Fusion of EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression

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.

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

“…The high response rate to Hsp90 inhibition observed clinically in EML4-ALK NSCLC (11) may be explained by the knowledge that such variants account for ∼70% of cases (2,26). However, Hsp90 inhibitor therapy may be less efficacious in the remaining cases, in which tumors harbor variants 3a/b or 5a/b.…”

Molecular pathology of lung cancer: key to personalized medicine

“…The histology of these tumors is typically characterized by mucin production and either a solid growth pattern containing signet ring cells in western patients or an acinar growth pattern in Asian patients. [159][160][161][162] Compared with patients with wildtype ALK and EGFR, patients with the EML4-ALK fusion gene tend to be younger (median, 52 vs 64 years), of Asian ethnicity, diagnosed at an advanced clinical stage at presentation, male dominant (58 vs 32%), and more likely to be never-smokers (74 vs 26%), but with a comparable response rate to chemotherapy and overall survival. 8,148,159,160 The EML4-ALK fusion gene was detected in 19 of 141 (13%) tumor samples by FISH.…”

Fluorescence In Situ Hybridization, Immunohistochemistry, and Next-Generation Sequencing for Detection of EML4-ALK Rearrangement in Lung Cancer

“…The fused gene product demonstrates constitutive kinase activity, and cancer cells with the EML4-ALK rearrangement are dependent on the activity of this kinase for uncontrolled growth and survival [5][6][7]. Patients harboring this rearrangement were younger, and most were nonsmokers or light smokers in the past [6,[8][9][10][11]. Analysis of the Israeli cohort shows that this rearrangement is most common in young men, and the chances for finding the fusion are reduced by 7% with each additional year in a lung cancer patient aged .52 years [12].…”