Abstract
EML4-ALK is a new driver gene of non-small cell lung cancer and a target of crizotinib. The objectives of this study were to determine the frequency of ALK rearrangements in a large cohort of patients with primary lung adenocarcinoma and to analyze the association of ALK rearrangements with clinicopathological characteristics and clinical outcomes. The roles of fluorescence in situ hybridization (FISH), Ventana immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR) in the detection of ALK rearrangements were evaluated. The ALK rearrangement was detected in 430 specimens from individual patients with primary lung adenocarcinoma using FISH and Ventana IHC based on tissue microarrays. The EGFR status was detected in all of the specimens through DNA sequencing. An RT-PCR was performed on 200 of the specimens and confirmed by sequencing. Of the 430 patients, 46 (10.7%) harbored ALK rearrangements. The ALK rearrangements were associated with a younger age and the EGFR wild type in comparison with ALK-negative patients. The sensitivity and specificity of the Ventana IHC were 100% and 98.2%, respectively, and the concordance rate between the FISH and the Ventana IHC was 98.4%. The sensitivity and specificity of RT-PCR were 95.5% and 87.0%, respectively, and the concordance rate between the FISH and the RT-PCR was 89.0%. The Cox analysis indicated that an early stage and EGFR-activating mutations were independently associated with a longer OS. This study demonstrated that ALK rearrangements are associated with a younger age and the EGFR wild type rather than with other clinicopathological factors. Although the FISH and Ventana IHC have better concordance, and RT-PCR is a more sensitive method and can identify different variants or partners, the IHC and RT-PCR need to be further evaluated in clinical trials to identify their roles in guiding patients’ targeted therapy using crizotinib.
Highlights
The Echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion genes were discovered in non-small cell lung cancer (NSCLC) in 2007 [1]
The ALK rearrangements were screened in this study in a large randomly selected cohort of patients with lung adenocarcinoma by fluorescence in situ hybridization (FISH), IHC, and reverse transcriptase polymerase chain reaction (RT-PCR)
The incidence of ALK rearrangements was 10.7% (46/430) as obtained by FISH in this study, which was similar to the results previously published [13,14]
Summary
The Echinoderm microtubule-associated protein-like 4 and the anaplastic lymphoma kinase (EML4-ALK) fusion genes were discovered in non-small cell lung cancer (NSCLC) in 2007 [1]. The EML4-ALK gene is a fusion gene from a chromosome rearrangement between the N-terminal portion of the echinoderm microtubule associated protein-like 4 (EML4) gene and the tyrosine kinase (TK) domain of the anaplastic lymphoma kinase (ALK) gene, both located on the short arm of chromosome 2, leading to a chimeric oncoprotein with constitutive TK activity and oncogenic transforming activity. Crizotinib, an orally available small-molecule tyrosine kinase inhibitor (TKI) targeting ALK, ROS1 and MET, is highly effective in patients with ALK-positive NSCLC with an objective response rate of approximately 60% [9]. The U.S Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMEA), and the China Food and Drug Administration (CFDA) have granted full approval to crizotinib for the treatment of patients with ALK-positive NSCLC
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