at nucleotide 13 in exon 20 of ALK (V7), exon 15, and exon 18 ("V5", here as V9), as described in detail in Horn and Pao's review [23]
Summary
The anaplastic lymphoma kinase (ALK) gene is frequently involved in translocations that lead to gene fusions in a variety of human malignancies, including lymphoma and lung cancer. The ALK-EML4 fusion attaches the ALK gene to a gene involved in microtubule formation and stabilization, "echinoderm microtubule associated protein-like 4" (EML4) [20,21] This fusion generates a transforming fusion tyrosine kinase, several isoforms of which have been identified in lung cancers [8,22]. In some cell lines harboring EML4-ALK fusions, targeting of ALK using specific inhibitors has shown promising efficacy for treatment of lung cancer through inhibition of Akt and induction of apoptosis. For this reason, ALK inhibitors have been developed and assessed in early clinical trials [25,26]
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